Etiology of Experimental Osteoarthritis: Early Events and Potential Clinical Implications

Introduction Osteoarthritis (OA) is the most common form of arthritis and accounts for 50% of all chronic conditions in the elderly. One in two adults reported a chronic musculoskeletal condition in 2005, twice the rate of reported chronic heart or respiratory conditions(2). In addition, persons aged 45 to 64 account for an increasingly greater proportion of total musculoskeletal disease treatment costs and lost wages, a trend that will continue for the next several decades(3). Surgical treatment culminating in total joint replacement (TJR) remains the most effective therapy for late stage OA. Current treatment of pre-surgical OA consists of pain relieving medications (i.e. NSAIDs), physical therapy, and mechanical supports (i.e. braces, canes, and walkers). Despite the wealth of clinical data on OA, there is currently no cure for the disease. Our previous work in developing potential disease-modifying osteoarthritis drugs (DMOADs) had yielded promising results, showing a decrease in OA cartilage lesion areas and histological grades (Figure 1). Interestingly, we noted that animals treated for only the first 3 weeks demonstrated near 6-week levels of OA reduction. These differences in treatment responsiveness necessitate a better characterization of the specific cellular phases of OA throughout the natural disease progression. The current study was undertaken to clarify this progression of early OA events. Methods OA was induced in the right knees of 10-week-old male 129 S6/SvEv (Taconic) mice via DMM surgery. Mice receiving sham surgery with no destabilization were used as negative controls. Both groups were sacrificed at 4, 8, 12, 16, and 20-day intervals in order to evaluate OA progression. Knees were harvested, processed, and sectioned at 6um intervals. Sections were stained for cartilage composition (Safranin-O) and scored for progression and severity of OA by 3 blinded observers using a 0-5 scale (modified Mankin System)(4). Both ‘mean maximal’ scores (highest scores per knee), and ‘mean summed scores (sum of scores per knee) were generated using this scale. All scores were averaged across observers. Cartilage lesion area, subchondral bone area (sclerosis), and apoptosis (TUNEL method) were measured using a histomorphometric analysis package (ImageJ)(5). Conclusions Measurable osteoarthritic changes in articular cartilage and underlying bone following meniscal injury occur far earlier than previously described. Some changes are clearly degenerative (OA grade, stage & lesion area), however, some changes (subchondral bone thickening) could be regarded as compensatory supportive mechanisms. Cell death (apoptosis) is an acute event following relatively minor changes to knee biomechanics. Our results suggest an opportunity for intervention early on in OA before the resulting articular changes become irreversible. Specifically, consideration of anti-apoptosis based therapies could prevent much of the subsequent structural changes in articular cartilage. Future Directions Apoptosis data suggests pursuing an anti-apoptotic therapy strategy in the DMM model of OA Early bone sclerotic events suggest bone tissue as a target for anti-OA therapy. Translationally, preventing or delaying OA due to soft tissue injuries (e.g., sports injuries) may be possible with early medical treatment of OA proximal to the time of injury. References (1) International Bone and Joint Decade 2000-2010 Organization, 1999. (2) National Center for Health Statistics, National Health Interview Survey, 2005. (3) Kurtz, SM, Lau, E, et al. Future Young Patient Demand for Primary and Revision Joint Replacement: National Projections from 2010 to 2030. Clinical Orthopaedics and Related Research, April 2009. (4) Kurtz, SM, Ong, K, et. al. Projections of Primary and Revision Hip and Knee Arthroplasty in the United States from 2005 to 2030. The Journal of Bone and Joint Surgery, 2007;89:780-5. (5) http://rsbweb.nih.gov/ij

The Varus Knee Reveals Differential Expression Patterns of miRNAs in Spared vs. Non-spared Compartments

