Dissertations / Theses on the topic 'Osteoarthritis and obesity'

Osteoarthritis (OA) is the most common degenerative joint disease affecting more than 40% of people above the age of 65 (Neogi et al., 2013). Obesity is one of the main risk factors of OA and has become a major problem in Western societies. With sedentary lifestyle and the aging of the population, it is estimated that more than 50% of British adults will be obese in 2030 (Wang et al., 2011). So far, the effect of obesity on joint degeneration has primarily been explained by the increased load on the joints. However, a growing number of studies have revealed that adipose tissue can affect cartilage and other joint tissues at a molecular level. The main goal of this thesis was to investigate the role of local knee joint tissues in obese patients with OA. The expression of molecular markers was investigated in local knee tissues: cartilage, synovium, infrapatellar fat pad (IPFP) and subchondral bone collected during Total Knee Replacement (TKR). A range of techniques (RT-PCR, Real Time qPCR, WB, IHC/ICC and ELISA) was used to examine the differences between genes and proteins expression in both lean and obese patients with OA. Further, the local immune cell infiltration was investigated in knee adipose tissue depots (synovium and IPFP) using flow cytometry. In addition, the subchondral bone microstructure was analysed using micro-Computed Tomography (μCT) and IHC techniques. Chondrocytes from OA patients were found to express a range of obesity-related genes. ADIPOR1 was produced significantly higher than ADIPOR2 in OA chondrocytes. Furthermore, CCL2 was produced at higher while PPARγ and visfatin were produced at a lower level in obese patients’ chondrocytes in comparison to lean ones. Synovium and IPFP also expressed a range of obesity-related genes. PPARγ and visfatin expression was lower in obese synovium and IPFP in comparison to lean. Surprisingly, adiponectin was expressed at a significantly lower level in obese patients’ synovium. In contrast, adiponectin was not differently expressed in lean and obese patients’ IPFP. The IPFP was found to be a significantly higher producer of PPARγ and adiponectin in comparison to synovium. Synovium, on the other hand, has an increased expression of VCAM-1, TLR4 and CCL2 in obese patients. An increased number of macrophages (defined by CD45+CD14+ and CD14+CD206+ markers expression) was detected in the synovium and IPFP from obese OA patients. Furthermore, there was an increased number of CD86+CD14+ cells in the synovium from obese patients. Other macrophage-related proteins including HLA-DR, CD36 were also expressed at a higher level in synovium from obese patients. T-lymphocyte detection revealed a higher number of CD3+CD4+ T cells in the synovium (but not IPFP) from obese patients but no change in the CD3+CD8+ population in both the synovium and IPFP. Subchondral bone analysis revealed possible differences in this tissue in obese male patients with OA in comparison to lean patients. μCT examination of subchondral bone showed a significantly lower bone mineral density (BMD) in obese in comparison to lean male OA patients. IHC analysis of bone sections suggested that there was an increased number of bone marrow adipose tissue macrophages. In addition, osteoblasts obtained from obese OA donors expressed a significantly higher level of ADIPOR2 and lower level of PPARγ mRNA in comparison to lean patients’ osteoblasts. The data obtained suggests that there were differences between lean and obese patients with OA at a molecular level. This proposes possible future directions for targeting these diseases. The limitation of the study were as follows: 1) possible different stages of end-stage OA between analysed patients, which could lead to differences in obtained data, 2) no non-OA control samples included in the study. However, the presented study may suggest that all tissues in the knee joint contribute to the interplay between OA and obesity. In addition, the data obtained is the first to suggest that there are differences in gene and protein expression in the synovium and IPFP from the same donor. Furthermore, there are differences in the immune cell populations in local adipose tissue depots (synovium and IPFP) from OA joints, which are linked to obesity. All of this data has helped to increase our understanding of the interaction between obesity and OA.

Thesis (M.S.)--Wake Forest University. Dept. of Health and Exercise Science, 2009.<br>Title from electronic thesis title page. Thesis advisor: Stephen P. Messier. Vita. Includes bibliographical references (p. 66-73).

Obesity has been attributed in a major risk factor for developing and accelerating disease progression in osteoarthritis. To date, there is a lack of clinically proven therapies to halt osteoarthritis, the developments of such therapies are therefore a national as well as an international research priority. This research provides a new overview of the involvement of synovitis in promoting the destruction of synovial joints in obesity-induced osteoarthritis and might therefore by used as a therapeutic strategy for the development of disease-modifying anti-osteoarthritis drugs.

L'obésité (Ob) est un facteur de risque majeur pour l'arthrose (OA). L'angiogenèse de l'os sous-chondral est impliquée dans la pathophysiologie de l'OA et peut réagir différemment aux facteurs de promotion de l'OA. L’objectif était de discriminer le rôle respectif de la charge liée au surpoids et des troubles métaboliques sur la dégradation articulaire et l'angiogenèse, dans un modèle de souris arthrosique. Des souris C57BL/6j ont subi une déstabilisation chirurgicale du ménisque médiale pour induire l'OA. Des souris OA-Mince ont ensuite été soumises à une hypergravité pour imiter les effets du surpoids. Les autres souris ont été conservées à 1g. Des souris OA-mince et des souris OA-Ob ont été traitées avec un anti-VEGF. Après la perfusion de baryum, le genou droit a été imagé et la microstructure osseuse, la moelle osseuse et les réseaux vasculaires sous-chondraux ont été quantifiés. L'histologie quantitative de l'os sous-chondral a été effectué. La dégradation du cartilage articulaire était similaire entre les groupes OA. L'hypergravité n'a pas aggravé l'amincissement du cartilage induit par l’OA mais a empêché l'épaississement lié à l'OA de la plaque osseuse sous-chondrale. Les souris OA-Ob avaient un volume osseux trabéculaire épiphysaire inférieur à celui des souris Mince-OA. L’OA a induit une angiogenèse à travers la plaque sous-chondrale dans les groupes OA-Mince 1g et 2g. En revanche, la densité vasculaire de la Mo était plus faible chez les OA-Ob que chez OA-Mince. L'obésité et le 2g ont eu des effets opposés sur la taille des vaisseaux. Le bevacizumab a empêché l'angiogenèse induite par l'OA dans le groupe OA-Mince mais n'a eu aucun effet dans le groupe Ob<br>Obesity is a major risk factor for osteoarthritis (OA). Subchondral bone angiogenesis is involved in OA pathophysiology and may respond differently to OA promoting factors. Aim was to discriminate the respective role of overweight-related-load and of metabolic disorders due to fat accumulation, in joint degradation and angiogenesis, in a mouse model of surgically Induced knee osteoarthritis. C57BL/6j male mice underwent surgical medial meniscus destabilization (MMD) to induce OA and Lean mice were sham operated (Sham-lean). At 2 Mo, gps were fed with high fat diet to induce insulino-resistance and obesity (Ob). OA-Lean mice were then submitted to 2g hypergravity in a centrifuge to mimic the effects of overweight. OA-lean mice and OA-Ob mice were treated with an anti-VEGF. After barium infusion, the right knee was imaged by high-resolution and bone microstructure, bone marrow (bm) and subchrondral vascular networks were quantified. After MMA embedding, OARSI scoring and subchondral bone quantitative histology were then carried out at the medial tibia plateau.Articular cartilage degradation was similar between the OA groups

