text: Medicine https://hdl.handle.net/2123/3947 2020-04-02T06:39:12Z 2020-04-02T06:39:12Z EFFECTS OF INTENSIVE DIET AND EXERCISE ON KNEE JOINT LOADS, INFLAMMATION, AND CLINICAL OUTCOMES AMONG OVERWEIGHT AND OBESE ADULTS WITH KNEE OSTEOARTHRITIS Messier, Stephen P Mihalko, Shannon L Legault, Claudine Miller, Gary D. Nicklas, Barbara J. DeVita, Paul Beavers, Daniel P Hunter, David J. Lyles, Mary F. Eckstein, Felix Williamson, Jeff D Carr, J. Jeffery Guermazi, Ali Loeser, Richard F. https://hdl.handle.net/2123/10302 2014-10-16T15:18:37Z 2013-01-01T00:00:00Z EFFECTS OF INTENSIVE DIET AND EXERCISE ON KNEE JOINT LOADS, INFLAMMATION, AND CLINICAL OUTCOMES AMONG OVERWEIGHT AND OBESE ADULTS WITH KNEE OSTEOARTHRITIS Messier, Stephen P; Mihalko, Shannon L; Legault, Claudine; Miller, Gary D.; Nicklas, Barbara J.; DeVita, Paul; Beavers, Daniel P; Hunter, David J.; Lyles, Mary F.; Eckstein, Felix; Williamson, Jeff D; Carr, J. Jeffery; Guermazi, Ali; Loeser, Richard F. Importance Knee osteoarthritis (OA), a common cause of chronic pain and disability, has biomechanical and inflammatory origins and is exacerbated by obesity. Objective To determine whether a ≥10% reduction in body weight induced by diet, with or without exercise, would improve mechanistic and clinical outcomes more than exercise alone. Design, Setting, and Participants Single-blind, 18-month, randomized clinical trial at Wake Forest University between July 2006 and April 2011. The diet and exercise interventions were center-based with options for the exercise groups to transition to a home-based program. Participants were 454 overweight and obese older community-dwelling adults (age ≥55 years with body mass index of 27-41) with pain and radiographic knee OA. Interventions Intensive diet-induced weight loss plus exercise, intensive diet-induced weight loss, or exercise. Main Outcomes and Measures Mechanistic primary outcomes: knee joint compressive force and plasma IL-6 levels; secondary clinical outcomes: self-reported pain (range, 0-20), function (range, 0-68), mobility, and health-related quality of life (range, 0-100). Results Three hundred ninety-nine participants (88%) completed the study. Mean weight loss for diet + exercise participants was 10.6 kg (11.4%); for the diet group, 8.9 kg (9.5%); and for the exercise group, 1.8 kg (2.0%). After 18 months, knee compressive forces were lower in diet participants (mean, 2487 N; 95% CI, 2393 to 2581) compared with exercise participants (2687 N; 95% CI, 2590 to 2784, pairwise difference [Δ]exercise vs diet = 200 N; 95% CI, 55 to 345; P = .007). Concentrations of IL-6 were lower in diet + exercise (2.7 pg/mL; 95% CI, 2.5 to 3.0) and diet participants (2.7 pg/mL; 95% CI, 2.4 to 3.0) compared with exercise participants (3.1 pg/mL; 95% CI, 2.9 to 3.4; Δexercise vs diet + exercise = 0.39 pg/mL; 95% CI, −0.03 to 0.81; P = .007; Δexercise vs diet = 0.43 pg/mL; 95% CI, 0.01 to 0.85, P = .006). The diet + exercise group had less pain (3.6; 95% CI, 3.2 to 4.1) and better function (14.1; 95% CI, 12.6 to 15.6) than both the diet group (4.8; 95% CI, 4.3 to 5.2) and exercise group (4.7; 95% CI, 4.2 to 5.1, Δexercise vs diet + exercise = 1.02; 95% CI, 0.33 to 1.71; Ppain = .004; 18.4; 95% CI, 16.9 to 19.9; Δexercise vs diet + exercise, 4.29; 95% CI, 2.07 to 6.50; Pfunction < .001). The diet + exercise group (44.7; 95% CI, 43.4 to 46.0) also had better physical health-related quality of life scores than the exercise group (41.9; 95% CI, 40.5 to 43.2; Δexercise vs diet + exercise = −2.81; 95% CI, −4.76 to −0.86; P = .005). Conclusions and Relevance Among overweight and obese adults with knee OA, after 18 months, participants in the diet + exercise and diet groups had more weight loss and greater reductions in IL-6 levels than those in the exercise group; those in the diet group had greater reductions in knee compressive force than those in the exercise group. 2013-01-01T00:00:00Z A Randomized Trial of Realignment Therapy for Treatment of Medial Tibiofemoral Osteoarthritis Hunter, David J. Gross, K. Douglas McCree, Paula Li, Ling Hirko, Kelly Harvey, William F https://hdl.handle.net/2123/10025 2015-02-08T23:28:52Z 2009-09-01T00:00:00Z A Randomized Trial of Realignment Therapy for Treatment of Medial Tibiofemoral Osteoarthritis Hunter, David J.; Gross, K. Douglas; McCree, Paula; Li, Ling; Hirko, Kelly; Harvey, William F Objectives: The objective of this 30-week randomized crossover trial was to determine whether a multi-modal realignment therapy would be successful in relieving pain and improving function among persons with medial tibiofemoral OA. METHODS: We conducted a double blind, randomized crossover trial of a multi-modal realignment therapy for persons with medial tibiofemoral OA. Trial participants met ACR criteria for OA with knee pain, aching or stiffness on most days of the past month and radiographic evidence of a definite osteophyte with predominant medial tibiofemoral OA. We tested two different treatments: A) CONTROL TREATMENT consisting of a neutral knee brace (no valgus angulation), flat unsupportive foot orthoses, and shoes with a flexible midsole; and B) ACTIVE TREATMENT consisting of a valgus knee brace, customized neutral foot orthoses, and shoes designed for motion control. For each subject, the trial lasted 30 weeks, including 12 weeks each of active and control treatment separated by a 6-week washout period. The primary outcome of the linear regression model was change in knee pain and function as assessed by the WOMAC Osteoarthritis Index. RESULTS: 80 participants with medial tibiofemoral OA were randomized. Their mean age was 62 years, mean BMI was 34 kg/m2 and mean WOMAC pain score was 9.2 (0-20 scale). There was no evidence of a carryover effect. The regression model demonstrated that the mean difference in pain between the active and control treatments was -1.82 units (95% confidence interval: -3.05 to -0.60 [p=0.004]) on the WOMAC pain scale, indicating a small, but statistically significant decrease in pain with the multi-modal active treatment. For WOMAC function the realignment intervention had a non-significant effect on function with a -2.90 unit decrease (95% CI -6.60 to 0.79) compared with the control condition (p=0.12). CONCLUSION: Multi-modal realignment therapy decreases pain in persons with medial tibiofemoral OA. 2009-09-01T00:00:00Z Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears. Stein, Verena Li, Ling Guermazi, Ali Zhang, Yuqing Kwoh, C. Kent Eaton, Charles B Hunter, David J. https://hdl.handle.net/2123/9977 2014-11-21T00:05:31Z 2012-02-01T00:00:00Z Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears. Stein, Verena; Li, Ling; Guermazi, Ali; Zhang, Yuqing; Kwoh, C. Kent; Eaton, Charles B; Hunter, David J. OBJECTIVE: The aim of this study was to evaluate the morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis (OA) of the knee. METHODS: One hundred fifty-eight knee joints from 133 patients that subsequently underwent total knee joint arthroplasty from January 2008 to December 2009 were enrolled. There were 26 men and 107 women. Their ages ranged from 56 to 81 (mean 67.4 + 6.5 years). All study participants had complete obliteration of the lateral joint space identified by weight-bearing radiography. Meniscal position was assessed by measuring meniscal subluxation and meniscal height. The meniscal morphology was assessed using a modification of the whole-organ magnetic resonance imaging score (WORMS). The frequency of different meniscal morphology and their respective positions was calculated. RESULTS: The predominant type (42.4%, 53.8% and 52.5% in the anterior horn, mid-body and posterior horn, respectively) of abnormal meniscal morphology was a complete maceration/destruction or complete resection. The anterior horn of non-macerated lateral meniscus was more subluxed than that of the non-macerated medial meniscus in patients with lateral OA. CONCLUSION: This study suggests that the lateral meniscus in persons with end-stage lateral OA are mostly macerated or destroyed. Also, unlike isolated end-staged medial compartment OA, the anterior horn of the lateral meniscus in isolated end-stage lateral OA is commonly affected. Copyright 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. 2012-02-01T00:00:00Z Side Differences of Thigh Muscle Cross-Sectional Areas and Maximal Isometric Muscle Force in Bilateral Knees with the Same Radiographic Disease Stage, but Unilateral Frequent Pain – Data from the Osteoarthritis Initiative Sattler, Martina Dannhauer, Torben Hudelmaier, Martin I Wirth, Wolfgang Sanger, Alexandra Kwoh, C. Kent Eckstein, Felix https://hdl.handle.net/2123/9976 2015-02-12T22:50:48Z 2012-06-01T00:00:00Z Side Differences of Thigh Muscle Cross-Sectional Areas and Maximal Isometric Muscle Force in Bilateral Knees with the Same Radiographic Disease Stage, but Unilateral Frequent Pain – Data from the Osteoarthritis Initiative Sattler, Martina; Dannhauer, Torben; Hudelmaier, Martin I; Wirth, Wolfgang; Sanger, Alexandra; Kwoh, C. Kent; Eckstein, Felix Objective To determine whether anatomical thigh muscle cross-sectional areas (MCSAs) and strength differ between osteoarthritis (OA) knees with frequent pain compared with contra-lateral knees without pain, and to examine the correlation between MCSAs and strength in painful vs painless knees. Methods Forty-eight subjects (31 women; 17 men; age 45–78 years) were drawn from 4,796 Osteoarthritis Initiative (OAI) participants, in whom both knees displayed the same radiographic stage (KLG2 or 3), one with frequent pain (most days of the month within the past 12 months) and the contra-lateral one without pain. Axial MR images were used to determine MCSAs of extensors, flexors and adductors at 35% femoral length (distal to proximal) and in two adjacent 5 mm images. Maximal isometric extensor and flexor forces were used as provided from the OAI database. Results Painful knees showed 5.2% lower extensor MCSAs (P = 0.00003; paired t-test), and 7.8% lower maximal extensor muscle forces (P = 0.003) than contra-lateral painless knees. There were no significant differences in flexor forces, or flexor and adductor MCSAs (P > 0.39). Correlations between force and MCSAs were similar in painful and painless OA knees (0.44 < r < 0.66). Conclusions Knees with frequent pain demonstrate lower MCSAs and force of the quadriceps (but not of other thigh muscles) compared with contra-lateral knees without knee pain with the same radiographic stage. Frequent pain does not appear to affect the correlations between MCSAs and strength in OA knees. The findings suggest that quadriceps strengthening exercise may be useful in treating symptomatic knee OA. 2012-06-01T00:00:00Z The MeTeOR Trial (Meniscal Tear in Osteoarthritis Research): Rationale and design features Katz, Jeffrey N. Chaisson, Christine E Cole, Brian Guermazi, Ali Hunter, David J. Jones, Morgan Levy, Bruce A Mandi, Lisa A Martin, Scott Marx, Robert G Safran-Norton, Clare Roemer, Frank W. Skoniecki, Debra Solomon, Daniel H. Spindler, Kurt P. Wright, John Wright, Rick W Losina, Elena https://hdl.handle.net/2123/9975 2014-12-10T00:27:20Z 2012-11-01T00:00:00Z The MeTeOR Trial (Meniscal Tear in Osteoarthritis Research): Rationale and design features Katz, Jeffrey N.; Chaisson, Christine E; Cole, Brian; Guermazi, Ali; Hunter, David J.; Jones, Morgan; Levy, Bruce A; Mandi, Lisa A; Martin, Scott; Marx, Robert G; Safran-Norton, Clare; Roemer, Frank W.; Skoniecki, Debra; Solomon, Daniel H.; Spindler, Kurt P.; Wright, John; Wright, Rick W; Losina, Elena This paper presents the rationale and design features of the MeTeOR Trial (Meniscal Tear in Osteoarthritis Research; Clinical Trials.gov NCT00597012). MeTeOR is an NIH-funded seven-center prospective randomized controlled trial (RCT) designed to establish the efficacy of arthroscopic partial meniscectomy combined with a standardized physical therapy program as compared with a standardized physical therapy program alone in patients with a symptomatic meniscal tear in the setting of mild to moderate knee osteoarthritic change (OA). The design and execution of a trial that compares surgery with a nonoperative treatment strategy presents distinctive challenges. The goal of this paper is to provide the clinical rationale for MeTeOR and to highlight salient design features, with particular attention to those that present clinical and methodologic challenges. 