Publications by authors named "Margaret M Smith"

39 Publications

Implication of bone morphology in degenerative rotator cuff lesions: a prospective comparative study between Greater Tuberosity Angle and Critical Shoulder Angle.

Orthop Traumatol Surg Res 2021 Sep 3:103046. Epub 2021 Sep 3.

Division of Orthopaedics and Trauma Surgery, Hôpital du Valais, Martigny, Switzerland.

Background: Degenerative rotator cuff tear is a frequent and multifactorial pathology. The role of bone morphology of the greater tuberosity and lateral acromion has been validated, and can be measured with two plain radiographic markers on true anteroposterior views: the greater tuberosity angle (GTA) and the critical shoulder angle (CSA). However, the interdependence of both markers remains unknown, as well as their relationship with the level of professional and sports activities involving the shoulder. The aim of this prospective comparative study was to describe the correlation between the GTA and CSA in patients with degenerative rotator cuff tears.

Hypothesis: GTA and CSA are independent factors from one another and from demographic factors, such as age, dominance, sports, or professional activities.

Patient And Methods: All patients presenting to a shoulder specialized clinic were assigned to two groups. The first consisted of patients with a symptomatic degenerative rotator cuff tear visible on MRI and the control group consisted of patients with any other shoulder complaints and no history or visible imaging of any rotator cuff lesion.

Results: There were 51 shoulders in 49 patients in the rotator cuff tear group (RCT) and 53 shoulders in 50 patients in the control group. Patient demographics were similar in both groups. Mean GTA was 72.1° ± 3.7 (71.0 - 73.1) in the RCT group and 64.0° ± 3.3 (63.1 - 64.9) in the control group (P < 0.001). Mean CSA was 36.7° ± 3.7 (35.7 - 37.8) in the RCT group, and 32.1° ± 3.7 (31.1 - 33.1) in the control group (P < 0.001). A summation of GTA and CSA values over 103° increased the odds of having a rotator cuff tear by 97-fold (P < 0.001). There was no correlation between GTA and CSA, nor between GTA or CSA and age, sex, tear size, or dominance. Patients with different levels of professional and sports activities did not have significantly different GTA or CSA values.

Conclusion: GTA and CSA are independent radiologic markers that can reliably predict the presence of a degenerative rotator cuff tear. A sum of both values over 103° increases the odds of having a rotator cuff tear by 97-fold. These markers are not correlated with patient demographic or environmental factors, suggesting that the variability of the native acromion and greater tuberosity morphology may be individual risk factors for rotator cuff tear.

Level Of Evidence: II; diagnostic study.
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http://dx.doi.org/10.1016/j.otsr.2021.103046DOI Listing
September 2021

A single dose of tranexamic acid reduces blood loss after reverse and anatomic shoulder arthroplasty: a randomized controlled trial.

J Shoulder Elbow Surg 2021 Jul 6;30(7):1553-1560. Epub 2021 Jan 6.

Sydney Shoulder Research Institute, Sydney, NSW, Australia.

Background: Hematoma formation and the need for blood transfusions are commonly reported complications after shoulder arthroplasty. Tranexamic acid (TXA) has been widely used in hip and knee arthroplasty to decrease perioperative blood loss. The role of TXA is still being established in shoulder arthroplasty.

Materials And Methods: We conducted a double-blind randomized controlled trial comparing intravenous TXA vs. placebo in 60 patients undergoing primary anatomic or reverse shoulder arthroplasty. Of these patients, 29 received a placebo whereas 31 received a single dose of 2 g of intravenous TXA. Patient demographic characteristics, as well as drain tube output, blood loss, hematoma formation, transfusion requirement, length of hospital stay, and pain score, were recorded. Patients were followed up for 12 weeks to assess for complications.

Results: Patients who received TXA had a lower drain tube output at all time points: 41 mL vs. 133 mL at 6 hours, 75 mL vs. 179 mL at 12 hours, and 94 mL vs. 226 mL at 24 hours (P < .001 for all). They also had a higher postoperative hemoglobin (Hb) level (12.3 g/dL vs. 11.4 g/dL, P = .009), lower change in Hb level (1.7 g/dL vs. 2.3 g/dL, P = .011), lower total Hb loss (0.078 g vs. 0.103 g, P = .042), lower blood volume loss (0.55 L vs. 0.74 L, P = .021), higher postoperative hematocrit level (36.7% vs. 34.6%, P = .020), and lower hematocrit change (5.4% vs. 7.6%, P = .022). There was no significant difference in pain score or length of hospital stay, and no patients required a transfusion.

Conclusion: A single dose of 2 g of intravenous TXA decreases blood loss and drain tube output in primary anatomic and reverse arthroplasty of the shoulder. No differences were detected in the occurrence of complications, need for transfusion, pain score, or length of hospital stay. With the mounting evidence now available, patients undergoing elective primary shoulder arthroplasty should be given intravenous TXA to decrease perioperative blood loss.
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http://dx.doi.org/10.1016/j.jse.2020.11.022DOI Listing
July 2021

Accuracy of arthroscopic fluid pump systems in shoulder surgery: a comparison of 3 different pump systems.

J Shoulder Elbow Surg 2020 Dec 9;29(12):2626-2631. Epub 2020 Jun 9.

Sydney Shoulder Research Institute, Sydney, Australia.

Background: Extra-articular fluid extravasation is a known complication during shoulder arthroscopy. The risk and amount of extravasation to a large degree is dependent on the fluid pressure delivered to the surgical site. Accurate measurement, knowledge, and control of the pressure delivered is thus important to surgeons, anesthetists, and the patient. The purpose of this study was to compare the pressure measurement accuracy of 3 arthroscopic fluid pumps, with 2 of them having 2 different settings.

Methods: Twenty-five patients (n = 5 per group) undergoing shoulder arthroscopy were selected. Three different arthroscopic fluid pumps (ConMed 24K, Stryker Crossflow, Arthrex Dual Wave) were tested in 5 different operational settings (Stryker, standard and dynamic mode; ConMed, with and without TIPS; Arthrex Dual Wave). In each operation, the set pump pressures and the subsequently delivered intra-articular surgical site fluid pressures were measured by a spinal needle connected to an anesthetic standard pressure transducer attached to the anesthetic machine. Independent measures of the surgical site pressures were obtained before multiple portals were created or extravasation had occurred. Measurements were taken at the beginning of surgery.

Results: Measurements of the mean intra-articular pressure were found to not be significantly different from the set pressure for the ConMed 24K with TIPS (0.98 ± 0.02-fold) and Stryker Crossflow in standard mode (0.98 ± 0.02-fold). However, actual pressure was significantly greater than the set pressure for the ConMed 24K without TIPS (by 1.30 ± 0.13-fold), Stryker Crossflow in dynamic mode (by 1.82 ± 0.08-fold), and Arthrex Dual Wave (by 2.19 ± 0.06-fold).

