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Gonzalez P.N.,University of Calgary | Gonzalez P.N.,McCaig Institute for Bone and Joint Health | Gonzalez P.N.,Alberta Childrens Hospital Research Institute for Child and Maternal Health | Gonzalez P.N.,CONICET | And 7 more authors.
Evolution and Development | Year: 2013

Organism size is controlled by interactions between genetic and environmental factors mediated by hormones with systemic and local effects. As changes in size are usually not isometric, a considerable diversity in shape can be generated through modifications in the patterns of ontogenetic allometry. In this study we evaluated the role of timing and dose of growth hormone (GH) release on growth and correlated shape changes in craniofacial bones. Using a longitudinal study design, we analyzed GH deficient mice treated with GH supplementation commencing pre- and post-puberty. We obtained 3D in vivo micro-CT images of the skull between 21 and 60 days of age and used geometric morphometrics to analyze size and shape changes among control and GH deficient treated and non-treated mice. The variable levels of circulating GH altered the size and shape of the adult skull, and influenced the cranial base, vault, and face differently. While cranial base synchondroses and facial sutures were susceptible to either the direct or indirect effect of GH supplementation, its effect was negligible on the vault. Such different responses support the role of intrinsic growth trajectories of skeletal components in controlling the modifications induced by systemic factors. Contrary to the expected, the timing of GH treatment did not have an effect on catch-up growth. GH levels also altered the ontogenetic trajectories by inducing changes in their location and extension in the shape space, indicating that differences arose before 21 days and were further accentuated by a truncation of the ontogenetic trajectories in GHD groups. © 2013 Wiley Periodicals, Inc.


News Article | February 22, 2017
Site: www.eurekalert.org

New study highlights the need for heightened prevention and management of depression in psoriasis patients, reports the Journal of Investigative Dermatology Philadelphia, PA, February 22, 2017 - Psoriasis is a lifelong disease that is associated with significant cosmetic and physical disability and puts patients at increased risk for many major medical disorders. A multidisciplinary team of researchers at the University of Calgary, Canada, have found that psoriasis patients who developed depression were at a 37% greater risk of subsequently developing psoriatic arthritis, compared with psoriasis patients who did not develop depression. Their findings are published in the Journal of Investigative Dermatology. Psoriasis is a long-lasting inflammatory skin disease characterized by red, itchy, and scaly patches of skin. Approximately 8.5% of psoriasis patients have psoriatic arthritis, which is characterized by psoriasis plus inflammation of and around the joints. "For many years, the rheumatology and dermatology communities have been trying to understand which patients with psoriasis go on to develop psoriatic arthritis and how we might detect it earlier in the disease course," explained senior investigator Cheryl Barnabe, MD, MSc, of the McCaig Institute for Bone and Joint Health and the O'Brien Institute for Public Health, Cumming School of Medicine, at the University of Calgary, Alberta, Canada. Depression is common among patients with psoriasis. Based on recent laboratory work demonstrating that major depressive disorder is associated with increased systemic inflammation, the team of researchers hypothesized that psoriasis patients who develop depression are at increased risk of subsequently developing psoriatic arthritis. Investigators used The Health Improvement Network (THIN), a primary care medical records database in the United Kingdom, to identify over 70,000 patients with a new diagnosis of psoriasis. Through follow-up records, they identified individuals who subsequently developed depression and those who developed psoriatic arthritis. Patients were followed for up to 25 years or until they developed psoriatic arthritis. Statistical analysis showed that patients with psoriasis who developed major depressive disorder were at 37% greater risk of subsequently developing psoriatic arthritis compared with patients who did not develop depression, even after accounting for numerous other factors such as age and use of alcohol. The study highlights the need for physicians to manage patients with psoriasis to identify and address depression. This could include rapid, effective treatment of psoriasis and psychosocial management of the cosmetic burden of psoriasis. The study also draws into question the biological mechanisms by which depression increases the risk for developing psoriatic arthritis. These mechanisms may include altered systemic inflammation as a consequence of depression, or even the role of lifestyle behaviors such as physical activity or nutrition, which are typically worsened by depression, and which may place an individual at risk for psoriatic arthritis. "There is a tendency to think of depression as a purely 'psychological' or 'emotional' issue, but it also has physical effects and changes in inflammatory and immune markers have been reported in depressed people," commented Scott Patten, MD, PhD, the O'Brien Institute for Public Health, Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Cumming School of Medicine. "Depression may be a risk factor for a variety of chronic conditions and this research is an example of how big data approaches can identify these associations." Laurie Parsons, MD, of the Cumming School of Medicine, added: "It is evident to physicians who treat patients with psoriasis, that there is a significant psychological and social burden associated with this disease, which is reflected in an increase in the rates of depression. This study brings us a little closer to understanding the role of chronic inflammation as a systemic player in both the physical and psychological manifestations of psoriasis and underscores the need for closer attention to symptoms of depression in this group of patients." "This study raises important questions on the role of systemic inflammation, which is also elevated in depression, in driving a disease phenotype, which needs to be confirmed in clinical cohorts," concluded Dr Barnabe.