Title: The association of physical activity, obesity and injury on the risk of knee osteoarthritis (OA) Purpose: 1) To examine the effect of interactions between physical activity, obesity and injury on the incidence and progression of radiographic and symptomatic knee OA; 2) To establish age and gender specific normative data for knee pain, symptoms, function and knee related quality of life (QOL) as the clinical outcome measures in assessing people with knee OA and to examine their associations with OA risk factors including obesity, injury and physical activity. Methods: 1) Using existing cohort data from Osteoarthritis Initiative (OAI) and Multicenter Osteoarthritis Study (MOST) for interaction analyses Participants without radiographic knee OA at baseline were followed for the incidence of radiographic and symptomatic knee OA. In OAI, the focus was on the tibiofemoral joints (TF) only, so TF-OA was defined as a knee with a Kellgren and Lawrence (KL) grade 2 or greater. In MOST, knee OA was defined as a knee with TF-OA (KL ≥2) and/or patellofemoral- OA (osteophyte ≥2; or joint space narrowing ≥1 plus any cyst, osteophyte, or sclerosis using Osteoarthritis Research Society International atlas). The co-occurrence of radiographic knee OA and the frequent knee symptoms (pain, ache, or stiffness on most days of a month over the past 12 months) at the last follow-up was considered as the incidence of symptomatic knee OA. Progression of radiographic knee OA was determined as either one grade increase in KL score or one grade worsening in joint space narrowing at the last follow-up, in participants with radiographic knee OA at baseline. For the progression of symptomatic knee OA, participants with frequent knee symptoms at baseline were included. An increase of greater than 9.29 points in the total Western Ontario and McMaster Universities Osteoarthritis Index score from baseline to last follow-up was considered as a cut-off point (minimal clinical important worsening) for considering a person with symptom progression. Body mass index (obese/non-obese), injury (yes/no), physical activity (active/inactive), age and gender data were also collected at baseline in both databases. The measures of interactions on both additive and multiplicative scales were computed using the generalized estimation equation. 2) Establishing age and gender specific reference values data for Knee Injury and Osteoarthritis Outcome Score (KOOS) and Oxford Knee Score (OKS) Volunteer participants were recruited via a postal survey. From a list of 25,695 postcodes specified by Nottinghamshire local authorities and in the City of Nottingham, 2,500 postcodes were randomly selected. This was based on the proportion of the population in each local authority and in the City of Nottingham. 2,500 postcodes were then equally and randomly assigned into three age groups of 18-44, 45-69 and ≥70 years old. From each postcode assigned to the specific age group, one name and address was randomly selected. Participants were required to complete the questionnaire booklet once only. The questionnaire booklet consisted of the OKS and the KOOS questionnaires. It also collected information regarding participants’ age, gender, height, weight, history of injury and knee joint replacement and physical activity. Results: Interaction analysis In both cohorts, active and inactive people had a similar risk of incident radiographic or symptomatic knee OA (p > 0.05). This effect was not modified by obesity and/or injury in either cohort (p interactions > 0.05). No significant interactions were also found between physical activity, obesity and injury on the risk of radiographic or symptomatic knee OA progression (p interaction > 0.05). Obese people in both cohorts were significantly at a higher risk of incident radiographic and symptomatic knee OA when compared to non-obese people (p < 0.01); injury also increased the incident risk of knee OA (p < 0.01). There were some evidence of positive interactions between obesity and injury on the risk of incident knee OA. This reached statistical significance on additive and multiplicative scales in OAI (aOR-Symptomatic-multiplicative interaction: 2.83, 95%CI: 1.01 to 7.93; aOR-Symptomatic-additive interaction: 3.13, 95%CI: 0.05 to 6.21) and on additive scale in MOST (aOR- Radiological-additive interaction: 1.51, 95%CI: 0.10 to 2.93). There was no evidence of any statistically significant interaction between obesity and injury on the progressive risk of knee OA. Reference values data The overall response rate was 16.5% (n =414, 45% male, 55% female), with the highest in the middle age group with 24%, 18% in the old age and 8% in young age group. A significant dose response relationship was seen between increasing age and worsening scores of KOOS-Pain; KOOS- Activities of daily living (ADL); KOOS-QOL; and OKS (p < 0.05). The median (M) and inter quartile range (IQ) in old, middle and young age groups were as follows: KOOS-Pain (M, IQ: 91.6, 58.3-100; 94.4, 77.7-100; 100, 80.5-100), KOOS- ADL (M, IQ: 91.1, 59.3-100; 98.5, 77.2-100; 100, 89.7-100), KOOS-QOL (M, IQ: 81.2, 43.7-100; 87.5, 62.5-100; 87.5, 68.7-100), and OKS (M,IQ: 42.3, 29-48; 46, 38-48; 47, 42- 48). The oldest age group had the worst scores in KOOS-Pain, KOOS-ADL; KOOS-QOL; and OKS compared to the young or middle age groups (p < 0.05). However, the differences between young and middle age groups were not statistically significant in any KOOS or OKS scores (p > 0.05). Data were also stratified by gender. There was no gender difference in any KOOS or OKS scores (p > 0.05). Obesity and injury were also found as the strongest predictors for the worsening score in all KOOS and OKS subscale scores (p < 0.05), whereas physical activity was significantly associated with a lower risk of knee related complaints (p < 0.05). Conclusion: Physical activity did not increase the risk of incident or progressive knee OA at any level of obesity and/or injury in middle aged and older people with or at high risk of knee OA. In addition, meeting the minimum physical activity guidelines was significantly associated with lower self-reported knee complaints evaluated by KOOS and OKS. Therefore, moderate levels of physical activity appears to be safe to recommend to the general population and people with or at high risk of knee OA regardless of obesity and injury status. There was also some modest evidence of positive interaction between obesity and injury on the risk of incident knee OA. Hence, weight gain prevention strategies may protect injured people against further increase in the risk of knee OA. This study also provided normative data for KOOS and OKS. The self-reported knee complaints were found to vary with age (not gender) being highest in the oldest age group. This suggests that treatment outcomes in people with knee injury and knee OA should be compared against age-matched reference values from the general population.

L'obésité est associée à un risque de fragilité musculo-squelettique, en particulier d’arthrose (OA). Notre but est d’explorer leurs contributions des conditions métaboliques et du surpoids. L’obésité MM (mécanique et métabolique) est obtenue par un régime alimentaire. L’obésité M (mécanique) est mimée par hypergravité à 2g. L’OA est induite par acte chirurgicale. Nous avons exploré les effets des obésités MM et M sur le système musculo-squelettique de souris non OA. Les MM ont un os trabéculaire préservé, un os cortical détérioré et des muscles fragilisés. Chez les M, l’os est préservé et les muscles sont renforcés. Les troubles métaboliques sont responsables de la fragilisation de l’os cortical et du muscle. Dans une 2ème partie, les conséquences de l’OA sont évaluées chez des souris non obèses, MM ou M. L’OA chez les non obèses fragilise uniquement l’os trabéculaire. L’OA chez les MM accentue la diminution de l’épaisseur corticale. L’OA chez les souris M fragilise encore plus l’os cortical et le muscle que chez les souris MM. Cependant si on ne considère que les souris OA, la composante MM est toujours plus délétère que la composante M. Finalement, nous avons testé les vibrations corps entiers pendant les 4 dernières semaines comme traitement potentiel des détériorations musculo-squelettiques des MM couplée ou non à l’OA. Les vibrations n’impactent pas l’obésité et l’OA. Un effet musculaire est observé au niveau moléculaire, ces diminutions étant plus importantes chez les OA. Aucun changement de masse musculaire n’est observé. Le tissu osseux n’est pas influencé<br>Obesity is associated with a risk of musculoskeletal fragility, especially osteoarthritis (OA). Our goal is to explore their contributions of metabolic and overweight conditions. MM obesity (mechanical and metabolic) is obtained through a diet. Obesity M (mechanical) is mimed by hypergravity at 2g. OA is induced by surgery. We explored the effects of MM and M obesity on the non-OA mouse musculoskeletal system. MMs have preserved trabecular bone, deteriorated cortical bone and weakened muscles. In M, bone is preserved and muscles are strengthened. Metabolic disorders are responsible for the weakening of cortical bone and muscle. In a second part, the consequences of OA are evaluated in non-obese mice, MM or M. OA in non-obese only weakens the trabecular bone. OA in MM accentuates the decrease in cortical thickness. OA in M mice further weakens cortical bone and muscle than in MM mice. However, if we consider only the OA mice, the MM component is always more deleterious than the M component. Finally, we tested entire body vibrations during the last 4 weeks as a potential treatment for musculoskeletal deterioration of MM, whether or not coupled to OA. Vibrations do not affect obesity and OA. A muscular effect is observed at the molecular level, these decreases being greater in OA. No change in muscle mass is observed. The bone tissue is not influenced

京都大学<br>新制・課程博士<br>博士(医学)<br>甲第23379号<br>医博第4748号<br>新制||医||1052(附属図書館)<br>京都大学大学院医学研究科医学専攻<br>(主査)教授 石見 拓, 教授 戸口田 淳也, 教授 中山 健夫<br>学位規則第4条第1項該当<br>Doctor of Medical Science<br>Kyoto University<br>DFAM