Introduction MicroRNAs (miRNAs) function by repressing cellular protein levels to provide a sophisticated level of gene regulation that coordinates a broad spectrum of biological processes. MiRNA inhibition of mRNA translation has emerged as an important regulator of chondrogenic and osteogenic development, osteoblast, osteoclast and chondrocyte cell growth and differentiation, and tissue homeostasis in the adult skeleton. MiRNAs control many layers of regulation in adult tissues connected to both normal biological and pathologic cellular activities. The study of miRNAs in skeletal disorders is in its infancy. Osteoarthritis (OA) is a disease that progresses from degeneration of the articular cartilage to remodeling of the underlying subchondral bone over many years. While miRNAs have been identified with the inflammatory pathogenesis of rheumatoid arthritis (RA), only a few studies have been performed on OA tissue (1,2) . Here we performed a systematic analysis of the articular cartilage from varus OA knee replacements, comparing multiple tissue samples from the lateral (spared) and medial (diseased) compartments. Before proceeding to a miRNA profiling, each sample was analyzed for expression of a small set of miRNAs that have been reported in association with RA, OA and cartilage formation. These preliminary findings have identified a spectrum of changes in surface cartilage between control and diseased tissue. Methods Human tissues: 6 individual articular cartilage samples were harvested from a total of 5 osteoarthritic varus human knees. Cartilage samples were exempt from IRB review as they are discarded materials. Samples were removed with a biopsy punch and were approximately 6 x 2mm (diameter x thickness). Cartilage specimens were harvested from the more normal-appearing lateral (‘spared’) compartments and from the more OA-affected, medial compartments of the knees. This sampling technique allows direct comparison of more significantly OA-affected cartilage samples with those of lower OA grade from the same set of individuals. Knee ages ranged from 53-74 years old and averaged 65 years old. RNA and miRNA Isolation: Each osteochondral specimen was placed in RNA Later (Sigma) immediately following surgical removal, in order to preserve the integrity of the total RNA. Specimens were transported to the lab where individual samples were removed carefully with RNase-treated tools and were transferred intofresh RNA Later solution and incubated overnight at 4C to allow penetration and maximal inhibition of RNase activity. Samples were then removed from RNA Later, blotted briefly and frozen in liquid N2, and then pulverized using a Bessman tissue pulverizer (Fisher). The pulverized samples were immediately placed into Trizol (InVitrogen) and homogenized using a polytron device. Total RNA was isolated to include small RNAs of \u3e17 nucleotides, according to the manufacturer’s protocol (InVitrogen). Purified RNA was obtained using precipitated total RNAs filtered through glass columns according to the manufacturer’s protocol (Zymo Research). RNAs were reverse-transcribed into DNA using 900ng of each purified RNA sample using the TaqMan microRNA Reverse Transcription Kit (Applied Biosystems). TaqMan qPCR analysis for small RNAs was performed using the following human primer-probe sets from Applied Biosystems: hsa-miRs-: 9, 22, 27a, 29a and 34a. Human U6 was used to normalize all qPCR data and data was plotted as normalized relative values. Normalized relative values were averaged for each of the complement of medial vs. lateral samples. Results MiRs were found to be either up- or down-regulated in a manner that suggests a mechanism of de-repression of pro-inflammatory cytokine signaling and repression of pro-inflammatory events in medial vs. lateral varus knee OA cartilage samples, respectively. MiRs 9, 27a, and 29a were found to up-regulated in lateral varus knee cartilage samples vs. medial varus knee cartilage samples (Fig.1. A,C,E,F). Conversely, miRs 22 and 34a were found to upregulated in medial vs. lateral cartilage samples (Fig1, B, D). Discussion The functional characterization of global gene expression patterns through miRNAs in OA is lacking. Particularly, the roles of miRs in OA disease development, as biomarkers, and in disease outcomes are at question. A few large-scale microarray approaches have previously identified expression signatures of potential OA-involved miRNAs (2). By comparing cartilage samples that derive from more advanced (medial) vs. less advanced (lateral) OA stages in varus human knees, we seek to combine miRNA expression analysis with clinicopathologic features. MiRs -9, -22 and -34a are known to be involved in regulating pro-inflammatory events in OA. Higher levels of miRs, -9, -27a & -140 in less-affected lateral compartment cartilage are consistent with previous reports of reduced TNFa, MMP-13 & ADAMTS-5 expression events, respectively (Fig.1, F, E & A) (3,4,5). MiRs -22 and -34a have been shown to be associated with promoting tissue catabolism by their presence and are here shown to be increased in more affected medial compartment cartilage (Fig.1, B, D) (4). In addition, miR-34a deficiency has been previously shown to inhibit chondrocyte apoptosis, consistent with the lower expression level found in lateral cartilage (Fig.1, D) (6). MiR-29a was found in a previous microarray analysis to be the highest-fold down-regulated miRNA in OA vs. normal cartilage, consistent with our finding of under-expression in medial cartilage samples (Fig.1, C) (1). The goal of these studies is to begin to understand how miRNAs can both contribute to and protect against OA. Here we show that the comparison of cartilage-derived miRNAs in medial and lateral compartment pairs from the same knee may facilitate validation of candidate OA miRNAs. Significance The aims of this project are to provide an internally-controlled platform of study for the miRNAs of OA using the natural disease differences inherent in spared vs. non-spared cartilage compartments from a varus OA knee. Such efforts may provide an alternative methodology when compared to the significant barrier of obtaining age-matched, non-OA control knee cartilage. References 1.) Iliopoulus D. PLoS One. 2008;3(11):e3740. Epub 2008 Nov 17. 2.) Goldring MB. Curr Opin Rheumatol. 2011 Jul 22. [Epub]. 3.) Yu C. J Int Med Res. 2011;39(1):1-9. 4.) Alcaraz MJ. Biochem Pharmacol. 2010 Jul 1;80(1):13-21. 5.) Miyaki S. Genes Dev. 2010 Jun 1;24(11):1173-85. 6.) Abouheif MM. Rheumatology. 2010 Nov;49(11):2054-60