2012-11-01T00:00:00Z THE RELATIONSHIP OF TIBIAL BONE PERFUSION TO PAIN IN KNEE OSTEOARTHRITIS. Seah, S Wheaton, D Li, Ling Dyke, J P Talmo, C Harvey, William F Hunter, David J. https://hdl.handle.net/2123/9974 2015-02-08T23:28:12Z 2012-12-01T00:00:00Z THE RELATIONSHIP OF TIBIAL BONE PERFUSION TO PAIN IN KNEE OSTEOARTHRITIS. Seah, S; Wheaton, D; Li, Ling; Dyke, J P; Talmo, C; Harvey, William F; Hunter, David J. Objective To confirm altered perfusion within tibial bone marrow lesions (BMLs) and improve our understanding on the relationship between BMLs and pain in knee osteoarthritis (OA). Methods Participants with moderate to severe knee OA were recruited and pain was assessed using the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Subchondral tibial BMLs were identified and graded on magnetic resonance imaging (MRI) proton density-weighted (PDW) fat suppressed images. A pharmacokinetic model was used to analyze perfusion parameters on dynamic contrast enhanced (DCE) MRI which represent transfer rates in and out of the BMLs. The relation between perfusion and pain was evaluated using multivariable linear regression after adjustment for BML grade, age, gender and body mass index (BMI). Results There were 37 participants (mean age 64.9 years, range 46–86) with radiographic Kellgren and Lawrence grades of 3 and 4 in the study knee; 75.6% had BMLs that were classified grades 1 and 2. The mean WOMAC pain score was 10.3 (0–20 scale). There was a significant correlation between BML Kel (rate of contrast elimination) and BML grade (P = 0.001 univariate, P = 0.002 multivariate analyses), although we did not demonstrate any significant multivariate association between BML perfusion and pain. We also found an inverse relationship between pain at sleep and BML grade (P < 0.05). Conclusions The absence of any significant association between bone perfusion and pain implies that the relationship of tibial BMLs to pain in OA is still incompletely understood. BMLs are just one component of the whole knee joint and are formed from various causes, all of which interact and collectively contribute to the genesis of pain in OA. 2012-12-01T00:00:00Z Risk Factors for Medial Meniscus Posterior Root Tear Hwang, Byoung-Yoon Kim, Sung Jae Lee, Sang-Won Lee, Ha-Eun Lee, Choon-Key Hunter, David J. Jung, Kwang-Am https://hdl.handle.net/2123/9973 2014-11-10T00:42:28Z 2012-07-01T00:00:00Z Risk Factors for Medial Meniscus Posterior Root Tear Hwang, Byoung-Yoon; Kim, Sung Jae; Lee, Sang-Won; Lee, Ha-Eun; Lee, Choon-Key; Hunter, David J.; Jung, Kwang-Am Background: Medial meniscus posterior root tears (MMPRT) have a different clinical effect from other types of meniscal tears. These tears are very common among Asian people and may be related to the frequent use of postures such as the lotus position or squatting. Purpose: The present study was designed to identify the risk factors for MMPRT among an Asian sample. Study Design: Cohort study; Level of evidence, 3. Methods: An observational study was performed of 476 consecutive patients undergoing an arthroscopic procedure on their medial meniscus from January 2010 to December 2010. One hundred four patients had MMPRT (group 1), and the other patients had other types of medial meniscal tears (group 2). Demographic characteristics (age, sex, body mass index [BMI]), radiographic features (mechanical axis angle, tibia vara angle, tibial slope angle, Kellgren-Lawrence grade [KLG]), and environmental factors (occupation, trauma history, sports activity level, table use or not, bed use or not—variables that are representative of the oriental lifestyle of lotus position and squatting) were surveyed. We assessed the relation of these risk factors to the type of meniscal tear (group 1 or 2). Results: In group 1, there were 7 male and 97 female patients, with an average age of 58.2 years (range, 39-78 years) and BMI of 26.7 ± 3.4 kg/m2. In group 2, there were 136 male and 236 female patients (P < .01 compared with group 1), with an average age of 54.3 years (range, 17-77 years; P < .01) and a BMI of 24.9 ± 3.1 kg/m2 (P < .01). With regard to radiographic features, the mechanical axis angle demonstrated a significantly increased varus alignment in group 1 (4.5° ± 3.4°) compared with group 2 (2.4° ± 2.7°; P < .01), and the KLG was 1.4 ± 0.8 in group 1 and 0.9 ± 0.6 in group 2 (P < .01). Environmental factors showed no differences in occupation, table use or not, and bed use or not, except sports activity level. There were 41 patients (42.7%) in group 1 and 77 patients (20.6%) in group 2 who did not participate in any recreational activity (P < .01). Multiple logistic regression analysis showed that female sex was associated with a 5.9-fold increase in risk (95% confidence interval [CI], 2.138-16.575), a varus mechanical axis angle with a 3.3-fold increase (95% CI, 1.492-7.153), a BMI more than 30 kg/m2 with a 4.9-fold increase (95% CI, 1.160-20.955), and lower sports activity level with a 2.7-fold increase (95% CI, 1.011-7.163) for MMPRT. Conclusion: Persons with MMPRT had significantly increased age, female sex predominance, higher BMI, increased KLG, greater varus mechanical axis angle, and lower sports activity level compared with persons with other types of meniscal tear. After adjusting for other factors, sex, BMI, mechanical axis angle, and lower sports activity level remained strong determinants of MMPRT. Interestingly, oriental postural positions including the lotus position and squatting showed no contribution to increased risk of MMPRT. This suggests that intrinsic risk factors (similar to those that predispose to osteoarthritis) predispose to MMPRT. 2012-07-01T00:00:00Z Quantification of Walking Ability in Participants with Neurogenic Claudication from Lumbar Spinal Stenosis – A Comparative Study Rainville, James Childs, Lisa Pena, Enrique Suri, Pradeep Limke, Janet Jouve, Cristin Hunter, David J. https://hdl.handle.net/2123/9972 2014-11-10T00:40:53Z 2012-02-01T00:00:00Z Quantification of Walking Ability in Participants with Neurogenic Claudication from Lumbar Spinal Stenosis – A Comparative Study Rainville, James; Childs, Lisa; Pena, Enrique; Suri, Pradeep; Limke, Janet; Jouve, Cristin; Hunter, David J. Background context Walking limitations caused by neurogenic claudication (NC) are typically assessed with self-reported measures, although objective evaluation of walking using motorized treadmill test (MTT) or self-paced walking test (SPWT) has periodically appeared in the lumbar spinal stenosis (LSS) literature. Purpose This study compared the validity and responsiveness of MTT and SPWT for assessing walking ability before and after common treatments for NC. Study design Prospective observational cohort study. Patient sample Fifty adults were recruited from an urban spine center if they had LSS and substantial walking limitations from NC and were scheduled to undergo surgery (20%) or conservative treatment (80%). Outcome measures Walking times, distances, and speeds along with the characteristics of NC symptoms were recorded for MTT and SPWT. Self-reported measures included back and leg pain intensity assessed with 0 to 10 numeric pain scales, disability assessed with Oswestry Disability Index, walking ability assessed with estimated walking times and distances, and NC symptoms assessed with the subscales from the Spinal Stenosis Questionnaires. Methods Motorized treadmill test used a level track, and SPWT was conducted in a rectangular hallway. Walking speeds were self-selected, and test end points were NC, fatigue, or completion of the 30-minute test protocol. Results from MTT and SPWT were compared with each other and self-reported measures. Internal responsiveness was assessed by comparing changes in the initial results with the posttreatment results and external responsiveness by comparing walking test results that improved with those that did not improve by self-reported criteria. Results Mean age of the participants was 68 years, and 58% were male. Neurogenic claudication included leg pain (88%) and buttock(s) pain (12%). Five participants could not safely perform MTT. Walking speeds were faster and distances were greater with SPWT, although the results from both tests correlated with each other and self-reported measures. Of the participants, 72% reported improvement after treatment, which was confirmed by significant mean differences in self-reported measures. Motorized treadmill test results did not demonstrate internal responsiveness to change in clinical status after treatment but SPWT results did, with increased mean walking times (6 minutes) and distances (387 m). When responsiveness was assessed against external criterion, both SPWT and MTT demonstrated substantial divergence with self-reported changes in clinical status and alternative outcome measures. Conclusions Both MTT and SPWT can quantify walking abilities in NC. As outcome tools, SPWT demonstrated better internal responsiveness than MTT, but neither test demonstrated adequate external responsiveness. Neither test should be considered as a meaningful substitution for disease-specific measures of function 2012-02-01T00:00:00Z Purine-Rich Foods Intake and Recurrent Gout Attacks Zhang, Yuqing Chen, Clara Choi, Hyon Chaisson, Christine E Hunter, David J. Niu, Jingbo Neogi, Tuhina https://hdl.handle.net/2123/9971 2014-12-18T00:05:47Z 2012-09-01T00:00:00Z Purine-Rich Foods Intake and Recurrent Gout Attacks Zhang, Yuqing; Chen, Clara; Choi, Hyon; Chaisson, Christine E; Hunter, David J.; Niu, Jingbo; Neogi, Tuhina OBJECTIVE: To examine and quantify the relation between purine intake and the risk of recurrent gout attacks among gout patients. METHODS: The authors conducted a case-crossover study to examine associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed online for 1 year. Participants were asked about the following information when experiencing a gout attack: the onset date of the gout attack, clinical symptoms and signs, medications (including antigout medications), and presence of potential risk factors (including daily intake of various purine-containing food items) during the 2-day period prior to the gout attack. The same exposure information was also assessed over 2-day control periods. RESULTS: This study included 633 participants with gout. Compared with the lowest quintile of total purine intake over a 2-day period, OR of recurrent gout attacks were 1.17, 1.38, 2.21 and 4.76, respectively, with each increasing quintile (p for trend <0.001). The corresponding OR were 1.42, 1.34, 1.77 and 2.41 for increasing quintiles of purine intake from animal sources (p for trend <0.001), and 1.12, 0.99, 1.32 and 1.39 from plant sources (p=0.04), respectively. The effect of purine intake persisted across subgroups by sex, use of alcohol, diuretics, allopurinol, NSAIDs and colchicine. CONCLUSIONS: The study findings suggest that acute purine intake increases the risk of recurrent gout attacks by almost fivefold among gout patients. Avoiding or reducing amount of purine-rich foods intake, especially of animal origin, may help reduce the risk of gout attacks. 