Lacny S.,University of Calgary | Wilson T.,University of Calgary | Clement F.,University of Calgary | Roberts D.J.,University of Calgary | And 7 more authors.
Clinical Orthopaedics and Related Research | Year: 2015

Background: Although Kaplan-Meier survival analysis is commonly used to estimate the cumulative incidence of revision after joint arthroplasty, it theoretically overestimates the risk of revision in the presence of competing risks (such as death). Because the magnitude of overestimation is not well documented, the potential associated impact on clinical and policy decision-making remains unknown. Questions/purposes: We performed a meta-analysis to answer the following questions: (1) To what extent does the Kaplan-Meier method overestimate the cumulative incidence of revision after joint replacement compared with alternative competing-risks methods? (2) Is the extent of overestimation influenced by followup time or rate of competing risks? Methods: We searched Ovid MEDLINE, EMBASE, BIOSIS Previews, and Web of Science (1946, 1980, 1980, and 1899, respectively, to October 26, 2013) and included article bibliographies for studies comparing estimated cumulative incidence of revision after hip or knee arthroplasty obtained using both Kaplan-Meier and competing-risks methods. We excluded conference abstracts, unpublished studies, or studies using simulated data sets. Two reviewers independently extracted data and evaluated the quality of reporting of the included studies. Among 1160 abstracts identified, six studies were included in our meta-analysis. The principal reason for the steep attrition (1160 to six) was that the initial search was for studies in any clinical area that compared the cumulative incidence estimated using the Kaplan-Meier versus competing-risks methods for any event (not just the cumulative incidence of hip or knee revision); we did this to minimize the likelihood of missing any relevant studies. We calculated risk ratios (RRs) comparing the cumulative incidence estimated using the Kaplan-Meier method with the competing-risks method for each study and used DerSimonian and Laird random effects models to pool these RRs. Heterogeneity was explored using stratified meta-analyses and metaregression. Results: The pooled cumulative incidence of revision after hip or knee arthroplasty obtained using the Kaplan-Meier method was 1.55 times higher (95% confidence interval, 1.43–1.68; p < 0.001) than that obtained using the competing-risks method. Longer followup times and higher proportions of competing risks were not associated with increases in the amount of overestimation of revision risk by the Kaplan-Meier method (all p > 0.10). This may be due to the small number of studies that met the inclusion criteria and conservative variance approximation. Conclusions: The Kaplan-Meier method overestimates risk of revision after hip or knee arthroplasty in populations where competing risks (such as death) might preclude the occurrence of the event of interest (revision). Competing-risks methods should be used to more accurately estimate the cumulative incidence of revision when the goal is to plan healthcare services and resource allocation for revisions. © 2015, The Association of Bone and Joint Surgeons®.


Nishiyama K.K.,University of Calgary | Nishiyama K.K.,McCaig Institute for Bone and Joint Health | Macdonald H.M.,University of British Columbia | Macdonald H.M.,Child and Family Research Institute | And 5 more authors.
Osteoporosis International | Year: 2013