Conclusion: Independently measured intra-articular pressure can be more than double the set pressure for some arthroscopic pumps. Measuring intra-articular pressure can thus aid in adjusting the set pressure. This could minimize the risk of intraoperative complications.
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http://dx.doi.org/10.1016/j.jse.2020.03.039DOI Listing
December 2020

The relationship between synovial inflammation, structural pathology, and pain in post-traumatic osteoarthritis: differential effect of stem cell and hyaluronan treatment.

Arthritis Res Ther 2020 02 14;22(1):29. Epub 2020 Feb 14.

Raymond Purves Bone and Joint Laboratory, Institute of Bone and Joint Research, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Level 10 Kolling Building - B6, Royal North Shore Hospital, St. Leonards, NSW, 2065, Australia.

Background: Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA.

Methods: Skeletally mature C57BL6 male mice underwent medial-meniscal destabilisation (DMM) surgery followed by intra-articular injection of saline, a hyaluronan hexadecylamide derivative (Hymovis), bone marrow-derived stem cells (MSCs), or MSC + Hymovis. We quantified the progression of OA-related cartilage, subchondral bone and synovial histopathology, and associated pain sensitization (tactile allodynia). Synovial lymphocytes, monocyte/macrophages and their subpopulations were quantified by fluorescent-activated cell sorting (FACS), and the expression of key inflammatory mediators and catabolic enzyme genes quantified by real-time polymerase chain reaction (PCR).

Results: MSC but not Hymovis significantly reduced late-stage (12-week post-DMM) cartilage proteoglycan loss and structural damage. Allodynia was initially reduced by both treatments but significantly better at 8 and 12 weeks by Hymovis. Chondroprotection by MSCs was not associated with specific changes in synovial inflammatory cell populations but rather regulation of post-injury synovial Adamts4, Adamts5, Mmp3, and Mmp9 expression. Reduced acute post-injury allodynia with all treatments coincided with decreased synovial macrophage and T cell numbers, while longer-term effect on pain sensitization with Hymovis was associated with increased M2c macrophages.

Conclusions: This therapeutic study in mice demonstrated a poor correlation between cartilage, bone or synovium (histo)pathology, and pain sensitization. Changes in the specific synovial inflammatory cell subpopulations may be associated with chronic OA pain sensitization, and a novel target for symptomatic treatment.
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http://dx.doi.org/10.1186/s13075-020-2117-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023816PMC
February 2020

A Biomechanical Comparison of Different Suture Materials Used for Arthroscopic Shoulder Procedures.

Arthroscopy 2020 03 11;36(3):708-713. Epub 2019 Nov 11.

Sydney Shoulder Research Institute, Sydney, Australia.

Purpose: To evaluate the viscoelastic properties of 4 commercially available cord-like sutures and 2 commercially available suture tapes when subjected to physiological loads, as well as to compare them with each other and to identify the clinically most desirable combination of suture material properties.

Methods: Six suture materials (Ethibond, FiberWire, FiberTape, Orthocord, Ultrabraid, and Ultratape) underwent creep testing (n = 7, 60 N, 10 minutes) to determine specimen stiffness, initial elongation at 60 N of load, static creep (during 10 minutes of loading), and relaxed elongation (material recovery 3 minutes after removal of load). Furthermore, cyclic testing (n = 7, 10-45 N, 0.5 Hz, 500 cycles) was carried out to determine dynamic creep, peak-to-peak displacement, and relaxed elongation. Mechanical testing was conducted on a material testing machine in 37°C phosphate-buffered saline solution.

Results: FiberTape showed the greatest stiffness (23.9 ± 3.2 N/mm, P < .001), the smallest amounts of static (0.38 ± 0.10 mm, P < .001) and dynamic (0.16 ± 0.09 mm, P = .003) creep, and the smallest peak-to-peak displacement (0.20 ± 0.02 mm, P < .001). FiberTape and FiberWire showed the smallest initial elongation (1.17 ± 0.17 mm and 1.63 ± 0.25 mm, respectively; P < .001). Ultrabraid showed the greatest relaxed elongation, both statically (4.73 ± 0.73 mm, P < .001) and dynamically (4.18 ± 0.83 mm, P = .002).

Conclusions: FiberTape consistently displayed less creep, greater stiffness, and less extensibility than the other suture types. Ultrabraid showed the largest amount of relaxed elongation on both static and dynamic testing.

Clinical Relevance: When considering high stiffness in combination with low initial extension and low static creep to be ideal parameters to achieve optimal initial construct stability and considering low dynamic creep in combination with low peak-to-peak displacement to be ideal conditions for the repetitive loading of the construct during the healing process, tapes seem to be superior to cord-like sutures for performing rotator cuff repair.
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http://dx.doi.org/10.1016/j.arthro.2019.08.048DOI Listing
March 2020

Functionally distinct tendons have different biomechanical, biochemical and histological responses to in vitro unloading.

J Biomech 2019 Oct 19;95:109321. Epub 2019 Aug 19.

Murray Maxwell Biomechanics Laboratory, Institute for Bone and Joint Research, Kolling Institute, Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia. Electronic address:

Tendons with different in vivo functions are known to have different baseline biomechanics, biochemistry and ultrastructure, and these can be affected by changes in loading. However it is not know whether different tendon types respond in the same, or different ways, to changes in loading. This study performed in vitro un-loading (stress deprivation) in culture on ovine medial extensor tendons (MET, a positional tendon), and superficial and deep digital flexor tendons (SDFTs and DDFTs, with energy-storing and intermediate functions respectively), for 21 days (n = 14 each). Tensile strength and elastic modulus were then measured, followed by biochemical assays for sulphated glycosaminoglycan (sGAG) and hydroxyproline content. Histological inspection for cell morphology, cell density and collagen alignment was also performed. The positional tendon (MET) had a significant reduction (∼50%) in modulus and strength (P < 0.001) after in vitro stress-deprivation, however there were no significant effects on the energy-storing tendons (SDFT and DDFT). In contrast, sGAG was not affected in the MET, but was reduced in the SDFT and DDFT (P < 0.001). All tendons lost compactness and collagen organisation, and had reduced cell density, but these were more rapid in the MET than the SDFT and DDFT. These results suggest that different tendon types respond to identical stimuli in different ways, thus; (i) the results from an experiment in one tendon type may not be as applicable to other tendon types as previously thought, (ii) positional tendons may be particularly vulnerable to clinical stress-deprivation, and (iii) graft tendon source may affect the biological response to loading in ligament and tendon reconstruction.
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http://dx.doi.org/10.1016/j.jbiomech.2019.109321DOI Listing
October 2019

Efficacy of administered mesenchymal stem cells in the initiation and co-ordination of repair processes by resident disc cells in an ovine (Ovis aries) large destabilizing lesion model of experimental disc degeneration.

JOR Spine 2018 Dec 10;1(4):e1037. Epub 2018 Oct 10.

Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, Northern Sydney Local Health District St. Leonards New South Wales Australia.