2012-09-01T00:00:00Z A Randomized Trial of Patellofemoral Bracing for Treatment of Patellofemoral Osteoarthritis Hunter, David J. Harvey, William F Gross, K. Douglas Felson, D McCree, P Li, Ling Hirko, Kelly Zhang, B Bennell, Kim L https://hdl.handle.net/2123/9970 2015-02-10T22:34:47Z 2011-07-01T00:00:00Z A Randomized Trial of Patellofemoral Bracing for Treatment of Patellofemoral Osteoarthritis Hunter, David J.; Harvey, William F; Gross, K. Douglas; Felson, D; McCree, P; Li, Ling; Hirko, Kelly; Zhang, B; Bennell, Kim L Purpose The number of effective knee osteoarthritis (OA) interventions, especially those tailored to specific compartmental involvement, are small. The objective of this study was to determine the efficacy of a realigning patellofemoral (PF) brace in improving pain and function among persons with symptomatic lateral PF OA. Method We conducted a double blind, randomized crossover trial of a realigning PF brace for persons with lateral PF OA. Participants had lateral PF OA with anterior knee symptoms on most days of the month, lateral PF joint space narrowing, and radiographic evidence of a definite osteophyte in the PF joint. We compared two treatments: (1) Control treatment consisting of a BioSkin Q Brace with patellar realigning strap removed; and (2) Active treatment consisting of a realigning BioSkin Q Brace with the strap applied. For each participant, the trial lasted 18 weeks, including 6 weeks each of active and control treatment period separated by a 6-week washout period. The order of treatments was randomized. The primary outcome was change in knee pain on the visual analog scale (VAS). Secondary outcomes included WOMAC pain, function, and stiffness. An unstructured correlation matrix for observations within participants was used in generalized estimating equation fitting to derive a linear regression model that expressed the relation between the intervention and change in VAS pain. Results 80 participants (63 F) with a mean age and body mass index of 61 years and 28 kg/m2, respectively, were randomized by order of treatment. A model examining the main effects for change in VAS knee pain (0–100) demonstrated no significant treatment effect (−0.68 VAS units, 95% CI: −6.2, 4.8 units, P = 0.81) and no differential carryover effect. There was also no significant difference between active and control treatments for WOMAC pain, function, or stiffness outcomes. Conclusion The effects of a specific realigning PF brace are not of clinical or statistical significance. 2011-07-01T00:00:00Z Prevalence of Anatomic Impediments to Interlaminar Lumbar Epidural Steroid Injection Hameed, Farah Hunter, David J. Rainville, James Li, Ling Suri, Pradeep https://hdl.handle.net/2123/9968 2014-11-10T00:40:34Z 2012-02-01T00:00:00Z Prevalence of Anatomic Impediments to Interlaminar Lumbar Epidural Steroid Injection Hameed, Farah; Hunter, David J.; Rainville, James; Li, Ling; Suri, Pradeep OBJECTIVE: To determine the prevalence of anatomic impediments to interlaminar lumbar epidural steroid injection (LESI) in a community-based population. DESIGN: Cross-sectional observational study. SETTING: Community-based. PARTICIPANTS: Older adults (N=333) sampled irrespective of back pain status. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Computed tomography evaluation of 5 potential anatomic impediments to interlaminar LESI at the L2-S1 spinal levels, including (1) ligamentum flavum (LF) calcification, (2) interspinous ligament (ISL) calcification, (3) spinous process (SP) contact, (4) the absence of epidural fat in the posterior epidural space, and (5) the presence of fat density superficial to the LF in the midsagittal plane. Independent variables included age, sex, body mass index (BMI), and current smoking. RESULTS: LF and ISL calcifications were prevalent in 3% to 7% and 2% to 3% of spinal levels, respectively, without significant differences by spinal level. SP contact was most common at the L4-5 level (22%). Absence of posterior epidural fat was very common at L5-S1 (65%), but infrequent at other levels. The presence of midline fat density superficial to LF was most common at L5-S1 (55%). The prevalence of LF calcification, ISL calcification, and SP contact increased with age, but the prevalence of absence of posterior epidural fat and the presence of a midline fat density superficial to LF did not. Sex and smoking status were not associated with the prevalence of anatomic impediments, but higher BMI was associated with a lower prevalence of absence of posterior epidural fat. CONCLUSIONS: Anatomic impediments to interlaminar LESI were common in this community-based population, particularly at the L5-S1 spinal level. Because of the high overall prevalence of anatomic impediments, and differences in prevalence by spinal level, knowledge of the distribution and frequency of these impediments may aid in aspects of decision-making for the interventional spine physician. Copyright 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved. 2012-02-01T00:00:00Z Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Eckstein, Felix Kwoh, C. Kent Boudreau, Robert M Wang, Zhiiie Hannon, Michael J Cotofana, Sebastian Hudelmaier, Martin I Wirth, Wolfgang Guermazi, Ali Nevitt, Michael John, Markus R. Hunter, David J. https://hdl.handle.net/2123/9967 2014-11-10T00:41:08Z 2013-05-01T00:00:00Z Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. Eckstein, Felix; Kwoh, C. Kent; Boudreau, Robert M; Wang, Zhiiie; Hannon, Michael J; Cotofana, Sebastian; Hudelmaier, Martin I; Wirth, Wolfgang; Guermazi, Ali; Nevitt, Michael; John, Markus R.; Hunter, David J. OBJECTIVE: Knee osteoarthritis commonly requires joint replacement, substantially reduces quality of life and increases healthcare utilisation and costs. This study aimed to identify whether quantitative measures of articular cartilage structure predict knee replacement, and to establish their utility as outcomes in clinical trials of disease-modifying therapy. METHODS: A nested case-control study was performed in Osteoarthritis Initiative participants, a multicentre observational cohort of 4796 participants with or at risk of knee osteoarthritis. 127 knees were replaced between baseline and 4 years follow-up, and one control knee per case matched for baseline radiographic disease stage (Kellgren-Lawrence grade; KLG), gender and age. Quantitative cartilage measures were obtained from 3 T magnetic resonance images at the exam before knee replacement, and longitudinal change during the previous 12 months when available (n=110). RESULTS: Cartilage thickness loss in the central and total medial femorotibial compartment (primary and secondary predictor variables) was significantly greater in case than control knees (AUC=0.59/0.58). Differences in cartilage loss were greater at earlier than later radiographic disease stages (p<0.01 for interaction with KLG). Cartilage thickness loss in the central tibia was the most predictive longitudinal measure (AUC=0.64). Denuded bone areas in the medial femur were the most predictive and discriminatory cross-sectional measure between case and control knees (AUC=0.66). CONCLUSIONS: This study demonstrates the predictive value of quantitative, MRI-based measures of cartilage for the clinically relevant endpoint of knee replacement, providing support for their utility in clinical trials to evaluate the effectiveness of structure-modifying intervention. 2013-05-01T00:00:00Z Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Williams, Frances M K Bansal, Aruna T van Meurs, Joyce B Bell, Jordana T Meulenbelt, Ingrid Suri, Pradeep Rivadeneira, Fernando Sambrook, Philip N Hofman, Albert Bierm-Zeinstra, Sita Menni, Cristina Kloppenburg, Megreet Slagboom, P Eline Hunter, David J. MacGregor, Alex J Uitterlinden, Andre G. Spector, Tim D https://hdl.handle.net/2123/9966 2014-11-10T00:39:39Z 2013-07-01T00:00:00Z Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Williams, Frances M K; Bansal, Aruna T; van Meurs, Joyce B; Bell, Jordana T; Meulenbelt, Ingrid; Suri, Pradeep; Rivadeneira, Fernando; Sambrook, Philip N; Hofman, Albert; Bierm-Zeinstra, Sita; Menni, Cristina; Kloppenburg, Megreet; Slagboom, P Eline; Hunter, David J.; MacGregor, Alex J; Uitterlinden, Andre G.; Spector, Tim D OBJECTIVE: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. METHODS: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. RESULTS: This study of 4600 individuals identified four single nucleotide polymorphisms with p<5x10(-8), the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8x10(-8)) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (beta=8.74x10(-4), p=0.006). CONCLUSIONS: LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway. 2013-07-01T00:00:00Z Morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis of the knee. Hwang, Seung Hyun Jung, Kwang-Am Lee, Won Jun Yang, Ki Hyuk Lee, Dong Won Carter, Aaron Hunter, David J. https://hdl.handle.net/2123/9965 2015-02-18T00:43:08Z 2012-02-01T00:00:00Z Morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis of the knee. Hwang, Seung Hyun; Jung, Kwang-Am; Lee, Won Jun; Yang, Ki Hyuk; Lee, Dong Won; Carter, Aaron; Hunter, David J. OBJECTIVE: The aim of this study was to evaluate the morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis (OA) of the knee. METHODS: One hundred fifty-eight knee joints from 133 patients that subsequently underwent total knee joint arthroplasty from January 2008 to December 2009 were enrolled. There were 26 men and 107 women. Their ages ranged from 56 to 81 (mean 67.4 + 6.5 years). All study participants had complete obliteration of the lateral joint space identified by weight-bearing radiography. Meniscal position was assessed by measuring meniscal subluxation and meniscal height. The meniscal morphology was assessed using a modification of the whole-organ magnetic resonance imaging score (WORMS). The frequency of different meniscal morphology and their respective positions was calculated. RESULTS: The predominant type (42.4%, 53.8% and 52.5% in the anterior horn, mid-body and posterior horn, respectively) of abnormal meniscal morphology was a complete maceration/destruction or complete resection. The anterior horn of non-macerated lateral meniscus was more subluxed than that of the non-macerated medial meniscus in patients with lateral OA. CONCLUSION: This study suggests that the lateral meniscus in persons with end-stage lateral OA are mostly macerated or destroyed. Also, unlike isolated end-staged medial compartment OA, the anterior horn of the lateral meniscus in isolated end-stage lateral OA is commonly affected. Copyright 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. 