High-resolution peripheral quantitative computed tomography (HR-pQCT) measurements of distal radius and tibia bone microarchitecture and finite element (FE) estimates of bone strength performed well at classifying postmenopausal women with and without previous fracture. The HR-pQCT measurements outperformed dual energy x-ray absorptiometry (DXA) at classifying forearm fractures and fractures at other skeletal sites. Introduction: Areal bone mineral density (aBMD) is the primary measurement used to assess osteoporosis and fracture risk; however, it does not take into account bone microarchitecture, which also contributes to bone strength. Thus, our objective was to determine if bone microarchitecture measured with HR-pQCT and FE estimates of bone strength could classify women with and without low-trauma fractures. Methods: We used HR-pQCT to assess bone microarchitecture at the distal radius and tibia in 44 postmenopausal women with a history of low-trauma fracture and 88 age-matched controls from the Calgary cohort of the Canadian Multicentre Osteoporosis Study (CaMos) study. We estimated bone strength using FE analysis and simulated distal radius aBMD from the HR-pQCT scans. Femoral neck (FN) and lumbar spine (LS) aBMD were measured with DXA. We used support vector machines (SVM) and a tenfold cross-validation to classify the fracture cases and controls and to determine accuracy. Results: The combination of HR-pQCT measures of microarchitecture and FE estimates of bone strength had the highest area under the receiver operating characteristic (ROC) curve of 0.82 when classifying forearm fractures compared to an area under the curve (AUC) of 0.71 from DXA-derived aBMD of the forearm and 0.63 from FN and spine DXA. For all fracture types, FE estimates of bone strength at the forearm alone resulted in an AUC of 0.69. Conclusion: Models based on HR-pQCT measurements of bone microarchitecture and estimates of bone strength performed better than DXA-derived aBMD at classifying women with and without prior fracture. In future, these models may improve prediction of individuals at risk of low-trauma fracture. © 2012 International Osteoporosis Foundation and National Osteoporosis Foundation.


Nishiyama K.K.,Columbia University | Nishiyama K.K.,McCaig Institute for Bone and Joint Health | Ito M.,Nagasaki University | Harada A.,National Center for Geriatrics and Gerontology | And 2 more authors.
Osteoporosis International | Year: 2014

Summary: We used quantitative computed tomography and finite element analysis to classify women with and without hip fracture. Highly accurate classifications were achieved indicating the potential for these methods to be used for subject-specific assessment of fracture risk. Introduction: Areal bone mineral density (aBMD) is the current clinical diagnostic standard for assessing fracture risk; however, many fractures occur in people not defined as osteoporotic by aBMD. Finite element (FE) analysis based on quantitative computed tomography (QCT) images takes into account both bone material and structural properties to provide subject-specific estimates of bone strength. Thus, our objective was to determine if FE estimates of bone strength could classify women with and without hip fracture. Methods: Twenty women with femoral neck fracture and 15 women with trochanteric fractures along with 35 age-matched controls were scanned with QCT at the hip. Since it is unknown how a specific subject will fall, FE analysis was used to estimate bone stiffness and bone failure load under loading configurations with femoral neck internal rotation angles ranging from -30° to 45° with 15° intervals. Support vector machine (SVM) models and a tenfold cross-validation scheme were used to classify the subjects with and without fracture. Results: High accuracy was achieved when using only FE analysis for classifying the women with and without fracture both when the fracture types were pooled (82.9%) and when analyzed separately by femoral neck fracture (87.5%) and trochanteric fracture (80.0%). The accuracy was further increased when FE analysis was combined with volumetric BMD (pooled fractures accuracy, 91.4%) Conclusions: While larger prospective studies are needed, these results demonstrate that FE analysis using multiple loading configurations together with SVM models can accurately classify individuals with previous hip fracture. © International Osteoporosis Foundation and National Osteoporosis Foundation 2013.


Desmeules F.,University of Montréal | Toliopoulos P.,University of Montréal | Roy J.-S.,Laval University | Roy J.-S.,The Interdisciplinary Center | And 8 more authors.
BMC Musculoskeletal Disorders | Year: 2013