Background: Forty percent of low back pain cases are due to intervertebral disc degeneration (IVDD), with mesenchymal stem cells (MSCs) a reported treatment. We utilized an ovine IVDD model and intradiscal heterologous MSCs to determine therapeutic efficacy at different stages of IVDD.

Methodology: Three nonoperated control (NOC) sheep were used for MSC isolation. In 36 sheep, 6 × 20 mm annular lesions were made at three spinal levels using customized blades/scalpel handles, and IVDD was allowed to develop for 4 weeks in the Early (EA) and late Acute (LA) groups, or 12 weeks in the chronic (EST) group. Lesion IVDs received injections of 10 × 10 MSCs or PBS, and after 8 (EA), 22 (LA) or 14 (EST) weeks recuperation the sheep were sacrificed. Longitudinal lateral radiographs were used to determine disc heights. IVD glycosaminoglycan (GAG) and hydroxyproline contents were quantified using established methods. An Instron materials testing machine and customized jigs analyzed IVD (range of motion, neutral zone [NZ] and stiffness) in flexion/extension, lateral bending and axial rotation. qRTPCR gene profiles of key anabolic and catabolic matrix molecules were undertaken. Toluidine blue and hematoxylin and eosin stained IVD sections were histopathologically scoring by two blinded observers.

Results: IVDD significantly reduced disc heights. MSC treatment restored 95% to 100% of disc height, maximally improved NZ and stiffness in flexion/extension and lateral bending in the EST group, restoring GAG levels. With IVDD qRTPCR demonstrated elevated catabolic gene expression () in the PBS IVDs and expession normalization in MSC-treated IVDs. Histopathology degeneracy scores were close to levels of NOC IVDs in MSC IVDs but IVDD developed in PBS injected IVDs.

Discussion: Administered MSCs produced recovery in degenerate IVDs, restored disc height, composition, biomechanical properties, down regulated MMPs and fibrosis, strongly supporting the efficacy of MSCs for disc repair.
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http://dx.doi.org/10.1002/jsp2.1037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686814PMC
December 2018

Effects of tendon injury on uninjured regional tendons in the distal limb: An in-vivo study using an ovine tendinopathy model.

PLoS One 2019 23;14(4):e0215830. Epub 2019 Apr 23.

Raymond Purves Bone and Joint Research Laboratories, The Kolling Institute, Sydney Medical School, University of Sydney, Sydney, Australia.

Following injury to a tendon little is known about potential for pathology to develop in other regional tendons from overloading or altered function. The aim of this study was to investigate the gene expression and histopathological changes that occur 1) within the deep digital flexor tendon (DDFT) after injury to the superficial digital flexor tendon (SDFT) and 2) within the flexor tendons (SDFT and DDFT) after injury to the extensor tendons. Merino wethers [Ovis aries] (n = 18) were divided into three equal groups and underwent either partial transection of the SDFT, complete transection of the extensor tendons or were left as non-operated controls. Tendons were harvested and sampled regionally for gene expression (real time PCR) and histologic analysis eight weeks after surgery. Transection of the SDFT resulted in increased expression of collagen III, versican, biglycan, lumican and MMP1 (P<0.026 for all genes) within the DDFT. There was no effect of transecting the extensor tendons on the expression of any gene tested in either the SDFT or the DDFT. The DDFT had elevated histopathology scores induced by transection of the SDFT, eight weeks previously. There were minimal histological differences in either the SDFT or DDFT after transection of the extensor tendons. Transection of the SDFT results in a mild, subclinical tendinopathy within the DDFT with potential implications on treatment and rehabilitation of SDFT injuries. Injury to the extensor tendons has minimal measured effect on the SDFT or DDFT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478347PMC
January 2020

Morbidity and mortality in cervical spine injuries in the elderly.

ANZ J Surg 2019 04 8;89(4):412-417. Epub 2018 Oct 8.

Department of Orthopaedics and Trauma Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Background: The aim of our study was to identify the demographics and complications in elderly cervical spine injuries and predictive factors for surgery, complications and mortality. We hypothesized younger healthier patients were more likely to undergo surgical intervention.

Methods: A retrospective review of 225 consecutive patients aged 65 years and over with cervical spine injuries was carried out over a 3-year period.

Results: There were 113 males and 112 females with an average of 79.7 years (range 65-98). The most common fracture was C2 peg type (21.8%). Five patients had complete spinal cord injury (2.2%), 25 had incomplete spinal cord injury (11.1%) and 84% were neurologically intact. Fifty-four patients were managed operatively (24%), while 171 patients were managed non-operatively (76%). The operative group had higher rates of pneumonia (odds ratio (OR) 5.3, 95% confidence interval (CI) 2.6-10.7, P < 0.01), cardiac arrhythmia (OR 4.1, 95% CI 1.5-11.2, P < 0.01) and respiratory failure (OR 2.6, 95% CI 1.2-5.5, P < 0.05). There was no difference in mortality between the operative and non-operative group (18.5% and 12.9%, P = 0.3). Patients with complete spinal cord injury had 100% mortality. Significant predictive factors for complications and death were neurological deficits, comorbidities and the presence of other injuries (P < 0.05). Surgery was not predictive for death and the operative group was younger than the non-operative group (P < 0.05).

Conclusions: In the setting of a high complication rate, consideration should be given to palliation in elderly patients with complete spinal cord injury and there must be good rational for surgery.
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http://dx.doi.org/10.1111/ans.14875DOI Listing
April 2019

Achilles and tail tendons of perlecan exon 3 null heparan sulphate deficient mice display surprising improvement in tendon tensile properties and altered collagen fibril organisation compared to C57BL/6 wild type mice.

PeerJ 2018 29;6:e5120. Epub 2018 Jun 29.

Raymond Purves Bone and Joint Laboratory, Kolling Institute of Medical Research, University of Sydney, Australia.

The aim of this study was to determine the role of the perlecan (Hspg2) heparan sulphate (HS) side chains on cell and matrix homeostasis in tail and Achilles tendons in 3 and 12 week old exon 3 null HS deficient () and C57 BL/6 Wild Type (WT) mice. Perlecan has important cell regulatory and matrix organizational properties through HS mediated interactions with a range of growth factors and morphogens and with structural extracellular matrix glycoproteins which define tissue function and allow the resident cells to regulate tissue homeostasis. It was expected that ablation of the HS chains on perlecan would severely disrupt normal tendon organization and functional properties and it was envisaged that this study would better define the role of HS in normal tendon function and in tendon repair processes. Tail and Achilles tendons from each genotype were biomechanically tested (ultimate tensile stress (UTS), tensile modulus (TM)) and glycosaminoglycan (GAG) and collagen (hydroxyproline) compositional analyses were undertaken. Tenocytes were isolated from tail tendons from each mouse genotype and grown in monolayer culture. These cultures were undertaken in the presence of FGF-2 to assess the cell signaling properties of each genotype. Total RNA was isolated from 3-12 week old tail and Achilles tendons and qRT-PCR was undertaken to assess the expression of the following genes Type VI collagen and perlecan were immunolocalised in tail tendon and collagen fibrils were imaged using transmission electron microscopy (TEM). FGF-2 stimulated tenocyte monolayers displayed elevated , compared to WT mice. Non-stimulated tendon showed no major differences between the two genotypes other than a decline with ageing while LTBP2 expression increased. Eln expression also declined to a greater extent in the perlecan exon 3 null mice ( < 0.05). Type VI collagen and perlecan were immunolocalised in tail tendon and collagen fibrils imaged using transmission electron microscopy (TEM). This indicated a more compact form of collagen localization in the perlecan exon 3 null mice. Collagen fibrils were also smaller by TEM, which may facilitate a more condensed fibril packing accounting for the superior UTS displayed by the perlecan exon 3 null mice. The amplified catabolic phenotype of mice may account for the age-dependent decline in GAG observed in tail tendon over 3 to 12 weeks. After Achilles tenotomy and WT mice had similar rates of recovery of UTS and TM over 12 weeks post operatively indicating that a deficiency of HS was not detrimental to tendon repair.
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http://dx.doi.org/10.7717/peerj.5120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056265PMC
June 2018