2012-02-01T00:00:00Z Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression Kraus, Virginia Byers Feng, Sheng Wang, Sheng Chu White, Scott Ainslie, Maureen Le Graverand, Marie-Pierre Hellio Brett, Alan Eckstein, Felix Hunter, David J. Lane, Nancy E Taljanovic, Mihra S. Schnitzer, Thomas Charles, H Cecil https://hdl.handle.net/2123/9964 2014-11-10T00:43:43Z 2013-07-01T00:00:00Z Subchondral Bone Trabecular Integrity Predicts and Changes Concurrently with Radiographic and MRI Determined Knee Osteoarthritis Progression Kraus, Virginia Byers; Feng, Sheng; Wang, Sheng Chu; White, Scott; Ainslie, Maureen; Le Graverand, Marie-Pierre Hellio; Brett, Alan; Eckstein, Felix; Hunter, David J.; Lane, Nancy E; Taljanovic, Mihra S.; Schnitzer, Thomas; Charles, H Cecil OBJECTIVE: To evaluate subchondral bone trabecular integrity (BTI) on radiographs as a predictor of knee osteoarthritis (OA) progression. METHODS: Longitudinal (baseline, 12-month, and 24-month) knee radiographs were available for 60 female subjects with knee OA. OA progression was defined by 12- and 24-month changes in radiographic medial compartment minimal joint space width (JSW) and medial joint space area (JSA), and by medial tibial and femoral cartilage volume on magnetic resonance imaging. BTI of the medial tibial plateau was analyzed by fractal signature analysis using commercially available software. Receiver operating characteristic (ROC) curves for BTI were used to predict a 5% change in OA progression parameters. RESULTS: Individual terms (linear and quadratic) of baseline BTI of vertical trabeculae predicted knee OA progression based on 12- and 24-month changes in JSA (P < 0.01 for 24 months), 24-month change in tibial (P < 0.05), but not femoral, cartilage volume, and 24-month change in JSW (P = 0.05). ROC curves using both terms of baseline BTI predicted a 5% change in the following OA progression parameters over 24 months with high accuracy, as reflected by the area under the curve measures: JSW 81%, JSA 85%, tibial cartilage volume 75%, and femoral cartilage volume 85%. Change in BTI was also significantly associated (P < 0.05) with concurrent change in JSA over 12 and 24 months and with change in tibial cartilage volume over 24 months. CONCLUSION: BTI predicts structural OA progression as determined by radiographic and MRI outcomes. BTI may therefore be worthy of study as an outcome measure for OA studies and clinical trials. Copyright 2013 by the American College of Rheumatology. 2013-07-01T00:00:00Z The association between reduced knee joint proprioception and medial meniscal abnormalities using MRI in knee osteoarthritis: results from the Amsterdam osteoarthritis cohort. van der Esch, Martin Knoop, Jesper Hunter, David J. Klein, Jan-Paul van der Leeden, Marike Knol, Dirk L Reiding, Dick Vooreman, Ramon E Gerritsen, Martijn Roorda, Leo D Lems, Willem F Dekker, Joost https://hdl.handle.net/2123/9963 2014-11-10T00:36:59Z 2013-05-01T00:00:00Z The association between reduced knee joint proprioception and medial meniscal abnormalities using MRI in knee osteoarthritis: results from the Amsterdam osteoarthritis cohort. van der Esch, Martin; Knoop, Jesper; Hunter, David J.; Klein, Jan-Paul; van der Leeden, Marike; Knol, Dirk L; Reiding, Dick; Vooreman, Ramon E; Gerritsen, Martijn; Roorda, Leo D; Lems, Willem F; Dekker, Joost BACKGROUND: Osteoarthritis (OA) of the knee is characterized by pain and activity limitations. In knee OA, proprioceptive accuracy is reduced and might be associated with pain and activity limitations. Although causes of reduced proprioceptive accuracy are divergent, medial meniscal abnormalities, which are highly prevalent in knee OA, have been suggested to play an important role. No study has focussed on the association between proprioceptive accuracy and meniscal abnormalities in knee OA. OBJECTIVE: To explore the association between reduced proprioceptive accuracy and medial meniscal abnormalities in a clinical sample of knee OA subjects. METHODS: Cross-sectional study in 105 subjects with knee OA. Knee proprioceptive accuracy was assessed by determining the joint motion detection threshold in the knee extension direction. The knee was imaged with a 3.0 T magnetic resonance (MR) scanner. Number of regions with medial meniscal abnormalities and the extent of abnormality in the anterior and posterior horn and body were scored according to the Boston-Leeds Osteoarthritis Knee Score (BLOKS) method. Multiple regression analyzes were used to examine whether reduced proprioceptive accuracy was associated with medial meniscal abnormalities in knee OA subjects. RESULTS: Mean proprioceptive accuracy was 2.9degree + 1.9degree. Magnetic resonance imaging (MRI)-detected medial meniscal abnormalities were found in the anterior horn (78%), body (80%) and posterior horn (90%). Reduced proprioceptive accuracy was associated with both the number of regions with meniscal abnormalities (P < 0.01) and the extent of abnormality (P = 0.02). These associations were not confounded by muscle strength, joint laxity, pain, age, gender, body mass index (BMI) and duration of knee complaints. CONCLUSION: This is the first study showing that reduced proprioceptive accuracy is associated with medial meniscal abnormalities in knee OA. The study highlights the importance of meniscal abnormalities in understanding reduced proprioceptive accuracy in persons with knee OA. Copyright 2013 Osteoarthritis Research Society International. All rights reserved 2013-05-01T00:00:00Z Quantitative Assessment of Abdominal Aortic Calcification and Disk Height Loss: The Framingham Study Suri, Pradeep Hunter, David J. Rainville, James Guermazi, Ali Katz, Jeffrey N. https://hdl.handle.net/2123/9961 2014-11-10T00:41:55Z 2012-04-01T00:00:00Z Quantitative Assessment of Abdominal Aortic Calcification and Disk Height Loss: The Framingham Study Suri, Pradeep; Hunter, David J.; Rainville, James; Guermazi, Ali; Katz, Jeffrey N. Abstract Background context Vascular disease has been proposed as a risk factor for disc height loss (DHL). Purpose To examine the relationship between quantitative measures of abdominal aortic calcifications (AACs) as a marker of vascular disease, and DHL, on computed tomography (CT). Study design Cross-sectional study in a community-based population. Patient sample Four hundred thirty-five participants from the Framingham Heart Study. Outcome measures Quantitative AAC scores assessed by CT were grouped as tertiles of "no" (reference), "low," and "high" calcification. Disc height loss was evaluated on CT reformations using a four-grade scale. For analytic purposes, DHL was dichotomized as moderate DHL of at least one level at L2–S1 versus less than moderate or no DHL. Methods We examined the association of AAC and DHL using logistic regression before and after adjusting for cardiovascular risk factors and before and after adjusting for age, sex, and body mass index (BMI). Results In crude analyses, low AAC (odds ratio [OR], 2.05 [1.27–3.30]; p=.003) and high AAC (OR, 2.24 [1.38–3.62]; p=.001) were strongly associated with DHL, when compared with the reference group of no AAC. Diabetes, hypercholesterolemia, hypertension, and smoking were not associated with DHL and did not attenuate the observed relationship between AAC and DHL. Adjustment for age, sex, and BMI markedly attenuated the associations between DHL and low AAC (OR, 1.20 [0.69–2.09]; p=.51) and high AAC (OR, 0.74 [0.36–1.53]; p=.42). Conclusions Abdominal aortic calcification was associated with DHL in this community-based population. This relationship was independent of cardiovascular risk factors. However, the association of AAC with DHL was explained by the effects of age, sex, and BMI. 2012-04-01T00:00:00Z Tibial coverage, meniscus position, size and damage in knees discordant for joint space narrowing - data from the Osteoarthritis Initiative. Bloecker, K Guermazi, Ali Wirth, W Benichou, O Kwoh, C. Kent Englund, M Hunter, David J. Resch, H Eckstein, Felix https://hdl.handle.net/2123/9960 2015-03-02T01:30:30Z 2013-03-01T00:00:00Z Tibial coverage, meniscus position, size and damage in knees discordant for joint space narrowing - data from the Osteoarthritis Initiative. Bloecker, K; Guermazi, Ali; Wirth, W; Benichou, O; Kwoh, C. Kent; Englund, M; Hunter, David J.; Resch, H; Eckstein, Felix INTRODUCTION: Meniscal extrusion is thought to be associated with less meniscus coverage of the tibial surface, but the association of radiographic disease stage with quantitative measures of tibial plateau coverage is unknown. We therefore compared quantitative and semi-quantitative measures of meniscus position and morphology in individuals with bilateral painful knees discordant on medial joint space narrowing (mJSN). METHODS: A sample of 60 participants from the first half (2,678 cases) of the Osteoarthritis Initiative cohort fulfilled the inclusion criteria: bilateral frequent pain, Osteoarthritis Research Society International (OARSI) mJSN grades 1-3 in one, no-JSN in the contra-lateral (CL), and no lateral JSN in either knee (43 unilateral mJSN1; 17 mJSN2/3; 22 men, 38 women, body mass index (BMI) 31.3 + 3.9 kg/m(2)). Segmentation and three-dimensional quantitative analysis of the tibial plateau and meniscus, and semi-quantitative evaluation of meniscus damage (magnetic resonance imaging (MRI) osteoarthritis knee score = MOAKS) was performed using coronal 3T MR images (MPR DESSwe and intermediate-weighted turbo spin echo (IW-TSE) images). CL knees were compared using paired t-tests (between-knee, within-person design). RESULTS: Medial tibial plateau coverage was 36 + 9% in mJSN1 vs 45 + 8% in CL no-JSN knees, and was 31 + 9% in mJSN2/3 vs 46 + 6% in no-JSN knees (both P < 0.001). mJSN knees showed greater meniscus extrusion and damage (MOAKS), but no significant difference in meniscus volume. No significant differences in lateral tibial coverage, lateral meniscus morphology or position were observed. CONCLUSIONS: Knees with medial JSN showed substantially less medial tibial plateau coverage by the meniscus. We suggest that the less meniscal coverage, i.e., less mechanical protection may be a reason for greater rates of cartilage loss observed in JSN knees. Copyright 2012 Osteoarthritis Research Society International. All rights reserved. 