L’arthrose est une maladie dégénérative des articulations et représente la deuxième cause d’invalidité en France. En raison des liens entre l’obésité et l’arthrose concernant à la fois les articulations portantes et non portantes, nous faisons l’hypothèse que des protéines produites par le tissu adipeux, les adipokines, constituent des facteurs clés impliqués dans cette arthropathie. En premier lieu, nous avons montré que l’expression de la leptine, de l’adiponectine et de leurs récepteurs évolue de façon inverse et dépend fortement de l’état de différenciation des chondrocytes. Dans une seconde étude, nous avons comparé la production des adipokines par le ligament adipeux de Hoffa à celle mesurée dans la graisse sous-cutanée et avons ainsi mis en évidence des différences entre les 2 tissus adipeux. Les travaux réalisés ensuite ont permis de préciser le rôle des adipokines dans l’arthrose. Ainsi, la production d’adiponectine par les chondrocytes augmente lorsque le cartilage se dégrade et apparaît directement reliée à celle de la MMP-13 et du TGF-[bêta]. En revanche, l’expression de son récepteur AdipoR1 est associée à l’expression d’éléments matriciels et d’un facteur de transcription spécifique du cartilage impliqué dans la synthèse de ces éléments. Le traitement des chondrocytes à l’adiponectine a permis de confirmer in vitro les données observées in vivo chez les patients atteints d’arthrose, à savoir que l’adiponectine induit l’expression du TGF-[bêta]et de la MMP-13. Les résultats obtenus avec la leptine indiquent par ailleurs que l’obésité influence fortement la réponse des chondrocytes à cette adipokine. Elle semble ainsi protéger le cartilage chez les patients non obèses en stimulant l’expression de l’IGF-1, du collagène de type 2 et du TIMP-2, mais contribue au processus dégénératif chez les patients obèses en augmentant l’expression de la MMP-13. Enfin l’induction d’une arthrose expérimentale chez le rat Zucker n’ayant pas de récepteur fonctionnel à la leptine a montré que cette adipokine est susceptible de préserver l’articulation des modifications du cartilage et surtout de l’os sous-chondral<br>Osteoarthritis (OA) is a degenerative joint disease and represents one of the most frequent and disabling disease. There is a positive association between obesity and OA, and not only for knee joints but also for non-weight-bearing joints suggesting that adipose-derived proteins, namely adipokines, may be some keys factors in OA pathophysiology. First, we found that leptin and adiponectin expression and their receptor evolves in an opposite way and depend on differenciation stage of chondrocyte. The production of adipokines were then compared according to adipose tissue and some differences were found between, the infrapatellat fat pad and subcutaneous adipose tissue. After this work, we aimed to further characterize the role of leptin and adiponectin in OA. Adiponectin production by chondrocytes increases when cartilage is damaged and seems to be directly related with MMP-13 and TGF-[bêta] expression. AdipoR1 expression is associated with the expression of matrix components and with Sox9, a transcription factor involved in their synthesis. Adiponectin treatment confirms data in OA patient, that is adiponectin can induce TGF-[bêta] and MMP-13. Then, we showed obesity influences the chondrocyte responsivness to leptin. This adipokine seems to protect cartilage collected from normal or overweight patient by stimulating IGF-1, type 2 collagen and TIMP-2 expression while leptin increases MMP-13 expression for obese patients. Finally, experimental OA in Zucker rat deficient in leptin receptor, showed the protective effect of leptin on cartilage and on subchondral bone

Background and aims: Knee osteoarthritis (KOA) is a common cause of disability and pain in adults. Obesity is increasingly recognized as the primary modifiable risk factor for the onset and progression of KOA. The mechanisms that link the two conditions are still not fully clarified but recent data suggest an important role mediated by the infrapatellar fat pad (IFP). Accordingly, we aimed to determine the histomorphological characteristics of IFP in individuals affected by KOA and compare them to those obtained from lean healthy individuals using a histological scoring system. Moreover, we determined the expression of certain adipocytokines in IFP of KOA subjects. Materials and Methods: We enrolled 28 subjects (BMI 35.5±5 kg/m2) undergoing total knee replacement for OA. The controls were represented by IFP and adjacent synovial membrane specimens sampled from bodies or bodies part of 8 healthy subjects without history of osteoarthritis involved in the Body Donation Program ‘Donation to Science’ held by the University of Padova. The microscopic anatomy of IFP was analyzed through histological and morphometrical methods. The histology of the synovial membrane adjacent to the IFP was also analyzed. We determined mRNA expression using Quantitative real time PCR for adipokines (leptin, adiponectin, Peroxisome proliferator-activated receptor gamm, fatty acid binding protein4) and cytokines (Interleukin 6 [IL-6], Tumor necrosis factor alfa[TNF-α], Monocyte chemoattractant protein-1[MCP-1], Vascular endothelial growth factor [VEGF]) in the IFP specimens of KOA subjects. Results: All the evaluated IFPs showed microscopical characteristics similar to white adipose tissue. IFPs were organized in adipose lobuli separated by fibrous septa. No differences were detected in the mean diameter of the adipose lobuli of the IFP in KOA patients and controls. Mononuclear infiltration was present in 22 KOA patients while it was not observed in any of the IFP used as control (p = 0.001). The average number of vessels and the thickness of interlobular septa were significantly higher in KOA patients compared to controls (p < 0.0001 and p = 0.004 respectively). BMI correlated positively with the thickness of the interlobular septa in IFP (p= 0.02, r= 0.42). Concerning synovial membrane, the presence of lymphocytic infiltration and hyperplasia was statistically higher in KOA compared to controls (p <0.001 and p = 0.001 respectively) and it was more vascularized and fibrotic compared to controls (p <0.001 and p = 0.002 respectively). Furthermore, in IFP samples it was noticed an expression of genes typical of inflammed adipose tissue such as IL-6, TNF-α, MCP-1 and VEGF. Moreover, we observed a positive correlation between the number of blood vessels of KOA synovial membrane and mRNA expression of VEGF in IFP (p=0.04). Conclusion: Our study describes for the first time the histopathological characteristics of IFP in a large cohort of patients with KOA. IFP showed pathologic structural changes in the lobule dimension, interlobular septa, vascularization and inflammatory infiltrate. These changes were associated with synovial inflammation. Moreover, we added evidence about the existence of a probable crosstalk between cytokines produced by IFP and the synovial membrane.<br>Introduzione e scopo dello studio: L’osteoartrosi del ginocchio (KOA) è la maggiore causa di disabilità e dolore nella popolazione anziana. L'obesità è considerata il fattore di rischio modificabile più comune per l'insorgenza e la progressione della KOA. Sebbene i meccanismi che collegano le due patologie sono poco chiari, dati recenti suggeriscono un ruolo significativo mediato dal tessuto adiposo infrapatellare (IFP). Lo scopo di questo lavoro è quello di descrivere le caratteristiche istomorofologiche dell’ IFP in soggetti affetti da KOA e confrontarle con quelle ottenute da soggetti sani, utilizzando un sistema di ‘score’ istologico. Inoltre, abbiamo valutato l'espressione dei varie adipocitochine nell’ IFP di soggetti con KOA. Materiali e Metodi: Sono stati arruolati 28 soggetti (BMI 35,5 ± 5 kg / m2) sottoposti a sostituzione totale del ginocchio per KOA. Sono stati utilizzati come controlli, campioni di IFP con membrana sinoviale adiacente prelevati da 8 donatori del programma “Donarsi alla Scienza” dell’Istituto di Anatomia Umana presso l'Università di Padova. L'aspetto microscopico dell’ IFP è stato analizzato con metodi istologici e morfometrici. E’ stato anche effettuato l'esame istologico della membrana sinoviale adiacente all’IFP. Abbiamo determinato l'espressione di mRNA utilizzando real time PCR quantitativa per le seguenti adipochine (leptina, adiponectina, Peroxisome proliferator-activated receptor gamma, Fatty acids binding protein 4) e citochine (interleuchina 6 [IL-6], fattore di necrosi tumorale alfa [TNF-α], Monocyte chemoattractant protein-1 [MCP-1], vascular endothelial growth factor [VEGF]) nei campioni dell’IFP dei soggetti affetti da KOA. Risultati:I campioni di IFP hanno evidenziato caratteristiche microscopiche simili al tessuto adiposo bianco. L’IFP è organizzato in lobuli adiposi separati da setti fibrosi. Non sono state rilevate differenze nel diametro medio del lobulo adiposo dell’IFP sia nei soggetti affetti da KOA che nei controlli. L’ infiltrazione Mononucleare è presente in 22 soggetti con KOA, mentre non è stata osservata in nessun IFP dei controlli (p = 0.001). Il numero medio dei vasi e lo spessore dei setti interlobulari sono significativamente più alti nei soggetti con KOA rispetto ai controlli (p <0.0001 e p = 0,004 rispettivamente). Il BMI correlava positivamente con lo spessore dei setti interlobulari nell’ IFP (p = 0.02, r = 0.42). Inoltre, l’infiltrazione linfocitaria e l’iperplasia sinoviale erano più accentuate nel KOA rispetto ai controlli (p <0.001 e p = 0.001 rispettivamente). La membrana sinoviale era anche più vascolarizzata e fibrotica rispetto ai controlli (p <0.001 e p = 0.002 rispettivamente).Per quanto riguarda l’analisi molecolari, l’ IFP mostrava un espressione dei geni tipiche del tessuto adiposo infiammato come IL-6, TNF-α, MCP-1 e VEGF. Inoltre, abbiamo osservato una correlazione positiva tra l’angiogenesi sinoviale e l’ espressione genica del VEGF nell’ IFP (p = 0.04). Conclusione: Il nostro studio è il primo che descrive le caratteristiche istopatologiche dell’ IFP in soggetti prevalentemente sovrappeso/obesi affetti da KOA. L’IFP aveva un fenotipo patologico caratterizzato dall’alterazione a livello della dimensione del lobulo, dello spessore dei setti interlobulari, del grado di vascolarizzazione ed dell’infiltrato infiammatorio. Queste alterazioni strutturali sono state associate ad un’infiammazione a livello della membrana sinoviale adiacente. Inoltre, abbiamo aggiunto un’altra prova dell'esistenza di una probabile crosstalk tra citochine prodotte dall’ IFP e la membrana sinoviale.