Comparative analysis of 2 glenoid version measurement methods in variable axial slices on 3-dimensionally reconstructed computed tomography scans.

J Shoulder Elbow Surg 2018 Oct 31;27(10):1809-1815. Epub 2018 May 31.

Department of Radiology, Royal North Shore Hospital, Sydney, NSW, Australia.

Background: Most glenoid version measurement methods have been validated on 3-dimensionally corrected axial computed tomography (CT) slices at the mid glenoid. Variability of the vault according to slice height and angulation has not yet been studied and is crucial for proper surgical implant positioning. The aim of this study was to analyze the variation of the glenoid vault compared with the Friedman angle according to different CT slice heights and angulations. The hypothesis was that the Friedman angle would show less variability.

Materials And Methods: Sixty shoulder CT scans were retrieved from a hospital imaging database and were reconstructed in the plane of the scapula. Seven axial slices of different heights and coronal angulations were selected, and measurements were carried out by 3 observers.

Results: Mid-glenoid mean version was -8.0° (±4.9°; range, -19.6° to +7.0°) and -2.1° (±4.7°; range, -13.0° to +10.3°) using the vault method and Friedman angle, respectively. For both methods, decreasing slice height or angulation did not significantly alter version. Increasing slice height or angulation significantly increased anteversion for the vault method (P < .001). Both interobserver reliability and intraobserver reliability were significantly higher using the Friedman angle.

Conclusion: Version at the mid and lower glenoid is similar using either method. The vault method shows less reliability and more variability according to slice height or angulation. Yet, as it significantly differs from the Friedman angle, it should still be used in situations where maximum bone purchase is sought with glenoid implants. For any other situation, the Friedman angle remains the method of choice.
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http://dx.doi.org/10.1016/j.jse.2018.03.016DOI Listing
October 2018

The greater tuberosity angle: a new predictor for rotator cuff tear.

J Shoulder Elbow Surg 2018 Aug 24;27(8):1415-1421. Epub 2018 Apr 24.

Sydney Shoulder Research Institute, Sydney, NSW, Australia.

Background: The implication of scapular morphology in rotator cuff tears has been extensively studied. However, the role of the greater tuberosity (GT) should be of equal importance. The aim of this study was to propose a new radiographic marker, the GT angle (GTA), which measures the position of the GT in relation to the center of rotation of the humeral head. The hypothesis was that a higher angle value would be associated with a higher likelihood in detecting a rotator cuff tear.

Methods: During 1 year, patients were prospectively recruited from a single institution specialized shoulder clinic in 2 different groups. The patient group consisted of individuals with a degenerative rotator cuff tear involving at least the supraspinatus. The control group consisted of individuals with no rotator cuff pathology. Individuals in both groups with congenital, post-traumatic, or degenerative alterations of the proximal humerus were excluded. The GTA was measured on an anteroposterior shoulder x-ray image with the arm in neutral rotation by 3 observers at 2 different times.

Results: The study recruited 71 patients (33 patients, 38 controls). Mean GTA value was 72.5° (range, 67.6°-79.2°) in patients and 65.2° (range, 55.8°-70.5°) for controls (P <.001). A value above 70° resulted in 93-fold higher odds of detecting a rotator cuff tear (P <.001). Interobserver and intraobserver reliability were high.

Conclusions: GT morphology is implicated in rotator cuff tears. The GTA is a reliable radiographic marker, with more than 70° being highly predictive in detecting such lesions.
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http://dx.doi.org/10.1016/j.jse.2018.02.051DOI Listing
August 2018

Disciplinary Practices, Metaparenting, and the Quality of Parent-Child Relationships in African-American, Mexican-American, and European-American Mothers.

Int J Behav Dev 2017;41(4):482-490. Epub 2017 Jul 1.

Southern Methodist University.

Coercive responses to children's behavior are well recognized to be problematic for children's adjustment. Less well understood is how parental social cognition is linked to discipline. In this study we sought to link metaparenting - parents' thoughts about their parenting - to the use of coercive discipline. We predicted that mothers who engaged in more metaparenting, thus reflecting more deliberate parenting, would use corporal punishment less frequently and instead engage in non-coercive discipline. We also expected that mothers who engaged in more metaparenting would report closer relationships with their children. In order to assess a diverse sample, data were collected from approximately equal numbers of African-American, European-American, and Mexican-American mothers. Participants included 113 mothers with target children in three age groups, ranging from 2 to 12 years. The results indicated reports of corporal punishment as well as non-coercive discipline did not significantly differ across child sex and child age groups, but did differ significantly across race/ethnicity. Reports of frequency of metaparenting also differed across racial/ethnic groups; African-American mothers reported more metaparenting than European-American mothers on three of four subscales. Metaparenting was significantly related to reports of the mother-child relationship but in the opposite direction than predicted. Based on these results, future research directions linking parental social cognition to discipline are proposed.
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http://dx.doi.org/10.1177/0165025416687414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606149PMC
July 2017

A Histopathological Scheme for the Quantitative Scoring of Intervertebral Disc Degeneration and the Therapeutic Utility of Adult Mesenchymal Stem Cells for Intervertebral Disc Regeneration.

Int J Mol Sci 2017 May 12;18(5). Epub 2017 May 12.

Raymond Purves Bone and Joint Research Laboratory, Kolling Institute, Northern Sydney Local Health District, St. Leonards, NSW 2065, Australia.