Radiostereometric Analysis of Femoral Head Penetration in Cross-Linked Polyethylene in THR Patients

Background: In the young total hip replacement (THR) population limiting polyethylene liner wear is crucial to preventing premature implant failure. Highly cross-linked ultra-high molecular weight polyethylene (HXLPE) liners were designed to improve wear resistance of polyethylene liners. Radiostereometric analysis (RSA) provides highly precise measurements of liner wear. This study utilized RSA to characterize wear of conventional versus HXLPE liners up to five years following THR. Methods: This IRB-approved, prospective, randomized, blinded study, involved 46 patients with a mean age of 58 and BMI of 30. Each patient was double randomized to receive a conventional or HXLPE liner with an uncemented titanium mesh or tantalum trabecular metal cup. Both liners were prepared from compression-molded GUR 1050 resin without calcium stearate, while HXLPE liners undergo further e-beam irradiation and annealing. At the time of surgery, 1mm tantalum RSA markers were implanted around the liner periphery, femur and periacetabular bone. RSA examinations, Harris Hip, UCLA, WOMAC, SF-36 scores were obtained pre-operatively, post-operatively, at six weeks, six months and annually through five years. Results: All patients had statistically significant improvement in Harris Hip, WOMAC and SF-36 PCS scores following THR with no difference between cohorts. On RSA examination, of titanium shells, HXLPE liners revealed significantly lower femoral head penetration at each follow up except six weeks and six months (p Conclusion: In this young THR population RSA shows significantly less femoral head penetration in the HXLPE liners compared to conventional liners. Novel RSA techniques have been developed to determine polyethylene wear in patients

Tantalum versus Titanium Acetabular Shells in Young Active THR Patients: A Radiostereometric Analysis (RSA) Study

Introduction: In the active THR (total hip replacement) population, acetabular component stability is crucial for preventing implant failure. Titanium fiber metal coating is the most common material used in cementless THR. Trabecular metal, composed of porous tantalum, is designed to improve tissue infiltration and limit migration. It is unknown if tantalum offers an advantage over titanium in the biologic fixation of porous-coated acetabular shells. Radiostereometric analysis (RSA) provides highly precise measurements of micromotion that are otherwise not detectable by routine radiographs. Methods: In this IRB approved, prospective, randomized, blinded study, 46 patients received a primary THR by a single surgeon. Each patient was randomized to receive a titanium (23) or tantalum (23) uncemented cup. Tantalum RSA markers were implanted around the polyethylene liner and into the patient’s femur and periacetabular bone. Also, patients received either a highly cross-linked (n=25) or a conventional liner (n=21). RSA examinations, Harris Hip, UCLA, WOMAC, SF-12 scores were obtained at 10 days, 6 months, and annually through 5 years. Results: The randomized groups had comparable mean age, preoperative activity, and average BMI. The tantalum shells demonstrated less median translation than the titanium shells at each time-point, but there was no statistical difference between the two shells. At 6 months median translation of tantalum and titanium was -0.01mm and 0.04mm and remained stable with median translation of -0.02mm and 0.04mm at four years. Mean UCLA, WOMAC, Harris Hip, and SF-12 PCS and MCS scores improved similarly in both groups. Conclusions: After THR, both patient cohorts had excellent clinical outcomes with statistically significant improvements in function and pain relief. Although tantalum porous-coated acetabular shells demonstrated less y-translation and y-rotation at all time points, there was no statistically significant difference in shell migration and both shells demonstrated excellent stability with minimal micromotion at four years