Orientadores: Ibsen Bellini Coimbra, Arlete Maria Valente Coimbra<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas<br>Made available in DSpace on 2018-08-21T02:34:05Z (GMT). No. of bitstreams: 1 Iartelli_Isabele_M.pdf: 1301426 bytes, checksum: fece5d56839755d5c0d447114c3e97b5 (MD5) Previous issue date: 2012<br>Resumo: Osteoartrite (OA) é a doença osteoarticular mais comum na população ocidental idosa e frequentemente afeta as articulações da mão. Caracterizada pelo acometimento da cartilagem com a participação do osso subcondral e da membrana sinovial, além das estruturas periarticulares, constitui-se numa verdadeira insuficiência da articulação. Clinicamente apresenta-se com limitação de movimentos, dor, edema, perda de força e deformidades que causam danos funcionais importantes ao paciente. Alguns fatores podem favorecer o aparecimento ou agravamento da OA de mãos, destacando-se a idade, a genética, o sexo, a força muscular e a obesidade. Dessa forma, este estudo teve como objetivo analisar a relação entre a osteoartrite de mãos em idosas não institucionalizadas, com sua composição corporal, idade e força muscular. A amostra constitui-se de 73 idosas não institucionalizadas, que voluntariamente participaram de entrevista sócia demográfica, teste de força muscular com dinamômetro de preensão manual, realização de exames de raios-X de mãos e punhos, e densitometria de corpo todo. A OA radiográfica de mãos esteve presente em 73,9% das idosas, sendo que a maior prevalência (50%) ocorreu entre as idosas que estavam na sétima década de vida. Não houve relação estatisticamente significativa entre as variáveis estudadas e OA de mãos. Entretanto, quando realizado estudo de regressão logística, verificou-se que o Risco Relativo de mulheres com idade maior de 80 anos e índice de massa corporal (IMC) maior que 28 Kg/m2 apresentarem OA radiográfica das mãos foi maior do que nas mais jovens e com IMC normal. Observou-se, ainda, que idosas obesas apresentaram maior frequência de OA radiográfica das mãos e maior gravidade de lesões da OA. Embora as análises estatísticas não tenham apresentado significância, conclui-se que idosas não institucionalizadas, com mais de 80 anos e IMC maior que 28 Kg/m2 apresentam maior risco de apresentar OA radiográfica das mãos<br>Abstract: Osteoarthritis (OA) is the most common musculoskeletal disease in the elderly western population and often affects the joints of the hand. Characterized by impairment of cartilage involving the subchondral bone and synovium, and periarticular structures, constitutes a true failure of the joint. Clinically presents with limited movement, pain, swelling, loss of strength and functional deformities that cause important damage to the patient. Some factors may favor the emergence or worsening of OA of the hands, especially age, genetics, sex, muscle strength and obesity. Thus, this study aimed to analyze the relationship between hand osteoarthritis in elderly non-institutionalized, with their body composition, age and muscle strength. The sample consisted of 73 non-institutionalized elderly, who voluntarily participated in the interview partner demographic, muscle strength testing with a dynamometer handgrip, examinations of X-rays of hands and wrists, and whole body densitometry. The radiographic hand OA was present in 73.9% of the elderly, and the highest prevalence (50%) occurred among the elderly who were in the seventh decade of life. There was no statistically significant relationship between variables and hand OA. However, when performed logistic regression study, we found that the relative risk for women aged 80 years and BMI greater than 28 kg/m2 present radiographic hand OA was higher than in younger and with a normal BMI. There was also that Older obese increased prevalence of radiographic OA of the hands and greater severity of OA lesions. Although the statistical analysis did not present significance, it is concluded that noninstitutionalized elderly, with more than 80 years and BMI greater than 28 kg/m2 have a higher risk of developing radiographic hand OA<br>Mestrado<br>Gerontologia<br>Mestre em Gerontologia

Abstract Primary hallmark of osteoarthritis (OA) is the progressive degeneration of articular cartilage. An accurate estimation of cartilage mechanics is important when analyzing the subject-specific function of the knee joint and risks for the onset and development of OA due to cartilage damage. Finite element (FE) modeling can help to estimate peak joint stresses and strains and explain how they could lead to OA. FE models of the knee joint during simplified gait were developed to define the level of material complexity required for 3D FE modeling of the knee joint in estimation of reliable tissue stresses and strains within articular cartilage of the knee joint; and to investigate the predictive value of FE modeling of the knee joint on the development and progression of radiographic OA within obese and normal weight subjects. It was found that maximum principal stresses and strains within articular cartilage in the knee joint during walking are highly sensitive to the material parameters of cartilage. It was not possible to match simultaneously stresses, strains and contact pressures between simplified (non-fibrillar) and advanced (fibrillar) models. Though, it was possible to find parameters for transversely isotropic models that enable the estimation of stresses and strains throughout the depth of cartilage similarly to more advanced fibril reinforced models. Locations of peak cumulative stresses in obese subjects at the baseline without radiographic OA showed a good agreement with the locations of cartilage loss and magnetic resonance imaging (MRI) based scoring in four year follow-up when they had developed OA. Simulated weight loss in obese subjects significantly reduced the highest cumulative stresses in cartilage to the level of normal weight subjects. The cartilage degeneration algorithm was able to predict subject-specific progression of OA similarly with MRI follow-up data and separate subjects with radiographic OA from healthy subjects. The computational FE models developed in this thesis represent useful tools to identify possible risk locations within the knee joint and how they relate to OA onset and progression. The presented methods have clinical potential in the diagnostics of knee joint OA in a subject-specific manner and in simulating the effect of interventions on the progression of OA thus helping with an effective treatment planning<br>Tiivistelmä Nivelrikon tunnusomaisin piirre on nivelrustokudoksen rappeutuminen ja kuluminen. Nivelruston tehtävänä on tasata niveliin kohdistuvaa kuormitusta. Rustokudoksen mekaanisten ominaisuuksien määrittäminen on tärkeässä roolissa, kun halutaan arvioida tarkemmin polvinivelen toimintakykyä sekä rustokudoksen rappeutumista. Magneettikuvantamisen pohjalta tehtävä polvinivelen biomekaaninen tietokonemallinnus mahdollistaa rustokudoksen jännitys- ja puristusjakauman arvioinnin simuloidun kuormituksen aikana, mikä edelleen voi antaa vastauksia siihen, kehittyykö niveleen tulevaisuudessa nivelrikko, tai miten tietyn nivelrikkopotilaan sairaus etenee. Tämän tutkimuksen päätavoitteena oli kehittää kolmiulotteisia polvinivelen biomekaanisia tietokonemalleja, joiden perusteella simuloitiin normaalia kävelyä. Polvinivelen kolmiulotteinen geometria luotiin terveiden koehenkilöiden sekä nivelrikkopotilaiden magneettikuvista. Malleilla selvitettiin aluksi, miten monimutkaisena materiaalina nivelrusto tulee mallintaa, jotta mallin ennustama jännitys- ja puristusjakauma on silti realistinen. Tämän jälkeen tutkittiin, miten hyvin tietokonemallinnus ennustaa polvinivelrikon kehittymistä ja etenemistä sekä nivelruston rappeutumista ylipainoisilla potilailla. Tutkimuksessa havaittiin, että tietokonemallin ennustamat jännitys- ja puristusjakaumat nivelrustossa kävelyn aikana riippuvat merkittävästi nivelrustolle valitusta materiaalimallista ja sen parametreista. Tietokonemallien ennustamat nivelruston jännityskeskittymien sekä ruston rappeutumisen sijainnit vastasivat erittäin hyvin nivelrustokudoksen todellisen kulumisen sijainteja magneettikuvasta arvioituna neljän vuoden seuranta-ajan jälkeen. Tietokonemalleilla oli myös mahdollista simuloida painon pudotuksen vaikutusta, jolloin nivelrustokudoksen jännitys- ja puristusjakaumat palautuivat normaalien koehenkilöiden tasolle. Tässä tutkimuksessa kehitetyt polvinivelen tietokonemallit tarjoavat tutkijoille uuden työkalun paikallistaa sellaiset kohdat nivelpinnalta, joissa kuormituksen aiheuttama mekaaninen jännitys on suurta; nämä kohdat ovat kaikista riskialtteimpia nivelrikon kehittymiselle. Kehitettyjä malleja voidaan perustutkimuksen lisäksi jatkokehittää edelleen kohti kliinistä sovellusta, jolloin niitä voitaisiin hyödyntää esimerkiksi simuloitaessa erilaisten hoitojen vaikutusta kuormitusjakaumiin ja rustokudoksen rappeutumiseen