The purpose of this study was to develop a quantitative histopathological scoring scheme to evaluate disc degeneration and regeneration using an ovine annular lesion model of experimental disc degeneration. Toluidine blue and Haematoxylin and Eosin (H&E) staining were used to evaluate cellular morphology: (i) disc structure/lesion morphology; (ii) proteoglycan depletion; (iii) cellular morphology; (iv) blood vessel in-growth; (v) cell influx into lesion; and (vi) cystic degeneration/chondroid metaplasia. Three study groups were examined: 5 × 5 mm lesion; 6 × 20 mm lesion; and 6 × 20 mm lesion plus mesenchymal stem cell (MSC) treatment. Lumbar intervertebral discs (IVDs) were scored under categories (i-vi) to provide a cumulative score, which underwent statistical analysis using STATA software. Focal proteoglycan depletion was associated with 5 × 5 mm annular rim lesions, bifurcations, annular delamellation, concentric and radial annular tears and an early influx of blood vessels and cells around remodeling lesions but the inner lesion did not heal. Similar features in 6 × 20 mm lesions occurred over a 3-6-month post operative period. MSCs induced a strong recovery in discal pathology with a reduction in cumulative histopathology degeneracy score from 15.2 to 2.7 ( = 0.001) over a three-month recovery period but no recovery in carrier injected discs.
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http://dx.doi.org/10.3390/ijms18051049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454961PMC
May 2017

Hallux Valgus Correction Comparing Percutaneous Chevron/Akin (PECA) and Open Scarf/Akin Osteotomies.

Foot Ankle Int 2017 Aug 5;38(8):838-846. Epub 2017 May 5.

1 Orthopaedic and Arthritis Specialist Centre, Chatswood, Sydney, Australia.

Background: Minimally invasive surgery is being used increasingly, including for hallux valgus surgery. Despite the growing interest in minimally invasive procedures, there have been few publications on percutaneous chevron/akin (PECA) procedures, and no studies have been published comparing PECA to open scarf/akin osteotomies (SA).

Methods: This was a prospective, randomized study of 50 patients undergoing operative correction of hallux valgus using one of 2 techniques (PECA vs open SA). Data were collected preoperatively and on 1 day, 2 weeks, 6 weeks, and 6 months postoperatively. Outcome measures include the American Orthopaedic Foot & Ankle Society Hallux-Metatarsophalangeal-Interphalangeal (AOFAS-HMI) Score, visual analog pain score, hallux valgus angle (HVA), and 1-2 intermetatarsal angle (IMA). Twenty-five patients underwent PECA procedures and 25 patients received SA procedures.

Results: Both groups showed significantly improved AOFAS-HMI scores after surgery (PECA group: 61.8 to 88.9, SA group: 57.3 to 84.1, P = .560) with comparable final scores. HVA and IMA also presented similar outcomes at final follow-up ( P = .520 and P = .270, respectively). However, the PECA group showed significantly lower pain level (VAS) in the early postoperative phase (postoperative day 1 to postoperative week 6, P < .001 and P = .004, respectively). No serious complications were observed in either group.

Conclusion: Both groups showed comparable good to excellent clinical and radiologic outcomes at final follow-up. However, the PECA group had significantly less pain in the first 6 weeks following surgery. Level of Evidence Level II, prospective comparative study.
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http://dx.doi.org/10.1177/1071100717704941DOI Listing
August 2017

Contamination of the Surgical Field with Propionibacterium acnes in Primary Shoulder Arthroplasty.

J Bone Joint Surg Am 2016 Oct;98(20):1722-1728

Sydney Shoulder Specialists, St. Leonards, Australia.

Background: Propionibacterium acnes is a common pathogen identified in postoperative shoulder infection. It has been shown to be present in culture specimens during primary shoulder arthroplasty; however, recent work has suggested that it is most likely to be a contaminant. Our aim was to identify the potential sources of contamination in shoulder arthroplasty.

Methods: Tissue swabs were obtained for microbiological analysis from consecutive patients undergoing primary shoulder arthroplasty. Routine surgical technique was maintained, and 5 specimens were taken from different sites: (1) the subdermal layer, (2) the tip of the surgeon's glove, (3) the inside scalpel blade (used for deeper incision), (4) the forceps, and (5) the outside scalpel blade (used for the skin incision).

Results: Forty patients (25 female patients and 15 male patients) were included. Thirteen (33%) of the 40 patients had at least 1 culture specimen positive for P. acnes. Two (8%) of the 25 female patients and 11 (73%) of the 15 male patients had ≥1 culture specimen positive for P. acnes. The most common site of growth of P. acnes was the subdermal layer (12 positive samples), followed by the forceps (7 positive samples), the tip of the surgeon's glove (7 positive samples), the outside scalpel blade (4 positive samples), and the inside scalpel blade (1 positive sample). There were 27 of 75 swabs that were positive on culture for P. acnes in male patients compared with 4 of 125 swabs in female patients. Male patients had 66 times (95% confidence interval, 6 to 680 times) higher odds of having a positive culture indicating subdermal colonization compared with female patients (p < 0.001).

Conclusions: P. acnes is a common contaminant of the surgical field in primary shoulder arthroplasty. The subdermal layer may be the source of this contamination, and the prevalence of P. acnes in the surgical wound may be due to the surgeon's manipulation with gloves and instruments. Our findings are consistent with those regarding the increased rates of P. acnes bacterial load and intraoperative growth in male patients compared with female patients.

Clinical Relevance: P. acnes is likely to be spread throughout the surgical field from the subdermal layer via soft-tissue handling by the surgeon and instruments. Strategies need to be utilized to minimize this contact and to reduce the chance of colonization.
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http://dx.doi.org/10.2106/JBJS.15.01133DOI Listing
October 2016

Hyaluronan oligosaccharides stimulate matrix metalloproteinase and anabolic gene expression in vitro by intervertebral disc cells and annular repair in vivo.

J Tissue Eng Regen Med 2018 01 22;12(1):e216-e226. Epub 2017 Mar 22.

Raymond Purves Bone and Joint Research Laboratory, Kolling Institute Northern Sydney Local Health District, St Leonards, NSW, Australia.

The role of hyaluronan (HA) oligosaccharides in disc cell-mediated matrix metalloproteinase (MMP) and anabolic gene expression in vitro and annular repair in vivo were examined. Monolayer and alginate bead cultures of ovine intervertebral disc cells were stimulated with 10-12 mer hyaluronan oligosaccharides (HA-oligos). Annulus fibrosus (AF) monolayers were poorly responsive to the HA-oligos, proMMP-2 levels were marginally elevated and levels were MMP-9 unaffected. ProMMP-2 displayed a strong dose-dependent increase in the nucleus pulposus (NP) monolayers. In AF alginate bead cultures, proMMP-2 and active MMP-9 increased up to day 10, in NP cultures proMMP-2 was progressively converted to active MMP-2 over days 7-10 and active MMP-9 levels were elevated on day 10. A steady decline in MMP-2 and MMP-9 activity was evident over days 2-10 in the non-stimulated NP cultures. Disc cell viabilities were ≥92 ± 5% in all cultures indicating that the HA-oligo was not cytotoxic. Reverse-transcription polymerase chain reaction demonstrated an upregulation in MMP1, MMP113 and ADAMTS1 and the anabolic matrix repair genes ACAN, COL1A1 and COL2A1 in the NP by HA-oligos, whereas AF MMP13, ADAMTS1, ADAMTS4 and ADAMTS5, ACAN and COL2A1 were down-regulated; this differential regulation is expected to promote clearance of granulation/scar tissue from AF defects and matrix replenishment. The AF defect sites contained enlarged annular lamellae in vivo in response to the HA oligos, which is consistent with an active repair response. Masson trichrome and PicroSirius red histology and immunolocalization of type I collagen supported active remodelling in the outer lesion zone by the HA-oligo treatment but not the inner lesion. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2319DOI Listing
January 2018

Chondroitin sulphate glycosaminoglycans contribute to widespread inferior biomechanics in tendon after focal injury.