2013-03-01T00:00:00Z Osteoarthritis: What does imaging tell us about its etiology. Johnson, Victoria L Giuffre, Bruno M Hunter, David J. https://hdl.handle.net/2123/9959 2014-11-10T00:40:12Z 2012-11-01T00:00:00Z Osteoarthritis: What does imaging tell us about its etiology. Johnson, Victoria L; Giuffre, Bruno M; Hunter, David J. Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. Due to an aging population and increasing obesity, the incidence of OA is rising. The etiology of OA is multifactorial and complex; thus prevention of OA remains challenging. Risk factors can be divided into person-level factors such as age, sex, obesity, genetics, race/ethnicity, and diet, and joint-level factors including injury, malalignment, and abnormal loading of the joints. This review provides a brief overview of the person-level risk factors and a more in-depth analysis of those at the joint level. It is only through an improved understanding of risk factors for the disease that we may be able to intervene meaningfully and prevent its occurrence. 2012-11-01T00:00:00Z Lifetime risk and age of diagnosis of symptomatic knee osteoarthritis in the US Losina, Elena Weinstein, Alexander M. Reichmann, William M. Burbine, Sara A. Solomon, Daniel H. Daigle, Meghan E. Rome, Benjamin N. Chen, Stephanie P. Hunter, David J. Suter, Lisa G. Jordan, Joanne M. Katz, Jeffrey N. https://hdl.handle.net/2123/9958 2014-11-19T01:40:41Z 2013-05-01T00:00:00Z Lifetime risk and age of diagnosis of symptomatic knee osteoarthritis in the US Losina, Elena; Weinstein, Alexander M.; Reichmann, William M.; Burbine, Sara A.; Solomon, Daniel H.; Daigle, Meghan E.; Rome, Benjamin N.; Chen, Stephanie P.; Hunter, David J.; Suter, Lisa G.; Jordan, Joanne M.; Katz, Jeffrey N. OBJECTIVE: To estimate the incidence and lifetime risk of diagnosed symptomatic knee osteoarthritis (OA) and the age at diagnosis of knee OA based on self-reports in the US population. METHODS: We estimated the incidence of diagnosed symptomatic knee OA in the US by combining data on age-, sex-, and obesity-specific prevalence from the 2007-2008 National Health Interview Survey, with disease duration estimates derived from the Osteoarthritis Policy (OAPol) Model, a validated computer simulation model of knee OA. We used the OAPol Model to estimate the mean and median ages at diagnosis and lifetime risk. RESULTS: The estimated incidence of diagnosed symptomatic knee OA was highest among adults ages 55-64 years, ranging from 0.37% per year for nonobese men to 1.02% per year for obese women. The estimated median age at knee OA diagnosis was 55 years. The estimated lifetime risk was 13.83%, ranging from 9.60% for nonobese men to 23.87% in obese women. Approximately 9.29% of the US population is diagnosed with symptomatic knee OA by age 60 years. CONCLUSION: The diagnosis of symptomatic knee OA occurs relatively early in life, suggesting that prevention programs should be offered relatively early in the life course. Further research is needed to understand the future burden of health care utilization resulting from earlier diagnosis of knee OA. Copyright 2013 by the American College of Rheumatology. The definitive version is available at www3.interscience.wiley.com 2013-05-01T00:00:00Z Long term joint consequences of sporting activity: preventing and managing osteoarthritis in the athlete Bennell, Kim L Hunter, David J. Vicenzino, Bill https://hdl.handle.net/2123/9957 2014-11-10T00:38:34Z 2012-07-31T00:00:00Z Long term joint consequences of sporting activity: preventing and managing osteoarthritis in the athlete Bennell, Kim L; Hunter, David J.; Vicenzino, Bill Sports participation is associated with an increased risk of future osteoarthritis (OA), much of which results from joint injury. No strong evidence exists that moderate sporting activity in the presence of normal joints predisposes to OA. Whether high-level participation in sport, particularly impact-type sports, is truly associated with OA is unclear owing to difficulties in differentiating the confounding effect of joint injury. Attention to strategies that prevent joint injury in athletes is paramount. Evidence does support the use of targeted neuromuscular exercise programmes, ankle taping and/or bracing and equipment or rule changes to prevent joint injuries in athletes. Optimal injury management, including rehabilitation and surgery if appropriate, is needed to facilitate healing and address biomechanical and neuromuscular impairments to reduce the risk of re-injury and minimize the onset and extent of joint symptoms. Management of OA in athletes requires attention to load-reducing strategies, activity modification, muscle strengthening and weight control. 2012-07-31T00:00:00Z The Health and Structural Consequences of Acute Knee Injuries Involving Rupture of the Anterior Cruciate Ligament Riordan, Edward A Frobell, Richard B Roemer, Frank W. Hunter, David J. https://hdl.handle.net/2123/9953 2014-12-07T23:58:09Z 2013-02-01T00:00:00Z The Health and Structural Consequences of Acute Knee Injuries Involving Rupture of the Anterior Cruciate Ligament Riordan, Edward A; Frobell, Richard B; Roemer, Frank W.; Hunter, David J. Although there is an abundance of literature regarding the development of knee osteoarthritis after rupture of the anterior cruciate ligament (ACL), the mechanism underlying this link is not clear. Recent studies have reported that several factors may be predictive of the development of osteoarthritis, including damage to the menisci and articular cartilage during the initial trauma, altered knee biomechanics after injury, and episodic instability. This article summarizes recent developments in the understanding of the joint damage resulting from an ACL tear, and the influence that current and future treatment methods may have on the long-term progression to osteoarthritis. 2013-02-01T00:00:00Z 'Targeting care: tailoring non-surgical management according to clinical presentation' Eyles, Jillian Lucas, Barbara R Hunter, David J. https://hdl.handle.net/2123/9952 2014-11-10T00:43:16Z 2013-02-01T00:00:00Z 'Targeting care: tailoring non-surgical management according to clinical presentation' Eyles, Jillian; Lucas, Barbara R; Hunter, David J. International evidence-based guidelines recommend a multitude of nonsurgical treatment options for the management of osteoarthritis. This article summarizes the evidence available for patient characteristics that have been analyzed as potential predictors of response to nonsurgical interventions for patients with hip and knee osteoarthritis. The specific variables targeted for this review include body mass index, psychological factors, muscle strength, tibiofemoral alignment, radiographic changes, and signs of inflammation. Several studies provide moderate to good evidence of potential predictors of response to nonsurgical treatments, and areas for future research are illuminated. Copyright 2013 Elsevier Inc. All rights reserved. 2013-02-01T00:00:00Z Presence and Extent of Severe Facet Joint Osteoarthritis Are Associated with Back Pain in Older Adults Suri, Pradeep Hunter, David J. Rainville, James Guermazi, Ali Katz, Jeffrey N. https://hdl.handle.net/2123/9950 2014-11-10T00:41:22Z 2013-09-01T00:00:00Z Presence and Extent of Severe Facet Joint Osteoarthritis Are Associated with Back Pain in Older Adults Suri, Pradeep; Hunter, David J.; Rainville, James; Guermazi, Ali; Katz, Jeffrey N. Objective To determine whether the presence and extent of severe lumbar facet joint osteoarthritis (OA) are associated with back pain in older adults, accounting for disc height narrowing and other covariates. Design Two hundred and fifty-two older adults from the Framingham Offspring Cohort (mean age 67 years) were studied. Participants received standardized computed tomography (CT) assessments of lumbar facet joint OA and disc height narrowing at the L2–S1 interspaces using four-grade semi-quantitative scales. Severe facet joint OA was defined according to the presence and/or degree of joint space narrowing, osteophytosis, articular process hypertrophy, articular erosions, subchondral cysts, and intraarticular vacuum phenomenon. Severe disc height narrowing was defined as marked narrowing with endplates almost in contact. Back pain was defined as participant report of pain on most days or all days in the past 12 months. We used multivariable logistic regression to examine associations between severe facet joint OA and back pain, adjusting for key covariates including disc height narrowing, sociodemographics, anthropometrics, and health factors. Results Severe facet joint OA was more common in participants with back pain than those without (63.2% vs 46.7%; P = 0.03). In multivariable analyses, presence of any severe facet joint OA remained significantly associated with back pain (odds ratio (OR) 2.15 [95% confidence interval (CI) 1.13–4.08]). Each additional joint with severe OA conferred greater odds of back pain [OR per joint 1.20 (95% CI 1.02–1.41)]. Conclusions The presence and extent of severe facet joint OA on CT imaging are associated with back pain in community-based older adults, independent of sociodemographics, health factors, and disc height narrowing. 2013-09-01T00:00:00Z Osteoarthritis Preface Hunter, David J. https://hdl.handle.net/2123/9949 2014-11-10T00:39:53Z 2013-02-01T00:00:00Z Osteoarthritis Preface Hunter, David J. Osteoarthritis (OA) is the leading cause of disability among older adults. It is an incredibly prevalent condition affecting upward of 1 in 8 adults. Societal trends in aging, obesity, and increasing joint injury will lead to a doubling of the number of persons with OA in the next decade. In this context, this issue of Rheumatic Disease Clinics of North America is timely, as we envision this increasingly prevalent disabling condition in an era where health care expenditure is increasingly scrutinized. 