INTRODUÇÃO: A obesidade pode favorecer uma série de problemas musculoesqueléticos e está associada com dor e deficiência funcional. Este estudo teve por objetivo analisar a influência de dois níveis de obesidade grave (40 a 50 Kg/m2 versus maior 50 Kg/m2) sobre as alterações osteoarticulares e funcionais do joelho e pé em candidatos á cirurgia bariátrica. MÉTODOS: Foram analisados 81 indivíduos com indicação de gastroplastia com derivação intestinal em Y em Roux. Os indivíduos foram estratificados de acordo com IMC em dois grupos, sendo IMC1(40,0 a 49,6 Kg/m2) e IMC2 (50,0 a 81,3 Kg/m2). A população foi submetida á análise radiológica de joelho para verificação de osteoartrite (escala de Kellgren-Lawrence); Raio-x do pé para mensuração do ângulo tálus-primeiro metatarso (T1M); impressão plantar para cálculo do índice de Staheli (IS) e questionários funcionais, Western Ontario and McMaster Universities Ostheoarthritis Index (WOMAC) e Foot and Ankle Outcome Score (FAOS). Na análise estatística para as variáveis classificatórias foi executado o teste qui-quadrado ou teste exato de Fisher (frequência esperada 5). RESULTADOS: O gênero predominante foi feminino (77,8%), a média de idade de 40,7±10,0 anos e o IMC médio de 50,2±7,7 Kg/m2. Observou-se associação significativa entre IMC/T1M (p=0,03) e não significante para IMC/osteoartrite joelho e IMC/IS (p>0,05). Dor e dificuldades funcionais foram mais prevalentes no grupo de superobesos (p<0,05). CONCLUSÕES: A obesidade extremamente avançada (superobesidade) acentua a alteração da morfologia do arco plantar, favorecendo a instalação do pé pronado. Adicionalmente tem influência marcante sobre sintomatologia de dor e as alterações funcionais do joelho e do pé<br>Obesity can promote a variety of musculoskeletal disorders and is associated with pain and functional disability. This study aimed to analyze the influence of two levels of severe obesity (40 to 50 kg/m2 versus 50 kg/m2 higher) on osteoarticular and functional changes of the knee and foot in candidates for bariatric surgery. METHODS: We analyzed 81 subjects which were stratified according to BMI in two groups, with BMI1 (40,0 to 49,6 kg/m2) and BMI2 (50,0 to 81,3 kg/m2). The population underwent radiological analysis for knee osteoarthritis (Kellgren-Lawrence scale); x-ray of the foot to measure the talus-first metatarsal angle (T1M); footprint to calculate the Staheli index (SI) and functional questionnaires , Western Ontario and McMaster Universities Ostheoarthritis Index (WOMAC) and Foot and Ankle Outcome Score (FAOS). Statistical analysis for categorical variables was performed the chi-square or Fisher\'s exact test (expected frequency 5). RESULTS: The predominant gender was female (77,8%), mean age was 40,7 ± 10,0 years and mean BMI 50,2 ± 7,7Kg/m2. There was a significant association between BMI/T1M (p = 0,03) and not significant for BMI / knee osteoarthritis and BMI / SI (p> 0,05). Pain and functional disability were more prevalent in the group of superobese (p <0,05). CONCLUSIONS: Superobesity promotes additional alteration of the morphology of the plantar arch, favoring the installation of pronated foot. It has an important influence on symptoms of pain and functional changes of the knee and foot

Syftet med denna studie var att undersöka hur fetma/övervikt påverkar lederna och utvecklingav artros och hur sjuksköterskan kan informera, undervisa i förebyggande syfte. Metoden ären litteraturstudie. Tolv vetenskapliga artiklar granskades enl. Polit et al (2001) kriterier förvetenskaplighet. Därefter inleddes analysen där fyra huvudteman framträdde: BMI ochpåverkan på lederna, Smärtpåverkan vid artros, Genusskillnader vid artros och övervikt samtSjuksköterskans undervisande roll. Carnevalis omvårdnadsmodell användes som teoretiskreferensram.<br>The aim of this study was to describe how overweight/obesity influence on the joints and thedevelopment of osteoarthritis. And how the nurse can inform and teach to preventdevelopment of osteoarthritis. The result is based on 12 articles based on Polit et al (2001)criterion for science. The analysis resulted in four the mes: BMI and the influence on the joint,Pain with osteoarthritis, Gender difference at osteoarthritis and overweight and Nursesteaching role. Carnevali´s theory of caremodel was used as a theoretical framework.

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No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) tese_lorena_amaral.pdf: 1402709 bytes, checksum: dc0cdf39546ca7aa38b1d66d2153ecb3 (MD5) Previous issue date: 2014-10-02<br>Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul - FAPERGS<br>A pesquisa por marcadores precoces de inflamação tem sido o foco na medicina humana e veterinária durante as últimas décadas. Acredita-se que tanto o exercício físico quanto a obesidade sejam capazes de gerar a reação de fase aguda. O primeiro estudo teve como objetivo caracterizar a reação de fase aguda e sua relação com desempenho de cavalos submetidos a uma competição de longa distância. Foram avaliados 23 equinos os quais foram divididos em dois grupos sendo o grupo 1 composto pelos 10 primeiros colocados na competição e o grupo 2 composto pelos 13 animais que concluíram a competição em colocações inferiores. Foram efetuadas coletas sanguíneas em repouso (dia 0) e no ultimo dia de competição e foram realizados o teste de eletroforese em gel de poliacrilamida (SDS-PAGE). Os resultados demonstraram que o exercício físico imposto influenciou de forma significativa (p<0,0001) as concentrações séricas das proteínas inflamatórias. A haptoglobina foi superior nos animais com baixo desempenho. Conclui-se que o exercício prolongado é capaz de gerar reação de fase aguda e que o monitoramento da concentração de haptoglobina pode ser um sinalizador de processo inflamatório e baixo desempenho. O segundo estudo teve como objetivo associar a adiposidade corporal e a forma de criação de potros com o perfil energético sanguíneo, as concentrações sanguíneas de proteínas inflamatórias e lesões osteoarticulares no tarso comparando animais criados em regimes intensivo ou extensivo. Foram avaliados 40 potros com 18 meses de idade da raça crioula, sendo 20 animais criados em sistema extensivo e 20 animais em sistema intensivo. Foram efetuadas avaliação bioquímica e eletroforese proteica. Foram efetuadas a mensuração de acumulo de gordura através de ultrassonografia e estudo radiológico da região por tarso. Foi observado maiores níveis de colesterol total e LDL, glicemia, amiloide A sérica, transferina, haptoglobina, glicoproteina acida e proteína de 23Kda não identificada no animais do grupo intensivo com relação aos do grupo extensivo. Em 100% dos animais do grupo intensivo foram observados lesões articulares enquanto 23% dos animais do grupo extensivo apresentaram tais alterações. No teste de Fisher foi observado que os animais do grupo intensivo apresentaram 105% mais chance de desenvolver osteoartrite que os animais do grupo extensivo. Ainda, no teste de Pearson foi observada correlação positiva entre a gordura na crista do pescoço com o grau de comprometimento articular. Conclui-se que tanto o exercício quanto o sobre peso foram capazes de gerar uma reação de fase aguda, sendo que durante o exercício prolongado a haptoglobina apresentou relação com o desempenho dos animais. Já os potros em criação intensiva, além da reação de fase aguda, foi observada elevada incidência de osteoartrite juvenil e alterações no metabolismo energético<br>The search for early markers of inflammation has been the focus in human and veterinary medicine during the last decades. To determine the value of the measurement of proteins in the situations described, two studies were conducted. It is believed that both the physical exercise as obesity can generate an acute phase reaction. The first study aimed to characterize the acute phase reaction and its relation to performance of horses subjected to long distance competition. Was developed during the March of Resistance of Crioulo horses, consisting of a route of 750 km traveled. Were evaluated 23 horses, of wich were divided into two groups, with the first group consisting of the top 10 in the competition and the second group comprises the 13 animals that completed the competition in lower positions. Blood samples were collected at rest (day 0) and on the last day of competition and testing polyacrylamide electrophoresis (SDS-PAGE) gel were performed. The results showed that imposed physical exercise influenced significantly (p<0.0001) in serum concentrations of haptoglobin, ceruloplasmin, immunoglobulin A, acid glycoprotein and the protein with molecular weight of 23 kDa. Haptoglobin was higher in animals with low performance. The second study aimed to associate adiposity and the shape of creation of foals with blood energy profile, blood concentrations of inflammatory proteins and osteoarticular lesions in the tarsus comparing animals raised in intensive or extensive regimes. Were evaluated 40 Crioulo foals at 18 months old, 20 animals kept in extensive systems and 20 animals in intensive system. Protein electrophoresis and biochemical evaluation were performed. Measurement of fat accumulation were made by ultrasound and radiological study of the tarsus region. Higher levels of total cholesterol and LDL, blood glucose, serum amyloid A, transferrin, haptoglobin, acid glycoprotein and unidentified protein 23Kda of animals in the intensive group compared to the extensive group was observed. The intensive group also showed greater deposit of fat in the crest of the neck, retroperitoneal area and base of the tail region. In 100% of the animals in the intensive group were observed lesions compatible with juvenile osteoarthritis while 23% of the animals in extensive group showed such changes. In Fisher's exact test was observed that the animals in the intensive group had 105% more likely to develop osteoarthritis than animals from extensive group. Still, the Pearson test positive correlation between fat on the crest of the neck with the degree of joint involvement of foals was observed. We conclude that both the exercise and the overweight were able to generate an acute phase reaction, and during prolonged exercise haptoglobin were related to animal performance. Already foals in intensive farming, besides the acute phase reaction, high incidence of juvenile osteoarthritis and changes in energy metabolism was observed.