J Biomech 2016 09 6;49(13):2694-2701. Epub 2016 Jun 6.

Murray Maxwell Biomechanics Laboratory (Institute of Bone and Joint Research), Kolling Institute, Royal North Shore Hospital (Sydney Medical School, University of Sydney), St Leonards, New South Wales, Australia.

Both mechanical and structural properties of tendon change after injury however the causal relationship between these properties is presently unclear. This study aimed to determine the extent of biomechanical change in post-injury tendon pathology and whether the sulphated glycosaminoglycans (glycosaminoglycans) present are a causal factor in these changes. Equine superficial digital flexor tendons (SDF tendons) were surgically-injured in vivo (n=6 injured, n=6 control). Six weeks later they were harvested and regionally dissected into twelve regions around the lesion (equal medial/lateral, proximal/distal). Glycosaminoglycans were removed by enzymatic (chondroitinase) treatment. Elastic modulus (modulus) and ultimate tensile strength (UTS) were measured under uniaxial tension to failure, and tendon glycosaminoglycan content was measured by spectrophotometry. Compared to healthy tendons, pathology induced by the injury decreased modulus (-38%; 95%CI -49% to -28%; P<0.001) and UTS (-38%; 95%CI -48% to -28%; P<0.001) and increased glycosaminoglycan content (+52%; 95%CI 39% - 64%; P<0.001) throughout the tendon. Chondroitinase-mediated glycosaminoglycan removal (50%; 95%CI 21-79%; P<0.001) in surgically-injured pathological tendons caused a significant increase in modulus (5.6MPa/µg removed; 95%CI 0.31-11; P=0.038) and UTS (1.0MPa per µg removed; 95%CI 0.043-2; P=0.041). These results demonstrate that the chondroitin/dermatan sulphate glycosaminoglycans that accumulate in pathological tendon post-injury are partly responsible for the altered biomechanical properties.
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http://dx.doi.org/10.1016/j.jbiomech.2016.06.006DOI Listing
September 2016

Ablation of Perlecan Domain 1 Heparan Sulfate Reduces Progressive Cartilage Degradation, Synovitis, and Osteophyte Size in a Preclinical Model of Posttraumatic Osteoarthritis.

Arthritis Rheumatol 2016 Apr;68(4):868-79

Kolling Institute, Northern Sydney Local Health District, and the University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

Objective: To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG-2) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA) in a mouse gene-knockout model.

Methods: Maturational changes were evaluated histologically in the knees of 3-, 6-, and 12-week-old wild-type (WT) mice and Hspg2(Δ3-/Δ3-) mice (Hspg2 lacking domain 1 HS, generated by ablation of exon 3 of perlecan). Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and Hspg2(Δ3-/Δ3-) mice. Changes in cartilage expression of FGF-2, FGF-18, HSPG-2, FGF receptor 1 (FGFR-1), and FGFR-3 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin-1α (IL-1α), FGF-2, and FGF-18, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified.

Results: No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, Hspg2(Δ3-/Δ3-) mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA-induced loss of chondrocyte expression of FGF-2, FGF-18, and HSPG-2 occurred in both genotypes. Expression of FGFR-1 after OA induction was maintained in WT mice, while FGFR-3 loss after OA induction was significantly reduced in Hspg2(Δ3-/Δ3-) mice. There were no genotypic differences in GAG content or release between unstimulated control cartilage and IL-1α-stimulated cartilage. However, IL-1α-induced cartilage expression of Mmp3 mRNA was significantly reduced in Hspg2(Δ3-/Δ3-) mice. Cartilage GAG release in either the presence or absence of IL-1α was unaltered by FGF-2 in both genotypes. In cartilage cultures with FGF-18, IL-1α-stimulated GAG loss was significantly reduced only in Hspg2(Δ3-/Δ3-) mice, and this was associated with maintained expression of Fgfr3 mRNA and reduced expression of Mmp2/Mmp3 mRNA.

Conclusion: Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF/HS/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR-3 and increased FGF signaling.
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http://dx.doi.org/10.1002/art.39529DOI Listing
April 2016

Focal experimental injury leads to widespread gene expression and histologic changes in equine flexor tendons.

PLoS One 2015 2;10(4):e0122220. Epub 2015 Apr 2.

Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Kolling Institute of Medical Research (University of Sydney) at Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

It is not known how extensively a localised flexor tendon injury affects the entire tendon. This study examined the extent of and relationship between histopathologic and gene expression changes in equine superficial digital flexor tendon after a surgical injury. One forelimb tendon was hemi-transected in six horses, and in three other horses, one tendon underwent a sham operation. After euthanasia at six weeks, transected and control (sham and non-operated contralateral) tendons were regionally sampled (medial and lateral halves each divided into six 3 cm regions) for histologic (scoring and immunohistochemistry) and gene expression (real time PCR) analysis of extracellular matrix changes. The histopathology score was significantly higher in transected tendons compared to control tendons in all regions except for the most distal (P ≤ 0.03) with no differences between overstressed (medial) and stress-deprived (lateral) tendon halves. Proteoglycan scores were increased by transection in all but the most proximal region (P < 0.02), with increased immunostaining for aggrecan, biglycan and versican. After correcting for location within the tendon, gene expression for aggrecan, versican, biglycan, lumican, collagen types I, II and III, MMP14 and TIMP1 was increased in transected tendons compared with control tendons (P < 0.02) and decreased for ADAMTS4, MMP3 and TIMP3 (P < 0.001). Aggrecan, biglycan, fibromodulin, and collagen types I and III expression positively correlated with all histopathology scores (P < 0.001), whereas lumican, ADAMTS4 and MMP14 expression positively correlated only with collagen fiber malalignment (P < 0.001). In summary, histologic and associated gene expression changes were significant and widespread six weeks after injury to the equine SDFT, suggesting rapid and active development of tendinopathy throughout the entire length of the tendon. These extensive changes distant to the focal injury may contribute to poor functional outcomes and re-injury in clinical cases. Our data suggest that successful treatments of focal injuries will need to address pathology in the entire tendon, and that better methods to monitor the development and resolution of tendinopathy are required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383631PMC
April 2016

Subaxial injury classification scoring system treatment recommendations: external agreement study based on retrospective review of 185 patients.