2013-02-01T00:00:00Z Imaging of Osteoarthritis Guermazi, Ali Hayashi, Daichi Eckstein, Felix Hunter, David J. Duryea, Jeff Roemer, Frank W. https://hdl.handle.net/2123/9948 2014-11-10T00:38:46Z 2013-02-01T00:00:00Z Imaging of Osteoarthritis Guermazi, Ali; Hayashi, Daichi; Eckstein, Felix; Hunter, David J.; Duryea, Jeff; Roemer, Frank W. Osteoarthritis (OA) is the most prevalent joint disorder in the elderly, and there is no effective treatment. Imaging is essential for evaluating the synovial joint structures (including cartilage, meniscus, subchondral bone marrow and synovium) for diagnosis, prognosis, and follow-up. This article describes the roles and limitations of both conventional radiography and magnetic resonance (MR) imaging, and considers the use of other modalities (eg, ultrasonography, nuclear medicine, computed tomography [CT], and CT/MR arthrography) in clinical practice and OA research. The emphasis throughout is on OA of the knee. This article emphasizes research developments and literature evidence published since 2008. 2013-02-01T00:00:00Z Imaging Biomarker Validation and Qualification Report: 6th OARSI Workshop on Imaging in Osteoarthritis Combined with 3rd OA Biomarkers Workshop. Hunter, David J. Eckstein, Felix Kraus, Virginia Byers Lousina, Elena Sandell, Linda Guermazi, Ali https://hdl.handle.net/2123/9947 2014-11-10T00:38:05Z 2013-07-01T00:00:00Z Imaging Biomarker Validation and Qualification Report: 6th OARSI Workshop on Imaging in Osteoarthritis Combined with 3rd OA Biomarkers Workshop. Hunter, David J.; Eckstein, Felix; Kraus, Virginia Byers; Lousina, Elena; Sandell, Linda; Guermazi, Ali Summary The sixth Osteoarthritis Research Society International (OARSI) Workshop on Imaging in Osteoarthritis combined with the third osteoarthritis (OA) Biomarkers Workshop is the first to bring together the imaging and molecular biomarker communities to focus on clinical validation and qualification of OA biomarkers. The workshop was held in Hilton Head, SC, USA, from June 12–14, 2012; 138 attendees participated, including representatives from academia, pharmaceutical and magnetic resonance imaging (MRI) industries, Food and Drug Administration (FDA), and National Institutes of Health (NIH). Presentations and discussions raised awareness, consolidated knowledge, and identified strategies to overcome challenges for the development and application of imaging and biochemical biomarkers in OA research studies and clinical trials. Conclusion The OA research communities need to work alongside regulatory agencies across the world, to qualify and validate new chemical and imaging biomarkers for future research and clinical trials. 2013-07-01T00:00:00Z Disease-modifying drugs for knee osteoarthritis: can they be cost-effective? Losina, Elena Daigle, Meghan E. Reichmann, William M. Suter, Lisa G. Hunter, David J. Solomon, Daniel H. Walensky, Rochelle P. Jordan, Joanne M. Burbine, Sara A. Patiel, A. Daniel Katz, Jeffrey N. https://hdl.handle.net/2123/9946 2014-11-10T00:37:33Z 2013-05-01T00:00:00Z Disease-modifying drugs for knee osteoarthritis: can they be cost-effective? Losina, Elena; Daigle, Meghan E.; Reichmann, William M.; Suter, Lisa G.; Hunter, David J.; Solomon, Daniel H.; Walensky, Rochelle P.; Jordan, Joanne M.; Burbine, Sara A.; Patiel, A. Daniel; Katz, Jeffrey N. OBJECTIVE: Disease-modifying osteoarthritis drugs (DMOADs) are under development. Our goal was to determine efficacy, toxicity, and cost thresholds under which DMOADs would be a cost-effective knee OA treatment. DESIGN: We used the Osteoarthritis Policy Model, a validated computer simulation of knee OA, to compare guideline-concordant care to strategies that insert DMOADs into the care sequence. The guideline-concordant care sequence included conservative pain management, corticosteroid injections, total knee replacement (TKR), and revision TKR. Base case DMOAD characteristics included: 50% chance of suspending progression in the first year (resumption rate of 10% thereafter) and 30% pain relief among those with suspended progression; 0.5%/year risk of major toxicity; and costs of $1,000/year. In sensitivity analyses, we varied suspended progression (20-100%), pain relief (10-100%), major toxicity (0.1-2%), and cost ($1,000-$7,000). Outcomes included costs, quality-adjusted life expectancy, incremental cost-effectiveness ratios (ICERs), and TKR utilization. RESULTS: Base case DMOADs added 4.00 quality-adjusted life years (QALYs) and $230,000 per 100 persons, with an ICER of $57,500/QALY. DMOADs reduced need for TKR by 15%. Cost-effectiveness was most sensitive to likelihoods of suspended progression and pain relief. DMOADs costing $3,000/year achieved ICERs below $100,000/QALY if the likelihoods of suspended progression and pain relief were 20% and 70%. At a cost of $5,000, these ICERs were attained if the likelihoods of suspended progression and pain relief were both 60%. CONCLUSIONS: Cost, suspended progression, and pain relief are key drivers of value for DMOADs. Plausible combinations of these factors could reduce need for TKR and satisfy commonly cited cost-effectiveness criteria 2013-05-01T00:00:00Z Structural correlates of pain in joints with osteoarthritis. Hunter, David J. Guermazi, Ali Roemer, Frank Zhang, Yuqing Neogi, Tuhina https://hdl.handle.net/2123/9945 2014-11-10T00:43:05Z 2013-05-23T00:00:00Z Structural correlates of pain in joints with osteoarthritis. Hunter, David J.; Guermazi, Ali; Roemer, Frank; Zhang, Yuqing; Neogi, Tuhina Objective: To describe the insights on the epidemiology of pain-structure association and the ramifications of these studies for clinical trials. Design: Narrative review summarizing the pertinent literature in this area, summarizing some of the methodologic challenges inherent and proposing some research initiatives to further understanding of this complex science. Results: The predominant symptom in most patients presenting with osteoarthritis (OA) is pain. Over recent years a number of imaging based studies have narrowed the discord between structural findings on imaging and symptoms. The interpretation of pain in OA is still enigmatic and difficult to deal with both for clinicians and scientists. Conclusions: We would envisage that over the next few years many of the pressing questions pertaining to research into the structure pain relationship will continue to be addressed. With this, we can expect clinically appropriate therapeutic advance 2013-05-23T00:00:00Z Association between bone marrow lesions detected by magnetic resonance imaging and knee pain in community residents in Korea Kim, I. J. Kim, D. H. Jung, J. Y. Song, Y. W. Guermazi, Ali Crema, M. D. Hunter, David J. Kim, H. A. https://hdl.handle.net/2123/9944 2015-02-06T01:54:23Z 2013-05-01T00:00:00Z Association between bone marrow lesions detected by magnetic resonance imaging and knee pain in community residents in Korea Kim, I. J.; Kim, D. H.; Jung, J. Y.; Song, Y. W.; Guermazi, Ali; Crema, M. D.; Hunter, David J.; Kim, H. A. Objective: To describe the frequency of bonemarrowlesions (BMLs) detected bymagnetic resonance imaging (MRI), and to examine the association of BMLs with knee pain severity in community residents in Korea. Methods: Participants were randomly chosen from the population-based Hallym Aging Study, irrespective of whether they had knee osteoarthritis (OA) or pain. Demographic and knee pain data were obtained by questionnaire. Radiographic evaluations consisted of weight-bearing knee anteroposterior radiographs and 1.5-T MRI scans. MRI was performed in the dominant knees of subjects without knee pain and in the more symptomatic knees of subjects with knee pain. BMLs were graded according to the whole-organ MRI score. Results: The mean age of the 358 study subjects was 71.8 years, and 34.5% of subjects had radiographically detected knee OA. The prevalences of BMLs and large BMLs in the tibiofemoral compartments were 80.3% and 40.4%, respectively. After adjusting for age, sex, and body mass index, total and medial compartment BML scores were significantly associated with the presence of knee pain, and the association was stronger as the summary score for BML increased. In proportional regression analysis, knee pain severity increased with BML severity in any compartment and in the medial compartment. Conclusion: BMLs detected by MRI were highly prevalent in this elderly Asian population. BMLs were significantly linked to knee pain, and BML severity correlated with knee pain severity. BMLs may be important surrogate targets for monitoring pain and structure modification in OA therapeutics. 2013-05-01T00:00:00Z Acute low back pain is marked by variability: An internet-based pilot study Suri, Pradeep Rainville, James Fitzmaurice, Garrett M Katz, Jeffrey N. Jamison, Robert N Martha, Julia Hartigan, Carol Limke, Janet Jouve, Cristin Hunter, David J. https://hdl.handle.net/2123/9942 2014-11-19T01:52:53Z 2011-10-05T00:00:00Z Acute low back pain is marked by variability: An internet-based pilot study Suri, Pradeep; Rainville, James; Fitzmaurice, Garrett M; Katz, Jeffrey N.; Jamison, Robert N; Martha, Julia; Hartigan, Carol; Limke, Janet; Jouve, Cristin; Hunter, David J. BACKGROUND: Pain variability in acute LBP has received limited study. The objectives of this pilot study were to characterize fluctuations in pain during acute LBP, to determine whether self-reported 'flares' of pain represent discrete periods of increased pain intensity, and to examine whether the frequency of flares was associated with back-related disability outcomes. METHODS: We conducted a cohort study of acute LBP patients utilizing frequent serial assessments and Internet-based data collection. Adults with acute LBP (lasting <3 months) completed questionnaires at the time of seeking care, and at both 3-day and 1-week intervals, for 6 weeks. Back pain was measured using a numerical pain rating scale (NPRS), and disability was measured using the Oswestry Disability Index (ODI). A pain flare was defined as 'a period of increased pain lasting at least 2 hours, when your pain intensity is distinctly worse than it has been recently'. We used mixed-effects linear regression to model longitudinal changes in pain intensity, and multivariate linear regression to model associations between flare frequency and disability outcomes. RESULTS: 42 of 47 participants (89%) reported pain flares, and the average number of discrete flare periods per patient was 3.5 over 6 weeks of follow-up. More than half of flares were less than 4 hours in duration, and about 75% of flares were less than one day in duration. A model with a quadratic trend for time best characterized improvements in pain. Pain decreased rapidly during the first 14 days after seeking care, and leveled off after about 28 days. Patients who reported a pain flare experienced an almost 3-point greater current NPRS than those not reporting a flare (mean difference [SD] 2.70 [0.11]; p < 0.0001). Higher flare frequency was independently associated with a higher final ODI score (s [SE} 0.28 (0.08); p = 0.002). CONCLUSIONS: Acute LBP is characterized by variability. Patients with acute LBP report multiple distinct flares of pain, which correspond to discrete increases in pain intensity. A higher flare frequency is associated with worse disability outcomes. 