Osteoarthritis (OA) is a multifactorial disease of the joints, common among older adults, which can lead to pain, impaired function and reduced quality of life. This thesis aims to investigate the associations and predictive value of various hormonal, inflammatory and imaging biomarkers with OA outcomes in population-based studies of people with and without prevalent OA. Two population samples were used in this thesis. The first group was a population-based sample of older adults aged 50-80 years (mean age: 62 years; 51% female). Followup measurements were conducted 2.7 (2.6-3.3) years later and again for questionnaire data 5.0 (5.3-6.8) years later. Magnetic resonance imaging (MRI) on the right knees was undertaken at baseline and first followup: knee cartilage volume, tibial bone area, cartilage defects and bone marrow lesions (BMLs) were measured or scored; cartilage mean T1 signal intensity and thickness were measured by semi-automated software. Baseline knee and hip x-rays were scored for joint space narrowing (JSN) and osteophytes. Serum leptin and cytokine levels were measured by immunoassay at baseline and first followup. Body morphometry was measured at baseline. Fat and lean mass measures were measured at baseline using dual-energy x-ray absorptiometry (DXA). Knee pain was assessed by questionnaires (WOMAC, Western Ontario and McMasters Osteoarthritis Index) at all timepoints. The second group was a population-based sample of younger adults aged 26-51 (mean age 41; 64% female). Anthropometric, x-ray and MRI-derived scores and measures were obtained as in the first group. Urinary C-terminal crosslinking telopeptide of type II collagen (U-CTX-II) was measured by measured by immunoassay. This thesis consists of 6 studies. In the first study, in older adults, circulating levels of both leptin and interleukin-6 (IL-6) were associated with hip JSN in both sexes and females respectively, independently of BMI. Adiposity was associated with hip JSN, but not after adjustment for leptin. In the second study, baseline levels of both IL-6 and tumor necrosis factor alpha (TNF-α) were associated with medial tibiofemoral knee JSN. Baseline IL-6, change in IL-6 and change in TNF-α were associated with cartilage volume loss. In the third study, in older adults, baseline or change over 2.9 years in circulating levels of high sensitivity C-reactive protein (hs-CRP), IL-6 and TNF-α were associated with change over 5 years in sub-scale or total WOMAC knee pain. In the fourth study, higher leptin in older adults was significantly associated with lower femoral, tibial and patellar cartilage thickness. Fat measures were negatively associated with cartilage thickness, largely mediated by leptin. Baseline and change in leptin were associated with medial tibial cartilage thickness loss. In the fifth study, knee cartilage defects in older adults were found to be common, not likely to regress, and to predict cartilage volume loss and risk of knee replacement. In the final study, mean T1 MRI signal intensity of cartilage was negatively associated with BMI and same-region cartilage defects in younger and older adults; with U-CTX-II in younger adults; and with JSN and osteophytes in older adults at various sites. It predicted cartilage thickness loss over 2.7 years in older adults. In conclusion, inflammatory and metabolic factors may play important roles in aetiology of cartilage loss and/or symptoms in OA. Cartilage defects predict cartilage loss and risk of knee replacement, and mean T1 MRI signal intensity of cartilage predicts loss of cartilage thickness. All these are potential biomarkers for OA at risk of development or progression, and thus possible targets for intervention.

Obesity is a highly cited risk factor for knee osteoarthritis (OA) associated with increased risk of development of OA and accelerated disease progression. Rates of obesity are increasing internationally, and while obesity is well established as a risk factor, the precise role of obesity in knee OA pathogenesis and progression is not as clearly understood. Mechanical loading has been implicated as an important factor in knee OA initiation and progression. The purpose of this thesis was to further examine the roles of moderate knee OA disease presence and obesity on knee joint mechanics during gait, and to characterize their mechanical interaction. Two methods have been applied. First, principal component analysis has been applied to resultant waveforms from gait analysis and second, a sagittal plane joint contact force model has been applied. Using both methods, statistical differences in biomechanical loading has been associated with obesity, moderate knee OA, and their interaction.

Introdução: A relação entre Osteoartrose do Joelho (OAJ) e Obesidade é explicada pela sobrecarga mecânica na cartilagem e também por alguns fatores sistémicos que participam no processo patogénico. Dado que seis em cada dez indivíduos têm excesso de peso ou obesidade em Portugal, o objetivo deste estudo é estimar a prevalência de OAJ na população portuguesa com obesidade. Métodos: 655 voluntários (idade 46,1±13,8; IMC 29,4±5,9kg/m 2 ) responderam à versão on-line do Knee Osteoarthritis Pre-Screening Questionnaire (KOPS). A estatística descritiva e o coeficiente de correlação de Pearson foram usados para análise e o coeficiente de determinação foi usado para interpretar r, e foi obtido através do coeficiente de correlação r ao quadrado (r2 ). Teste T e Análise de Variância foram utilizados para comparar variáveis contínuas entre grupos. Resultados: Da amostra total, 36,5% eram homens (idade 46,1±13,9; IMC 29,6±4,7kg/m 2 ) e 63,5% eram mulheres (idade 46,1±13,8; IMC 29,3±6,5kg/m 2 ), enquanto 50,25% tinham obesidade (idade 47,8±13; IMC 34,6±3,9kg/m 2 ). No grupo com obesidade, a prevalência de OAJ foi de 56,6% (Score Total KOPS 18,3±9,3), enquanto no não-obeso foi de 23,6% (Score Total KOPS 12±7,1). Conclusão: A prevalência de OAJ na população com obesidade é significativamente maior que a prevalência na população em geral relatada na literatura.<br>Background: The relationship of Knee Osteoarthritis (KOA) and Obesity is explained by mechanical overloading on the cartilage and also by some systemic factors that participate in the pathogenic process. Since six in each ten individuals are overweight or obese in Portugal, this study’s goal is to estimate KOA’s prevalence in the Portuguese population with obesity. Methods: 655 volunteers (age 46,1±13,8; BMI 29,4±5,9kg/m2 ) answered to a Knee Osteoarthritis Pre-Screening Questionnaire (KOPS) Online version. Descriptive statistics and Pearson Correlation Coefficient were used for analyses and the coefficient of determination was used to interpret r and was obtained by squaring the correlation coefficient r (r2 ). Independent t-test and Analysis of Variance (ANOVA) were used to compare continuous variables between groups. Results: From total sample, 36,5% were male (age 46,1±13,9; BMI 29,6±4,7 kg/m2 ) and 63,5% were female (age 46,1±13,8; BMI 29,3±6,5kg/m2 ) while 50,25% had obesity (age 47,8±13; BMI 34,6±3,9kg/m2 ). In the Obese Group, KOA’s prevalence was 56,6% (KOPS Total Score 18,3±9,3) while in the Non-Obese was 23,6% (KOPS Total Score 12±7,1). Conclusion: KOA’s prevalence in the population with obesity is significantly higher than the prevalence in general population reported by literature.