Spine (Phila Pa 1976) 2015 Feb;40(3):137-42

From the Department of Orthopaedic and Traumatic Surgery, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

Study Design: Retrospective case series.

Objective: To test validity of subaxial injury classification (SLIC) treatment recommendations.

Summary Of Background Data: Although SLIC has been tested for reliability, external studies that test the validity of its treatment recommendations are lacking.

Methods: The SLIC score was determined by reviewing imaging studies and clinical records in a consecutive series of 185 patients with subaxial cervical spine trauma presenting to a level 1 spinal injury referral center. Details including attending surgeon responsible for treatment decision, treatment received, and surgical approach were collected.

Results: Treatment received matched SLIC guidelines in 93.6% nonsurgically managed patients and 96.3% surgically managed patients. The mean SLIC score of the surgically treated group of patients was significantly higher than that of the nonsurgical group (7.14 vs. 2.22; P<0.001). Sixty-six patients had a SLIC score of 3 or less, and 94% of them were nonsurgically managed (P<0.001). One hundred two patients had a SLIC score of 5 or more, and 95% of them were surgically managed (P<0.001). Seventeen patients had a SLIC score of 4, and 65% were nonsurgically managed (P=0.032). Injury morphology scores were not predictive of surgical approach. Increasing SLIC scores correlated with increasing complexity of treatment (r=0.77; P<0.001). The distribution of patients with regard to severity of injuries and treatment delivered by the 7 spinal surgeons was comparable. The past practice of these 7 fellowship-trained spine surgeons was individually in agreement with SLIC treatment recommendations.

Conclusion: Our past practice reflects SLIC treatment recommendations for nonsurgical treatment of patients with SLIC scores of 3 or less and surgical treatment of patients with SLIC scores of 5 or more. The use of SLIC as an ordinal severity scale is validated as increasing SLIC scores correlated with increasing complexity of treatment. The injury morphology score did not predict a surgical approach. Significantly higher numbers of patients with a SLIC score of 4 were treated nonsurgically.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000000666DOI Listing
February 2015

Depletion of protease-activated receptor 2 but not protease-activated receptor 1 may confer protection against osteoarthritis in mice through extracartilaginous mechanisms.

Arthritis Rheumatol 2014 Dec;66(12):3337-48

Kolling Institute of Medical Research and the University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

Objective: To explore the involvement of protease-activated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice.

Methods: OA was induced in the joints of wild-type (WT), PAR-1(+/+) , PAR-1(-/-) , and PAR-2(-/-) mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks post-DMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/activity were studied in cultures of mouse femoral head tissue with or without interleukin-1α (IL-1α). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry.

Results: Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1α-induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4+ T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2(-/-) mice compared to PAR-1(-/-) and WT mice.

Conclusion: Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMM-induced cartilage damage. The chondroprotection in PAR-2(-/-) mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.
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http://dx.doi.org/10.1002/art.38876DOI Listing
December 2014

Activation of matrix metalloproteinases 2, 9, and 13 by activated protein C in human osteoarthritic cartilage chondrocytes.

Arthritis Rheumatol 2014 Jun;66(6):1525-36

Kolling Institute of Medical Research, University of Sydney, and Royal North Shore Hospital, St. Leonards, New South Wales, Australia.

Objective: Levels of activated protein C (APC) are elevated in the synovial fluid of patients with osteoarthritis (OA), and increased APC levels are correlated with the levels of active matrix metalloproteinase 2 (MMP-2). This study sought to investigate whether APC is a relevant protein for activation of MMPs in the degradation of human OA cartilage, and to elucidate its mechanisms of action.

Methods: Human articular cartilage was cultured with or without interleukin-1α (IL-1α), in the presence or absence of APC or protein C, and an MMP or serine proteinase inhibitor. Aggrecan and collagen release and chondrocyte gene expression levels were quantified. Aggrecanase and MMP cleavage of aggrecan was examined with neoepitope-specific antibodies, and MMP activity was measured using gelatin zymography and fluorogenic peptide assay.

Results: In human OA cartilage, APC induced aggrecan and collagen release, whereas in non-OA cartilage, costimulation with IL-1α was required. Inhibition of MMP activity reduced APC-induced cartilage proteolysis, and MMP-induced aggrecanolysis was confirmed by Western blotting. In cultures with APC alone, the activity of MMPs 2, 9, and 13 was significantly increased in OA cartilage, although APC could not directly activate MMPs 2 or 9. Expression of MMP1, MMP2, MMP9, MMP13, TIMP1, and TIMP3 was not altered by APC in OA cartilage. Human OA chondrocytes expressed messenger RNA for protein C, endothelial protein C receptor, thrombomodulin, and protease-activated receptor 1, but these were unaltered or down-regulated by APC. The induction of MMP activation and cartilage degradation by APC was dependent on its serine protease activity.

Conclusion: APC is a physiologically relevant activator of MMPs and cartilage breakdown in human OA. The effects of APC are dependent on its proteolytic activity and as-yet-undefined cell and/or cartilage matrix factors, and inhibition of this pathway may provide a novel therapeutic target to halt the progression of cartilage damage in OA.
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http://dx.doi.org/10.1002/art.38401DOI Listing
June 2014

A hexadecylamide derivative of hyaluronan (HYMOVIS®) has superior beneficial effects on human osteoarthritic chondrocytes and synoviocytes than unmodified hyaluronan.

J Inflamm (Lond) 2013 27;10:26. Epub 2013 Jul 27.

Raymond Purves Bone and Joint Research Laboratories; Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney at Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

Background: Intra-articular hyaluronan (HA) injection provides symptomatic benefit in the treatment of osteoarthritis (OA). Previously we found superior beneficial effects in a large animal OA model of a hexadecylamide derivative compared with unmodified HA of the same initial molecular weight. The current study sought to define possible molecular mechanisms whereby this enhanced relief of symptoms was occurring.

Methods: Chondrocytes and synovial fibroblasts were isolated from tissues of patients undergoing arthroplasty for knee OA. Monolayer cultures of cells were treated with 0, 0.5, 1.0 or 1.5 mg/mL of unmodified HA (500-730 kDa) or a hexadecylamide derivative of HA of the same initial molecular weight (HYADD4®-G; HYMOVIS®) simultaneously or 1 hour before incubation with interleukin (IL)-1beta (2 ng/mL). Cultures were terminated 15 or 30 minutes later (chondrocytes and synovial fibroblasts, respectively) for quantitation of phosphorylated-(p)-JNK, p-NFkappaB, p-p38, or at 24 hours for quantitation of gene expression (MMP1 &13, ADAMTS4 &5, TIMP1 &3, CD44, COL1A1 &2A1, ACAN, PTGS2, IL6, TNF) and matrix metalloproteinase (MMP)-13 activity.