2011-10-05T00:00:00Z Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population Suri, Pradeep Miyakoshi, Asako Hunter, David J. Jarvik, Jeffrey G Rainville, James Guermazi, Ali Li, Ling Katz, Jeffrey N. https://hdl.handle.net/2123/9941 2014-11-19T01:53:08Z 2011-09-13T00:00:00Z Does lumbar spinal degeneration begin with the anterior structures? A study of the observed epidemiology in a community-based population Suri, Pradeep; Miyakoshi, Asako; Hunter, David J.; Jarvik, Jeffrey G; Rainville, James; Guermazi, Ali; Li, Ling; Katz, Jeffrey N. Background- Prior studies that have concluded that disk degeneration uniformly precedes facet degeneration have been based on convenience samples of individuals with low back pain. We conducted a study to examine whether the view that spinal degeneration begins with the anterior spinal structures is supported by epidemiologic observations of degeneration in a community-based population. Methods- 361 participants from the Framingham Heart Study were included in this study. The prevalences of anterior vertebral structure degeneration (disk height loss) and posterior vertebral structure degeneration (facet joint osteoarthritis) were characterized by CT imaging. The cohort was divided into the structural subgroups of participants with 1) no degeneration, 2) isolated anterior degeneration (without posterior degeneration), 3) combined anterior and posterior degeneration, and 4) isolated posterior degeneration (without anterior structure degeneration). We determined the prevalence of each degeneration pattern by age group < 45, 45-54, 55-64, ≥65. In multivariate analyses we examined the association between disk height loss and the response variable of facet joint osteoarthritis, while adjusting for age, sex, BMI, and smoking. Results- As the prevalence of the no degeneration and isolated anterior degeneration patterns decreased with increasing age group, the prevalence of the combined anterior/posterior degeneration pattern increased. 22% of individuals demonstrated isolated posterior degeneration, without an increase in prevalence by age group. Isolated posterior degeneration was most common at the L5-S1 and L4-L5 spinal levels. In multivariate analyses, disk height loss was independently associated with facet joint osteoarthritis, as were increased age (years), female sex, and increased BMI (kg/m2), but not smoking. Conclusions- The observed epidemiology of lumbar spinal degeneration in the community-based population is consistent with an ordered progression beginning in the anterior structures, for the majority of individuals. However, some individuals demonstrate atypical patterns of degeneration, beginning in the posterior joints. Increased age and BMI, and female sex may be related to the occurrence of isolated posterior degeneration in these individuals. 2011-09-13T00:00:00Z Strength Training for Arthritis Trial (START): design and rationale Messier, Stephen P Mihalko, Shannon L Beavers, Daniel P Nicklas, Barbara J. DeVita, Paul Carr, J. Jeffery Hunter, David J. Williamson, Jeff D Bennell, Kim L Guermazi, Ali Lyles, Mary Loeser, Richard F. https://hdl.handle.net/2123/9940 2014-11-24T00:51:23Z 2013-01-01T00:00:00Z Strength Training for Arthritis Trial (START): design and rationale Messier, Stephen P; Mihalko, Shannon L; Beavers, Daniel P; Nicklas, Barbara J.; DeVita, Paul; Carr, J. Jeffery; Hunter, David J.; Williamson, Jeff D; Bennell, Kim L; Guermazi, Ali; Lyles, Mary; Loeser, Richard F. Background Muscle loss and fat gain contribute to the disability, pain, and morbidity associated with knee osteoarthritis (OA), and thigh muscle weakness is an independent and modifiable risk factor for it. However, while all published treatment guidelines recommend muscle strengthening exercise to combat loss of muscle mass and strength in knee OA patients, previous strength training studies either used intensities or loads below recommended levels for healthy adults or were generally short, lasting only 6 to 24 weeks. The efficacy of high-intensity strength training in improving OA symptoms, slowing progression, and affecting the underlying mechanisms has not been examined due to the unsubstantiated belief that it might exacerbate symptoms. We hypothesize that in addition to short-term clinical benefits, combining greater duration with high-intensity strength training will alter thigh composition sufficiently to attain long-term reductions in knee-joint forces, lower pain levels, decrease inflammatory cytokines, and slow OA progression. Methods/Design This is an assessor-blind, randomized controlled trial. The study population consists of 372 older (age ≥ 55 yrs) ambulatory, community-dwelling persons with: (1) mild-to-moderate medial tibiofemoral OA (Kellgren-Lawrence (KL) = 2 or 3); (2) knee neutral or varus aligned knee ( -2° valgus ≤ angle ≤ 10° varus); (3) 20 kg.m-2 ≥ BMI ≤ 45 kg.m-2; and (3) no participation in a formal strength-training program for more than 30 minutes per week within the past 6 months. Participants are randomized to one of 3 groups: high-intensity strength training (75-90% 1Repetition Maximum (1RM)); low-intensity strength training (30-40%1RM); or healthy living education. The primary clinical aim is to compare the interventions' effects on knee pain, and the primary mechanistic aim is to compare their effects on knee-joint compressive forces during walking, a mechanism that affects the OA disease pathway. Secondary aims will compare the interventions' effects on additional clinical measures of disease severity (e.g., function, mobility); disease progression measured by x-ray; thigh muscle and fat volume, measured by computed tomography (CT); components of thigh muscle function, including hip abductor strength and quadriceps strength, and power; additional measures of knee-joint loading; inflammatory and OA biomarkers; and health-related quality of life. Discussion Test-retest reliability for the thigh CT scan was: total thigh volume, intra-class correlation coefficients (ICC) = 0.99; total fat volume, ICC = 0.99, and total muscle volume, ICC = 0.99. ICC for both isokinetic concentric knee flexion and extension strength was 0.93, and for hip-abductor concentric strength was 0.99. The reliability of our 1RM testing was: leg press, ICC = 0.95; leg curl, ICC = 0.99; and leg extension, ICC = 0.98. Results of this trial will provide critically needed guidance for clinicians in a variety of health professions who prescribe and oversee treatment and prevention of OA-related complications. Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of optimal strength training has the potential for immediate and vital clinical impact. 2013-01-01T00:00:00Z Management of osteoarthritis of the knee Bennell, Kim L Hunter, David J. Hinman, Rana S https://hdl.handle.net/2123/9939 2014-11-10T00:38:57Z 2012-07-30T00:00:00Z Management of osteoarthritis of the knee Bennell, Kim L; Hunter, David J.; Hinman, Rana S Osteoarthritis is a chronic disease; management should be patient centred and coordinated, with attention to modifiable risk factors and comorbidities Focus on conservative non-drug treatment, particularly exercise; for overweight or obese patients weight loss is recommended Management should be evidence based; do not use interventions with high cost and risk that outweigh their benefits Use paracetamol or non-steroidal anti-inflammatory drugs for pain relief, with due attention to precautions and contraindications Refer patients to a physiotherapist for exercise, manual therapy, and gait aids; orthotist for bracing; psychologist for cognitive behavioural therapy; and dietitian for nutritional advice Do not use arthroscopy for pain management; refer patients for joint replacement only when symptoms are severe and other treatments have failed 2012-07-30T00:00:00Z The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston–Leeds Osteoarthritis Knee Score) Hunter, David J. https://hdl.handle.net/2123/9938 2014-11-10T00:42:41Z 2007-05-01T00:00:00Z The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston–Leeds Osteoarthritis Knee Score) Hunter, David J. Aim: MRI provides unparalleled visualisation of all the anatomical structures involved in the osteoarthritis (OA) process. There is a need for reliable methods of quantifying abnormalities of these structures. The aim of this work was to assess the reliability of a novel MRI scoring system for evaluating OA of the knee and explore the validity of the bone marrow lesion (BML) scoring component of this new tool. Methods: After review of the relevant literature, a collaborative group of rheumatologists and radiologists from centres in the UK and USA established preliminary anatomical divisions, items (necessarily broadly inclusive) and scaling for a novel semi-quantitative knee score. A series of iterative reliability exercises were performed to reduce the initial items, and the reliability of the resultant Boston–Leeds Osteoarthritis Knee Score (BLOKS) was examined. A further sample had both the BLOKS and WORMS (Whole Organ MRI Score) bone marrow lesion (BML) score performed to assess the construct validity (relation to knee pain) and longitudinal validity (prediction of cartilage loss) of each scoring method. Results: The BLOKS scoring method assesses nine intraarticular regions and contains eight items, including features of bone marrow lesions, cartilage, osteophytes, synovitis, effusions and ligaments. The scaling for each feature ranges from 0–3. The inter-reader reliability for the final BLOKS items ranged from 0.51 for meniscal extrusion up to 0.79 for meniscal tear. The reliability for other key features was 0.72 for BML grade, 0.72 for cartilage morphology, and 0.62 for synovitis. Maximal BML size on the BLOKS scale had a positive linear relation with visual analogue scale (VAS) pain, however the WORMS scale did not. Baseline BML was associated with cartilage loss on both BLOKS and WORMS scale. This association was stronger for BLOKS than WORMS. Conclusion: We have designed a novel scoring system for MRI OA knee, BLOKS, that demonstrates good reliability. Preliminary inspection of the validity of one of the components of this new tool supports the validity of the BLOKS BML scoring method over an existing instrument. Further iterative development will include validation for use in both clinical trials and epidemiological studies. 