Introdução: A relação entre Osteoartrose do Joelho (OAJ) e Obesidade é explicada pela sobrecarga mecânica na cartilagem e também por alguns fatores sistémicos que participam no processo patogénico. Dado que seis em cada dez indivíduos têm excesso de peso ou obesidade em Portugal, o objetivo deste estudo é estimar a prevalência de OAJ na população portuguesa com obesidade. Métodos: 655 voluntários (idade 46,1±13,8; IMC 29,4±5,9kg/m2) responderam à versão on-line do Knee Osteoarthritis Pre-Screening Questionnaire (KOPS). A estatística descritiva e o coeficiente de correlação de Pearson foram usados para análise e o coeficiente de determinação foi usado para interpretar r, e foi obtido através do coeficiente de correlação r ao quadrado (r2). Teste T e Análise de Variância foram utilizados para comparar variáveis contínuas entre grupos. Resultados: Da amostra total, 36,5% eram homens (idade 46,1±13,9; IMC 29,6±4,7kg/m2) e 63,5% eram mulheres (idade 46,1±13,8; IMC 29,3±6,5kg/m2), enquanto 50,25% tinham obesidade (idade 47,8±13; IMC 34,6±3,9kg/m2). No grupo com obesidade, a prevalência de OAJ foi de 56,6% (Score Total KOPS 18,3±9,3), enquanto no não-obeso foi de 23,6% (Score Total KOPS 12±7,1). Conclusão: A prevalência de OAJ na população com obesidade é significativamente maior que a prevalência na população em geral relatada na literatura.<br>Background: The relationship of Knee Osteoarthritis (KOA) and Obesity is explained by mechanical overloading on the cartilage and also by some systemic factors that participate in the pathogenic process. Since six in each ten individuals are overweight or obese in Portugal, this study’s goal is to estimate KOA’s prevalence in the Portuguese population with obesity. Methods: 655 volunteers (age 46,1±13,8; BMI 29,4±5,9kg/m2) answered to a Knee Osteoarthritis Pre-Screening Questionnaire (KOPS) Online version. Descriptive statistics and Pearson Correlation Coefficient were used for analyses and the coefficient of determination was used to interpret r and was obtained by squaring the correlation coefficient r (r2). Independent t-test and Analysis of Variance (ANOVA) were used to compare continuous variables between groups. Results: From total sample, 36,5% were male (age 46,1±13,9; BMI 29,6±4,7 kg/m2) and 63,5% were female (age 46,1±13,8; BMI 29,3±6,5kg/m2) while 50,25% had obesity (age 47,8±13; BMI 34,6±3,9kg/m2). In the Obese Group, KOA’s prevalence was 56,6% (KOPS Total Score 18,3±9,3) while in the Non-Obese was 23,6% (KOPS Total Score 12±7,1). Conclusion: KOA’s prevalence in the population with obesity is significantly higher than the prevalence in general population reported by literature.

<p>Obesity due to a high-fat diet is characterized by accumulation of inflammatory macrophages in tissues, leading to chronic low-grade systemic inflammation. Obese individuals also exhibit impaired tissue healing. With a high-fat feeding, cells are exposed to the elevated levels of dietary fatty acids (FAs), and such a change of microenvironment may alter their properties. Stem cells are cells capable of multipotent differentiation, and this potential allows them to play a promising role in healing and regenerative medicine. However, the effect of obesity, particularly various types of dietary FAs, on the function of stem cells remains largely unknown. Furthermore, obesity is a primary risk factor of osteoarthritis (OA), a disease of entire of joint involving degradation of cartilage, synovitis, and subchondral bone changes. Yet, the mechanisms linking obesity and OA are not fully understood. Furthermore, although macrophages are well recognized for their inflammatory role in obesity, little is known regarding functionality of these cells in regulating the effect of obesity on OA. This dissertation develops fundamental stem cell isolation and culture techniques, and utilizes animal models to investigate (1) the influences of high-fat diet induced-obesity on function of adult stem cells, (2) examine the effect of obesity and dietary FAs on OA, and (3) evaluate the role of macrophages in obesity-associated OA by depleting macrophages using a transgenic mouse model.</p><p>A variety of adult stem cell populations including bone marrow-derived mesenchymal stem cells (MSCs), subcutaneous adipose-derived stem cells (sqASCs), and infrapatellar-derived stem cells (IFP cells) were successfully isolated from lean and obese mice and expanded in vitro. Obese stem cells demonstrated altered multilineage differentiation potential and distinct immunophenotypes as compared to lean stem cells. Furthermore, FA treatment of lean stem cells significantly changed their multipotency but did not completely recapitulate the properties of obese stem cells.</p><p>Supplementation of &#969;-3 polyunsaturated fatty acids (PUFAs) in a high-fat diet was capable to mitigate injury-induced OA and decrease serum inflammatory cytokine levels. &#969;-3 PUFAs also significantly enhanced wound repair, while saturated FAs and &#969;-6 PUFAs act as a detrimental factor in OA, synovitis, and wound healing. Spontaneous locomotion of the mice was independent of OA development. Furthermore, using mathematical models and weight-matched mice, we found that OA was significantly associated with dietary FA content but not with body weight and mouse activity. These results suggest that metabolic factor plays a more significant role in obesity-associated OA than mechanical factor. </p><p>Despite their temporary improved metabolic parameters and reduced osteophyte formation, obese mice receiving short-term, systemic macrophage depletion did not mitigate cartilage degeneration following joint injury. Instead, macrophage depletion significantly enhanced joint synovitis in the surgery-operated joint. Macrophage-depleted mice also exhibited up-regulated expression of inflammatory cytokines in synovial fluid. These findings indicate that despite their recognized pro-inflammatory role, macrophages are vital in regulating the homeostasis of immune cells in the joint following injury. </p><p>Taken together, this research further elucidates the relationships among obesity, stem cells, and OA. The results from our study may provide a framework to develop stem cell therapy for obese patients and intervention program for obese OA patients in the future.</p><br>Dissertation

With increasing rates of obesity, research has begun to focus of co-morbidities of obesity such as osteoarthritis. The majority of existing research has focused on older adults as the group most likely to suffer from osteoarthritis. The purpose of this study was to determine if overweight and obese young adults exhibit biomechanical risk factors for knee osteoarthritis, and to determine if young adults with biomechanical risk factors of osteoarthritis can modify these with instruction. This purpose was divided into two separate studies. Study 1: Thirty adults between 18-35 years old were recruited into three groups according to body mass index: normal, overweight, and obese. Participants walked through the lab while we collected 3-d kinematic and kinetic data. Overweight and obese young adults walked with similar gait compared to normal weight young adults. Study 2: Nine young adults between 18-35 years were recruited who walked with stiff-knee gait. Baseline measures of gait were collected in the form of 3-d kinematics and kinetics as participants walked through the laboratory. They then completed the gait instruction program which consisted of four blocks of training. Each block included ten single steps where the participant was provided feedback, followed by 100 practice steps around the laboratory. Participants were successful in increasing sagittal plane kinematics and kinetics of interest in the study. Conclusion: Identifying individuals who had biomechanical risk factors of osteoarthritis according to body mass index was not possible. According to the results of our study, obese and overweight young adults are not at increased risk of osteoarthritis compared to normal weight young adults. Individuals who may be at increased risk due to stiff-knee gait were able to improve their gait following instruction.

One of the most poorly understood co-morbidities associated with obesity is the pathway to osteoarthritis of the knee. To implement appropriate preventative strategies, it is important to explore how obesity is a causal factor for osteoarthritis. The present research compared the kinematics and kinetics of a group of young obese, but otherwise healthy, adults to a group of young, healthy-weight adults, in an attempt to identify mechanical abnormalities at the knee during walking that may predispose the obese to osteoarthritis of the knee. Optotrak motion capture (Northern Digital Inc. Waterloo, Ontario) and a forceplate (AMTI OR6-7, Advanced Mechanical Technology Inc, Watertown, MA) were used to measure ground reaction forces and moments of 16 participants – 8 obese and 8 sex-, age- and height-matched healthy-weight – to analyze knee joint kinematics and kinetics at three walking speeds. Participants wore an accelerometer (ActiGraph GT3X, Fort Walton Beach, USA) for seven days to measure daily steps counts. Dependent t-tests were performed to determine group differences in ground reaction forces, knee angles and knee moments, as well as knee adduction moment impulse and cumulative knee adductor load (CKAL). The obese group walked at a significantly slower self-selected speed (p=0.013). While not statistically significant, the obese group did present with a more valgus mean dynamic knee alignment than the health-weight group. A significantly greater maximum abduction angle (p=0.009) and smaller minimum knee flexion angle at heel contact (p=0.001) was found in the obese group. A significant difference was found in the peak medial rotation moment in the transverse plane (p=0.003). A greater stance duration lead to a significantly greater knee adduction moment impulse (p=0.049) in the obese group. While significant group differences were not found in the steps per day, the obese group had a significantly greater CKAL (p=0.025). Obese young adults with healthy knees demonstrated a gait pattern of reduced medial knee joint compartment loading through greater knee abduction, medial knee rotation and a slower walking speed compared to matched controls. The ramifications of gait modifications on long-term musculoskeletal health remain unknown, but compensations may lead to increased risk of osteoarthritis of the knee.