Results: The hexadecylamide derivative of HA had significantly better amelioration of IL-1beta-induced gene expression of key matrix degrading enzymes (MMP1, MMP13, ADAMTS5), and inflammatory mediators (IL6, PTGS2) by human OA chondrocytes and synovial fibroblasts. Pre-incubation of cells with the derivatized HA for 1 hour prior to IL-1beta exposure significantly augmented the inhibition of MMP1, MMP13, ADAMTS4 and IL6 expression by chondrocytes. The reduction in MMP13 mRNA by the amide derivative of HA was mirrored in reduced MMP-13 protein and enzyme activity in IL-1beta-stimulated chondrocytes. This was associated in part with a greater inhibition of phosphorylation of the cell signalling molecules JNK, p38 and NF-kappaB.

Conclusions: The present studies have demonstrated several potential key mechanisms whereby the intra-articular injection of a hexadecylamide derivative of HA may be acting in joints with OA.
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http://dx.doi.org/10.1186/1476-9255-10-26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727958PMC
May 2014

The ovine newborn and human foetal intervertebral disc contain perlecan and aggrecan variably substituted with native 7D4 CS sulphation motif: spatiotemporal immunolocalisation and co-distribution with Notch-1 in the human foetal disc.

Glycoconj J 2013 Oct 13;30(7):717-25. Epub 2013 Jun 13.

Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St. Leonards, NSW, 2065, Australia.

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 samples 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 samples. 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 samples (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.
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http://dx.doi.org/10.1007/s10719-013-9475-9DOI Listing
October 2013

Altered stress induced by partial transection of the infraspinatus tendon leads to perlecan (HSPG2) accumulation in an ovine model of tendinopathy.

Tissue Cell 2013 Feb 12;45(1):77-82. Epub 2012 Dec 12.

The Raymond Purves Bone and Joint Research Laboratories, Institute of Bone and Joint Research, Kolling Institute of Medical Research, University of Sydney, The Royal North Shore Hospital of Sydney, St. Leonards, NSW 2065, Australia.

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 diverse 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.
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http://dx.doi.org/10.1016/j.tice.2012.10.001DOI Listing
February 2013

Mechanical destabilization induced by controlled annular incision of the intervertebral disc dysregulates metalloproteinase expression and induces disc degeneration.

Spine (Phila Pa 1976) 2012 Jan;37(1):18-25

Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney, The Royal North Shore Hospital of Sydney, St Leonards, New South Wales, Australia.

Study Design: An investigation of mechanical destabilization of the lumbar ovine intervertebral disc (IVD) inducing IVD degeneration (IVDD) as determined by multiparameter outcome measures (magnetic resonance imaging [MRI], IVD composition, biomechanical testing, gene profiling, immunohistochemistry, and immunoblotting).

Objective: To assess the effect of IVD mechanical destabilization on matrix protein and metalloproteinase gene expression to investigate the pathophysiological mechanisms of lumbar IVDD.

Summary Of Background Data: Several earlier studies have used annular transection to induce IVDD in sheep, but none have optimized or validated the most appropriate lesion size.

Methods: The annulus fibrosus (AF) incision inducing maximal change in IVD biomechanics was applied to L1-L2, L3-L4, and L5-L6 discs in vivo to compare with a sham procedure at 3 months post operation. IVDs were evaluated by MRI, biomechanics, histopathology, proteoglycan and collagen content, gene expression, and aggrecan proteolysis by Western blotting.

Results: Significant changes were observed in lesion (6 × 20 mm(2)) compared with sham IVDs at 3 months post operation: reduced disc height on MRI; increased neutral zone in biomechanical testing; depleted proteoglycan and collagen content in the nucleus pulposus (NP) and lesion half of the AF but not in the contralateral AF; increased messenger RNA for collagen I and II, aggrecan, versican, perlecan, matrix metalloproteinase (MMP)-1 & 13, and ADAMTS-5, in the lesion-site AF and NP but not in the contralateral AF. ADAMTS-4 messenger RNA was increased in the lesion-site AF but decreased in the NP. Despite an upregulation in MMPs, there was no change in MMP- or ADAMTS-generated aggrecan neoepitopes in any region of the IVD in lesion or sham discs.

Conclusion: Lumbar IVDD was reproducibly induced with a 6 × 20 mm(2) annular lesion, with focal dysregulation of MMP gene expression, cell cloning in the inner AF, loss of NP aggrecan, and disc height. Loss of aggrecan from the NP was not attributable to increased proteolysis in the interglobular domain by MMPs or ADAMTS.
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http://dx.doi.org/10.1097/BRS.0b013e31820cd8d5DOI Listing
January 2012

Early results of reverse shoulder arthroplasty in patients with rheumatoid arthritis.

J Bone Joint Surg Am 2011 Oct;93(20):1915-23

Centre Orthopédique Santy, Lyon, France.

Background: Rheumatoid arthritis affecting the shoulder is typically associated with rotator cuff compromise and can also result in severe glenoid erosion. Since reverse shoulder arthroplasty is capable of addressing both rotator cuff disorders and glenoid bone deficiencies, our aim was to evaluate the outcome of reverse shoulder arthroplasty in patients with rheumatoid arthritis and either or both of these associated conditions.

Methods: We performed eighteen primary reverse total shoulder arthroplasties in sixteen patients with rheumatoid arthritis involving the shoulder as well as associated rotator cuff compromise and/or severe erosion of the glenoid bone between 2002 and 2007. Patients were assessed with use of the Constant score, patient satisfaction score, subjective shoulder value, range of shoulder motion, and imaging studies.

Results: The mean Constant score improved from 22.5 to 64.9 points at a mean of 3.8 years (range, 2.1 to 7.0 years) postoperatively. The patients were either very satisfied or satisfied with the outcome of the surgery in seventeen of the eighteen shoulders. The mean subjective shoulder value was 68.6% postoperatively. Active forward elevation improved from 77.5° to 138.6°, and external rotation with the arm in 90° of abduction improved from 16.9° to 46.1°. The mean Constant score improved from 28.0 points to 74.3 points in shoulders in which the teres minor muscle was normal before the surgery, and it improved from 20.8 to 54.6 points in shoulders with an atrophic teres minor muscle. Scapular notching was observed in ten of the eighteen shoulders. A fracture involving the acromion, acromial spine, coracoid, or greater tuberosity was observed either intraoperatively or postoperatively in four of the eighteen shoulders. One case of transient axillary nerve injury was noted. There were no cases of dislocation, infection, or component loosening. None of the patients required revision surgery for any reason.

Conclusions: Comparatively good outcomes were observed in the short to intermediate term after reverse shoulder arthroplasty in patients with rheumatoid arthritis. However, surgeons should be aware of the risk of intraoperative and postoperative fractures in this patient group.
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http://dx.doi.org/10.2106/JBJS.J.00300DOI Listing
October 2011

Colocalization in vivo and association in vitro of perlecan and elastin.

Histochem Cell Biol 2011 Oct 28;136(4):437-54. Epub 2011 Aug 28.

BioImaging Unit, Cardiff School of Biosciences, University of Cardiff, Cardiff, UK.

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.
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http://dx.doi.org/10.1007/s00418-011-0854-7DOI Listing
October 2011
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