Radiostereometric Analysis of Tantalum vs. Titanium Acetabular Shells in Young THR Patients

Introduction: In the active total hip replacement (THR) population, maintaining acetabular component stability and limiting polyethylene wear are crucial components to preventing premature implant failure. Titanium with Co/Cr/Mo fiber metal coating is among the most common materials used in cementless THR. Trabecular metal, composed of porous tantalum, has a metallic strut design resembling trabecular bone, designed to improve tissue infiltration and limit migration. This study assesses the stability and clinical outcomes of tantalum versus titanium acetabular shells using radiostereometric analysis (RSA) technology. Methods: In this IRB approved, prospective, randomized, blinded study, 46 patients received a primary THR by a single surgeon (DCA). Each patient was randomized to receive a titanium (23) (Trilogy, Zimmer) or tantalum (23) (Modular tantalum shell, Zimmer) uncemented hemispheric cup and either a highly-crosslinked or conventional polyethylene liner. Tantalum RSA markers were implanted around the liner periphery, femur, and periacetabular bone in each patient. RSA examinations, Harris Hip, UCLA, WOMAC, SF-36 scores were obtained at 10 days, 6 months, and annually with the furthest patients evaluated through 5 years. Results: Median translation was greater at all time points for the tantalum mesh cups except for the 3-year follow-up, however due to large standard errors, there was no significant difference between the two designs (p\u3e0.05). These large standard errors were predominantly caused by two outliers, neither of which had clinical evidence of loosening at 5 years follow-up. Mean UCLA, WOMAC, Harris Hip, and SF-36 PCS and MCS scores improved similarly in both groups. Conclusions: In this young THR population, both titanium and tantalum acetabular shells demonstrated excellent stability at five years follow up. Tantalum shells demonstrated slightly greater micromotion, but there was no statistically significant difference in shell migration. Outstanding clinical outcomes with statistically significant improvements in function and pain relief were observed in both groups

Making Mas: TruDynasty Carnival Takes Josephine Baker to the Caribbean Carnival

Jacqueline Taucar, in conversation with Thea and Dario Jackson, investigates the sculptural qualities of the Josephine Baker Mas for the Scotiabank Caribbean Carnival Festival in 2011. This article traces the conception, construction, and complexities of choreography for this carnivalesque reimagining of Baker in Paris of the twenties for a contemporary Canadian ambulant expression. This Queen Mas talks back to the objectification by Parisians and embodying Queen Mas as an instance of female empowerment

"The Book of Negroes’ illustrated edition: circulating African-Canadian history through the Middlebrow"

This article examines the 2009 deluxe illustrated edition of Lawrence Hill’s Commonwealth Writers’ Prize– and Canada Reads–winning novel The Book of Negroes, originally published in 2007. It relates the story of Aminata, a West African girl kidnapped and sold into slavery, and her experiences on an indigo plantation in the American south, followed by further displacements to Charleston, Nova Scotia, Sierra Leone, and London. In New York, as the Revolutionary War comes to a close, Aminata becomes the scribe for the Book of Negroes, documenting the Black Loyalists, as well as the slaves and indentured servants of white Loyalists, granted passage by the British to Canada. Hill has commented that the Book of Negroes is an important document about which Canadians are largely ignorant. This desire to circulate knowledge about African-Canadian history through the novel is particularly manifest in the illustrated edition of 2009, where a photograph of the Book of Negroes features prominently, along with countless other images and captions which supplement and interrupt Hill’s narrative. This article considers the significance and implications of this “keepsake” or “souvenir” edition, particularly its circulation of knowledge about African-Canadian history through visual pleasure

Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population

<p>Abstract</p> <p>Background</p> <p>Low intake of fish, polyunsaturated fatty acids (PUFA) and vitamin D deficiency has been suggested to play a role in the development of schizophrenia. Our aim was to evaluate the association between the intake of different fish species, PUFA and vitamin D and the prevalence of psychotic-like symptoms in a population-based study among Swedish women.</p> <p>Methods</p> <p>Dietary intake was estimated using a food frequency questionnaire among 33 623 women aged 30-49 years at enrolment (1991/92). Information on psychotic-like symptoms was derived from a follow-up questionnaire in the years 2002/03. Participants were classified into three predefined levels: low, middle and high frequency of symptoms. The association between diet and psychotic-like symptoms was summarized in terms of relative risks (RR) and corresponding 95% confidence intervals and was evaluated by energy-adjusted multinomial logistic regression.</p> <p>Results</p> <p>18 411 women were classified as having a low level of psychotic-like symptoms, 14 395 as middle and 817 as having a high level. The risk of high level symptoms was 53% (95% CI, 30-69%) lower among women who ate fish 3-4 times per week compared to women who never ate fish. The risk was also lower for women with a high intake of omega-3 and omega-6 PUFA compared to women with a lower intake of these fatty acids. The effect was most pronounced for omega-6 PUFAs. The RR comparing the highest to the lowest quartile of omega-6 PUFAs intake was 0.78 (95% CI, 0.64-0.97). The associations were J-shaped with the strongest reduced risk for an intermediate intake of fish or PUFA. For fatty fish (herring/mackerel, salmon-type fish), the strongest inverse association was found for an intermediate intake (RR: 0.81, 95% CI, 0.66-0.98), whereas a high intake of fatty fish was associated with an increased risk of psychotic-like symptoms (RR: 1.90, 95% CI, 1.34-2.70). Women in the highest compared with the lowest quartile of vitamin D consumption experienced a 37% (95% CI, 22-50%) lower risk of psychotic-like symptoms.</p> <p>Conclusion</p> <p>Our findings raise a possibility that adult women with a high intake of fish, omega-3 or omega-6 PUFA and vitamin D have a lower rate of psychotic-like symptoms.</p

Integrated Heart - Coupling multiscale and multiphysics models for the simulation of the cardiac function

Mathematical modelling of the human heart and its function can expand our understanding of various cardiac diseases, which remain the most common cause of death in the developed world. Like other physiological systems, the heart can be understood as a complex multiscale system involving interacting phenomena at the molecular, cellular, tissue, and organ levels. This article addresses the numerical modelling of many aspects of heart function, including the interaction of the cardiac electrophysiology system with contractile muscle tissue, the sub-cellular activation-contraction mechanisms, as well as the hemodynamics inside the heart chambers. Resolution of each of these sub-systems requires separate mathematical analysis and specially developed numerical algorithms, which we review in detail. By using specific sub-systems as examples, we also look at systemic stability, and explain for example how physiological concepts such as microscopic force generation in cardiac muscle cells, translate to coupled systems of differential equations, and how their stability properties influence the choice of numerical coupling algorithms. Several numerical examples illustrate three fundamental challenges of developing multiphysics and multiscale numerical models for simulating heart function, namely: (i) the correct upscaling from single-cell models to the entire cardiac muscle, (ii) the proper coupling of electrophysiology and tissue mechanics to simulate electromechanical feedback, and (iii) the stable simulation of ventricular hemodynamics during rapid valve opening and closure

Student politics, teaching politics, black politics: an interview with Ansel Wong

Ansel Wong is the quiet man of British black politics, rarely in the limelight and never seeking political office. And yet his ‘career’ here – from Black Power firebrand to managing a multimillion budget as head of the Greater London Council’s Ethnic Minority Unit in the 1980s – spells out some of the most important developments in black educational and cultural projects. In this interview, he discusses his identification with Pan-Africanism, his involvement in student politics, his role in the establishment of youth projects and supplementary schools in the late 1960s and 1970s, and his involvement in black radical politics in London in the same period, all of which took place against the background of revolutionary ferment in the Third World and the world of ideas, and were not without their own internal class and ethnic conflicts