2007-05-01T00:00:00Z Regrowth resistance: low-level platinum resistance mediated by rapid recovery from platinum-induced cell-cycle arrest Stordal, Britta Davey, Ross https://hdl.handle.net/2123/5687 2012-05-01T17:15:14Z 2009-01-01T00:00:00Z Regrowth resistance: low-level platinum resistance mediated by rapid recovery from platinum-induced cell-cycle arrest Stordal, Britta; Davey, Ross The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum drug resistance developed from H69 human small-cell lung cancer cells with eight 4-day treatments of 200 ng/ml cisplatin and 400 ng/ml oxaliplatin, respectively. A recovery period was given between treatments to emulate the cycles of chemotherapy given in the clinic. The resistant cell lines were approximately twofold resistant to cisplatin and oxaliplatin, and were cross-resistant to both drugs. Platinum resistance was not associated with increased cellular glutathione, decreased accumulation of platinum or increased DNA repair capacity. The H69 platinum sensitive cells entered a lengthy 3-week growth arrest in response to low-level cisplatin or oxaliplatin treatment. This is an example of the coordinated response between the cell cycle and DNA repair. In contrast, the H69CIS200 and H69OX400 cells have an alteration in the cell cycle allowing them to rapidly proliferate post drug treatment. The resistant cell lines also have many chromosomal rearrangements most of which are not associated with the resistant phenotype, suggesting an increase in the genomic instability in the resistant cell lines. We hypothesized that there was a lack of coordination between the cell cycle and DNA repair in the resistant cell lines allowing proliferation in the presence of DNA damage which has created an increase in genomic instability. The H69 cells and resistant cell lines have mutant p53 and consequently decrease the expression of p21 in response to platinum drug treatment; promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. A decrease in ERCC1 protein expression and an increase in RAD51B foci activity were observed with the platinum-induced cell-cycle arrest and did not correlate with resistance or altered DNA repair capacity. These changes may, in part, be mediating and maintaining the cell-cycle arrest in place of p21.The rapidly proliferating resistant cells have restored the levels of both these proteins to their levels in untreated cells. We use the term "regrowth resistance" to describe this low-level platinum resistance where cells survive treatment through increased proliferation. Regrowth resistance may play a role in the onset of clinical resistance. 2009-01-01T00:00:00Z Treating cisplatin-resistant cancer: a systematic analysis of oxaliplatin or paclitaxel salvage chemotherapy. Stordal, Britta Pavlakis, Nick Davey, Ross https://hdl.handle.net/2123/5686 2012-05-01T17:15:14Z 2009-01-01T00:00:00Z Treating cisplatin-resistant cancer: a systematic analysis of oxaliplatin or paclitaxel salvage chemotherapy. Stordal, Britta; Pavlakis, Nick; Davey, Ross Objective: To examine the pre-clinical and clinical evidence for the use of oxaliplatin or paclitaxel salvage chemotherapy in patients with cisplatin-resistant cancer. Methods: Medline was searched for 1) Cell models of acquired resistance reporting cisplatin, oxaliplatin and paclitaxel sensitivities and 2) Clinical trials of single agent oxaliplatin or paclitaxel salvage therapy for cisplatin/carboplatin-resistant ovarian cancer. Results: Oxaliplatin - Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. In contrast, data in cell models suggests that there is crossresistance between cisplatin and oxaliplatin in cellular models with resistance levels which reflect clinical resistance (<10 fold). Oxaliplatin as a single agent had a poor response rate in patients with cisplatin-resistant ovarian cancer (8%, n=91). Oxaliplatin performed better in combination with other agents for the treatment of platinum-resistant cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer. Paclitaxel – Cellular data 2 suggests that paclitaxel is active in cisplatin-resistant cancer. 68.1% of cisplatinresistant cells were sensitive to paclitaxel. Paclitaxel as a single agent had a response rate of 22% in patients with platinum-resistant ovarian cancer (n = 1918), a significant increase from the response of oxaliplatin (p<0.01). Paclitaxel-resistant cells were also sensitive to cisplatin, suggesting that alternating between agents may be beneficial. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously received paclitaxel had an improved response rate of 35.3% n=232 (p<0.01), suggesting that pre-treatment with paclitaxel improves the response of salvage paclitaxel therapy. Conclusions: Cellular models reflect the resistance observed in the clinic as the cross resistant agent oxaliplatin has a lower response rate compared to the non-cross resistant agent paclitaxel in cisplatin-resistant ovarian cancer. Alternating therapy with cisplatin and paclitaxel may therefore lead to an improved response rate in ovarian cancer. 2009-01-01T00:00:00Z ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair Stordal, Britta Davey, Ross https://hdl.handle.net/2123/5685 2012-05-01T17:15:14Z 2008-06-25T00:00:00Z ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair Stordal, Britta; Davey, Ross Background: The H69CIS200 and H69OX400 cell lines are novel models of low- level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1. 2008-06-25T00:00:00Z A 39 kDa fragment of endogenous ASK1 suggests specific cleavage not degradation by the proteasome Stordal, Britta Davey, Ross https://hdl.handle.net/2123/5684 2012-05-01T17:15:14Z 2008-02-19T00:00:00Z A 39 kDa fragment of endogenous ASK1 suggests specific cleavage not degradation by the proteasome Stordal, Britta; Davey, Ross Transfected human ASK1 produces a 150kDa protein. However, we have detected endogenous ASK1 predominantly as 39kDa and 50kDa C-terminal and 75kDa and 110kDa N-terminal fragments in a panel of non-transfected cancer cell lines and HUVEC endothelial cells. This suggests that in non-apoptotic cells, endogenous ASK1 protein is normally cleaved at a number of specific sites, some of which are in the kinase domain. Transfected ASK1 protein is known to be degraded by the proteasome. In contrast, the cleavage of endogenous ASK1 is independent of the proteasome as treatment with the proteasome inhibitor, lactacystin did not inhibit cleavage. Cisplatin treatment decreased the amount of 39kDa C-terminal ASK1 fragment in mutant p53 cell lines suggesting a decrease in cleavage associated with apoptosis. Transfected ASK1 may therefore not accurately reflect the role of endogenous ASK1. 2008-02-19T00:00:00Z A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship Stordal, Britta Pavlakis, Nick Davey, Ross https://hdl.handle.net/2123/4068 2009-02-24T11:30:11Z 2007-01-01T00:00:00Z A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship Stordal, Britta; Pavlakis, Nick; Davey, Ross We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for 1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and 2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. 137 models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs docetaxel, carboplatin vs paclitaxel and carboplatin vs docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. 65 eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3% n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01 Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5% n=88 compared to 49.4% n=85 for paclitaxel combined with other agents (p<0.001 Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets. 2007-01-01T00:00:00Z Understanding cisplatin resistance using cellular models Stordal, Britta Davey, Mary W https://hdl.handle.net/2123/4067 2014-12-18T02:27:20Z 2007-01-01T00:00:00Z Understanding cisplatin resistance using cellular models Stordal, Britta; Davey, Mary W Many mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 μg/ml. Cisplatin resistance in these cells correlated with increases in the antioxidant glutathione, yet treatment with buthionine sulphoximine, an inhibitor of glutathione synthesis, had no effect on resistance, suggesting that the increase in glutathione was not directly involved in cisplatin resistance. Two models were developed from H69 SCLC cells, H69-CP and H69CIS200 using 100 ng/ml or 200 ng/ml cisplatin respectively. Both cell models were 2-4 fold resistant to cisplatin, and have decreased expression of p21 which may increase the cell's ability to progress through the cell cycle in the presence of DNA damage. Both the H69-CP and H69CIS200 cells showed no decrease in cellular cisplatin accumulation. However, the H69-CP cells have increased levels of cellular glutathione and are cross resistant to radiation whereas the H69CIS200 cells have neither of these changes. This suggests that increases in glutathione may contribute to cross-resistance to other drugs and radiation, but not directly to cisplatin resistance. There are multiple resistance mechanisms induced by cisplatin treatment, even in the same cell type. How then should cisplatin-resistant cancers be treated? Cisplatin-resistant cell lines are often more sensitive to another chemotherapeutic drug paclitaxel (H69CIS200), or are able to be sensitised to cisplatin with paclitaxel pre-treatment (H69-CP). The understanding of this sensitisation by paclitaxel using cell models of cisplatin resistance will lead to improvements in the clinical treatment of cisplatin resistant tumours. 2007-01-01T00:00:00Z Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review Stordal, Britta Pavlakis, Nick Davey, Ross https://hdl.handle.net/2123/4066 2009-02-24T11:30:10Z 2007-01-01T00:00:00Z Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review Stordal, Britta; Pavlakis, Nick; Davey, Ross Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. We undertook a systematic review of the literature to identify, describe and critique the clinical and pre-clinical evidence for the use of oxaliplatin in patients with "cisplatin-resistant" cancer. We identified 25 pre-clinical cell models of platinum resistance and 24 clinical trials reporting oxaliplatin based salvage therapy for cisplatin-resistant cancer. The pre-clinical data suggests that there is cross-resistance between cisplatin and oxaliplatin in low-level resistance models. In models with high level resistance (>10 fold) there is less cross resistance between cisplatin and oxaliplatin, which may be a reason why oxaliplatin is thought to be active in cisplatin-resistant cancer. In clinical trials where oxaliplatin has been used as part of salvage therapy for patients who have failed cisplatin or carboplatin combination chemotherapy, there was a much lower response rate in patients with platinum-refractory or resistant cancers compared to platinum-sensitive cancers. This suggests that there may be cross-resistance between cisplatin and oxaliplatin in the clinic. Oxaliplatin as a single agent had a poor response rate in cisplatin refractory and resistant cancer. Oxaliplatin performed better in combination with other agents for the treatment of platinum resistant/refractory cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer. 2007-01-01T00:00:00Z Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells Stordal, Britta K Davey, Mary W Davey, Ross https://hdl.handle.net/2123/4065 2014-12-18T02:27:49Z 2006-01-01T00:00:00Z Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells Stordal, Britta K; Davey, Mary W; Davey, Ross Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold)resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC. 2006-01-01T00:00:00Z