Background: In Canada, new models of orthopaedic care involving advanced practice physiotherapists (APP) are being implemented. In these new models, aimed at improving the efficiency of care for patients with musculoskeletal disorders, APPs diagnose, triage and conservatively treat patients. Formal validation of the efficiency and appropriateness of these emerging models is scarce. The purpose of this study is to assess the diagnostic agreement of an APP compared to orthopaedic surgeons as well as to assess treatment concordance, healthcare resource use, and patient satisfaction in this new model. Methods. 120 patients presenting for an initial consult for hip or knee complaints in an outpatient orthopaedic hospital clinic in Montreal, Canada, were independently assessed by an APP and by one of three participating orthopaedic surgeons. Each health care provider independently diagnosed the patients and provided triage recommendations (conservative or surgical management). Proportion of raw agreement and Cohen's kappa were used to assess inter-rater agreement for diagnosis, triage, treatment recommendations and imaging tests ordered. Chi-Square tests were done in order to compare the type of conservative treatment recommendations made by the APP and the surgeons and Student t-tests to compare patient satisfaction between the two types of care. Results: The majority of patients assessed were female (54%), mean age was 54.1 years and 91% consulted for a knee complaint. The raw agreement proportion for diagnosis was 88% and diagnostic inter-rater agreement was very high (κ=0.86; 95% CI: 0.80-0.93). The triage recommendations (conservative or surgical management) raw agreement proportion was found to be 88% and inter-rater agreement for triage recommendation was high (κ=0.77; 95% CI: 0.65-0.88). No differences were found between providers with respect to imaging tests ordered (p≥0.05). In terms of conservative treatment recommendations made, the APP gave significantly more education and prescribed more NSAIDs, joint injections, exercises and supervised physiotherapy (p<0.05). Patient satisfaction was significantly higher for APP care than for the surgeons care (p<0.05). Conclusion: The diagnoses and triage recommendations for patients with hip and knee disorders made by the APP were similar to the orthopaedic surgeons. These results provide evidence supporting the APP model for orthopaedic care. © 2013 Desmeules et al.; licensee BioMed Central Ltd.


Weljie A.M.,University of Calgary | Bondareva A.,McCaig Institute for Bone and Joint Health | Zang P.,University of Calgary | Jirik F.R.,McCaig Institute for Bone and Joint Health
Journal of Biomolecular NMR | Year: 2011

Hypoxia can promote invasive behavior in cancer cells and alters the response to therapeutic intervention as a result of changes in the expression many genes, including genes involved in intermediary metabolism. Although metabolomics technologies are capable of simultaneously measuring a wide range of metabolites in an untargeted manner, these methods have been relatively under utilized in the study of cancer cell responses to hypoxia. Thus, 1H NMR metabolomics was used to examine the effects of hypoxia in the MDA-MB-231 human breast cancer cell line, both in vitro and in vivo. Cell cultures were compared with respect to their metabolic responses during growth under either hypoxic (1% O2) or normoxic conditions. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify a set of metabolites that were responsive to hypoxia. Via intracardiac administration, MDA-MB-231 cells were also used to generate widespread metastatic disease in immuno-compromised mice. Serum metabolite analysis was conducted to compare animals with and without a large tumor burden. Intriguingly, using a cross-plot of the OPLS loadings, both the in vitro and in vivo samples yielded a subset of metabolites that were significantly altered by hypoxia. These included primarily energy metabolites and amino acids, indicative of known alterations in energy metabolism, and possibly protein synthesis or catabolism. The results suggest that the metabolite pattern identified might prove useful as a marker for intra-tumoral hypoxia. © 2011 Springer Science+Business Media B.V.


Bertram K.L.,University of Calgary | Bertram K.L.,McCaig Institute for Bone and Joint Health | Krawetz R.J.,University of Calgary | Krawetz R.J.,McCaig Institute for Bone and Joint Health
Biochemical and Biophysical Research Communications | Year: 2012

Cartilage is one of few tissues where adult stem/progenitor cells have not been putatively identified. Recent studies have provided strong evidence that a sub-population of mesenchymal progenitor cells (MPCs) derived from the synovial fluid may be able to affect some degree of cartilage repair both in vivo and in vitro/ex vivo, however this does not appear to be the case in patients with arthritis. Previously, it has been found that synovial fluid osmolarity is decreased in patients with osteoarthritis (OA) or Rheumatoid arthritis (RA) and these changes in osmolarity have been linked to changes in chondrocyte gene regulation. However, it is yet unknown if changes in osmolarity regulate the gene expression in synovial fluid MPCs (sfMPCs), and by extension, chondrogenesis of this cell population. In the present study we have collected synovial fluid samples from normal, OA and RA knee joints, quantified the osmolarity of the fluid and modified the culture/differentiation media to span a range of osmolarities (264-375. mOsm). Chondrogenesis was measured with Alcian blue staining of cultures in addition to quantitative PCR (qPCR) using probes to Sox9, ACAN and Col2A1. Overall, sfMPCs from arthritic joints demonstrated decreased chondrogenic potential compared to sfMPCs isolated from normal synovial fluid. Furthermore, the sfMPCs retained increased chondrogenic potential if differentiated under the same osmolarity conditions for which they were initially derived within. In conclusion, it does appear the synovial fluid osmolarity regulates the chondrogenic potential of sfMPCs, however, further study is required to elucidate the mechanism by which the changes in osmolarity are sensed by the cells and regulate chondrogenic gene expression. © 2012.


Lacny S.,University of Calgary | Marshall D.A.,University of Calgary | Marshall D.A.,Alberta Bone and Joint Health Institute | Marshall D.A.,McCaig Institute for Bone and Joint Health | And 7 more authors.
British Journal of Sports Medicine | Year: 2014

Background/aim The risk of injury among Pee Wee (ages 11-12 years) ice hockey players in leagues that allow body checking is threefold greater than in leagues that do not allow body checking. We estimated the cost-effectiveness of a no body checking policy versus a policy that allows body checking in Pee Wee ice hockey. Methods Cost-effectiveness analysis alongside a prospective cohort study during the 2007-2008 season, including players in Quebec (n=1046), where policy did not allow body checking, and in Alberta (n=1108), where body checking was allowed. Injury incidence rates (injuries/1000 player-hours) and incidence proportions (injuries/100 players), adjusted for cluster using Poisson regression, allowed for standardised comparisons and meaningful translation to community stakeholders. Based on Alberta fee schedules, direct healthcare costs (physician visits, imaging, procedures) were adjusted for cluster using bootstrapping. We examined uncertainty in our estimates using cost-effectiveness planes. Results Associated with significantly higher injury rates, healthcare costs where policy allowed body checking were over 2.5 times higher than where policy disallowed body checking ($C473/1000 player-hours (95% CI $C358 to $C603) vs $C184/1000 player-hours (95% CI $C120 to $C257)). The difference in costs between provinces was $C289/1000 player-hours (95% CI $C153 to $C432). Projecting results onto Alberta Pee Wee players registered in the 2011-2012 season, an estimated 1273 injuries and $C213 280 in healthcare costs would be avoided during just one season with the policy change. Conclusion Our study suggests that a policy disallowing body checking in Pee Wee ice hockey is cost-saving (associated with fewer injuries and lower costs) compared to a policy allowing body checking. As we did not account for long-term outcomes, our results underestimate the economic impact of these injuries. © 2014 BMJ Publishing Group Ltd & British Association of Sport and Exercise Medicine.


Nishiyama K.K.,University of Calgary | Nishiyama K.K.,McCaig Institute for Bone and Joint Health | Gilchrist S.,University of British Columbia | Gilchrist S.,Center for Hip Health and Mobility | And 6 more authors.
Journal of Biomechanics | Year: 2013

Finite element (FE) analysis based on quantitative computed tomography (QCT) images is an emerging tool to estimate bone strength in a specific patient or specimen; however, it is limited by the computational power required and the associated time required to generate and solve the models. Thus, our objective was to develop a fast, validated method to estimate whole bone structural stiffness and failure load in addition to a sensitivity analysis of varying boundary conditions. We performed QCT scans on twenty fresh-frozen proximal femurs (age: 77±13 years) and mechanically tested the femurs in a configuration that simulated a sideways fall on the hip. We used custom software to generate the FE models with boundary conditions corresponding to the mechanical tests and solved the linear models to estimate bone structural stiffness and estimated failure load. For the sensitivity analysis, we varied the internal rotation angle of the femoral neck from -30° to 45° at 15° intervals and estimated structural stiffness at each angle. We found both the FE estimates of structural stiffness (R2=0.89, p<0.01) and failure load (R2=0.81, p<0.01) to be in high agreement with the values found by mechanical testing. An important advantage of these methods was that the models of approximately 500,000 elements took less than 11min to solve using a standard desktop workstation. In this study we developed and validated a method to quickly and accurately estimate proximal femur structural stiffness and failure load using QCT-driven FE methods. © 2013 Elsevier Ltd.

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