Osteoarthritis (OA) is a group of diseases entailing degradation of joints, and has been designated as one of the key conditions for special attention during the World Health Organization’s Bone and Joint Decade (2000-2010) (Brooks & Hart, 2000). Research has demonstrated that body weight is the number one modifiable risk factor associated with the onset and progression of knee OA (Felson, 1996). However, exercise programs that aim to initiate weight loss and improve pain and function in knee OA often increase loading on the knee joint, contributing to degeneration of the knee and progression of the disease (Miyazaki et al, 2002). The introduction of a new anti-gravity treadmill, which utilizes a technology called Lower Body Positive Pressure (LBPP), allows the examination of the relationship between weight, knee pain and knee loading via knee acceleration during exercise. The null hypothesis states that there will be no significant difference in knee pain, knee function and knee joint acceleration when comparing full weight bearing and LBPP treadmill walking exercise in a young knee OA population. Twenty-two overweight/obese patients with mild or moderate early-onset knee OA were recruited to complete two 25 minute treadmill walking sessions (one full weight-bearing and one LBPP walking session) one week apart and two walkway walking sessions. Knee pain and knee acceleration were recorded. Paired t-tests and ANOVAs were used to compare conditions. On average, an LBPP of 12.3% body weight reduction reduced knee pain in our population. Knee pain was significantly lower during LBPP walking than during full weight-bearing walking. Knee acceleration decreased with increasing LBPP. Heel strike and toe-off data from walkway walking trials illustrated significantly different knee acceleration about the knee (slow walking loads were lower / fast walking were higher), as compared to treadmill walking sessions. This study illustrates that treadmill walking at a minimal level of LBPP can decrease knee pain and attenuate knee joint loads while allowing patients to complete exercise programs aimed at initiating weight loss and improving pain and function in knee OA. LBPP appears to be a promising tool for rehabilitation for those with painful knee OA and other lower body musculoskeletal conditions.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders, of which knee and hip OA account for the biggest burden of disease. It is a multifactorial disease with many risk factors and determinants such as age, sex and lifestyle factors including obesity, physical activity and diet being associated with both the onset and progression of the disease. Owing to the complex nature of the disease, no definitive treatment is available for OA. In order to better manage and treat this condition, it is important to improve the understanding of the lifestyle and structural factors related to the progression of the disease as well as the management of these factors. Therefore, the overall aims of this thesis were to identify determinants, risk factors and potential management strategies for the progression of OA in older adults. In this thesis, data from two studies were utilised. The first study was a prospective population-based cohort study of older adults who were between 50 and 80 years of age named the Tasmanian Older Adults Cohort Study (TASOAC). The participants for the study were selected from sex-stratified random sampling from the electoral role in Southern Tasmania (population 229,000). Data was collected at baseline and at 2.5, 5 and 10 years after the initial clinic assessment. At baseline, information on objective measures of body composition using body mass index (BMI) obtained by weight and height measures and fat and lean mass using dual-energy x-ray absorptiometry (DXA) were obtained. Pedometer measured ambulatory activity (AA) was recorded at baseline and socioeconomic status (SES) of the participants was collected by matching each participant’s residential address to the corresponding Australian Bureau of Statistics (ABS) Census Collection District to determine the Socio-Economic Indexes for Areas (SEIFA) value from the 2001 census. Knee pain of the participants at baseline and the 10-year follow-up was collected using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In addition, various imaging modalities such as radiography of the knee and hip at baseline and Magnetic Resonance Imaging (MRI) of the knee at baseline and the 10-year follow-up were conducted. Based on the radiographs, the status of radiographic OA (ROA) was defined. Utilising the knee MRI of the participants, several structural features such as Tibial cartilage volume and bone-marrow lesions (BMLs) were measured. The incidence of primary (first-time) total knee replacements (TKR) and total hip replacements (THR) were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The second study was a single-blind, single-center, 18-month, randomized controlled trial of older adults aged over 55 years named the Intensive Diet and Exercise for Arthritis trial (IDEA). The study was designed to evaluate the effects of weight loss obtained by diet and/or exercise on OA outcomes of the knee. Participants were eligible for the study if they had Kellgren-Lawrence grade (KLG) 2-3 tibiofemoral or tibiofemoral with patellofemoral OA of at least one knee, pain on most days due to knee OA, a BMI between 27 and 41 kg/m\(^2\) and a sedentary lifestyle, i.e. <30 min/week of formal exercise over the past 6 months. The participants were randomized to one of three 18-month interventions: exercise only, diet only or diet+exercise. MRI was obtained in a random subsample (n=105) of the IDEA participants at baseline and the 18-month follow-up. Using these MRIs, the medial and lateral menisci were segmented, and position and size parameters were measured quantitatively, along with semiquantitative extrusion measures. In the first study of this thesis, we assessed the association between SES and time to THR and TKR due to OA in older adults. The results showed that less disadvantaged participants were less likely to have a THR (i.e. less disadvantaged participants had a longer time to THR) in comparison to the most disadvantaged participants; however, this association was attenuated adjustments for hip pain and hip ROA. This suggests that time to joint replacements is determined according to the symptoms/need of the participants rather than their SES, indicating reductions in expected disparity between SES and time to joint replacement. This further confirms the usefulness of using joint replacement as a marker of end-stage OA in the knee and hip. The second study evaluated the association between AA and body composition measures such as BMI, fat mass, lean mass and waist circumference with the risk of TKR and THR due to OA in a population of community-dwelling older adults. The results showed that AA was related to a higher risk of TKR and a lower risk of THR. BMI, total fat, trunk fat mass and waist circumference were associated with a higher risk of TKR although body composition measures were not related to THR. These finding suggest that habitual activity and obesity may have different causal pathways for OA progression in knee and hip joints. In the third study, we investigated the prospective associations between baseline hip morphology defined as hip shape modes using Statistical Shape Modelling (SSM) and the progression of several clinical and MRI-based knee OA outcomes in older adults. The results showed that longer, wider femoral neck and larger femoral head (mode 1) was associated with increased risk of worsening knee pain, whereas wider femoral neck (mode 9) was related to reduced risk of worsening knee pain. Larger greater trochanter (mode 7) and greater acetabular coverage (mode 10) were linked to lower cartilage volume loss, while shorter, wider femoral neck (mode 9) was associated with increased cartilage volume loss. Smaller femoral head (mode 4) was related to increased risk of worsening BMLs. Greater acetabular coverage (mode 10) was associated with a reduced risk of TKR. Overall these findings may imply that hip shape variations are important in the long-term progression of knee OA in older adults. The fourth study assessed whether weight loss achieved by diet and/or exercise is related to meniscus extrusion parameters in the medial and lateral meniscus over 18 months. The results showed that weight loss was related to less progression of medial meniscus extrusion as measured by the maximum and mean extrusion distances. Weight loss was not associated with lateral meniscus position, medial or lateral meniscus size or with semiquantitative measures. These findings suggest that weight loss is related to beneficial modifications of medial meniscus extrusion in older adults. In conclusion, this sequence of studies first established the importance of TKR and THR as a marker of end-stage OA and showed that habitual activity and obesity act differently on end-stage OA of the hip and knee joints. Additionally, variations in hip shape may be an important structural feature that is associated with the progression of knee OA. Lastly, weight loss was related to less progression of meniscus extrusion in older adults with knee OA. Overall, the findings of this thesis suggest the importance of certain lifestyle factors. Better management of these factors may help to reduce OA progression in older adults.

Doutoramento em Motricidade Humana na especialidade de Atividade Física e Saúde<br>Background: Aquatic exercise is a nonpharmacologic intervention recommended for knee osteoarthritis (KOA) management. This study aimed to determine the effectiveness of 3-months of aquatic exercise program on KOA symptoms, physical fitness, and quality of life in overweight/obese adults with KOA. Methods: Eligibility criteria were 40 ≤ age ≤ 65 years; BMI ≥ 28 kg/m2; clinical and radiographic KOA. Participants were randomized in aquatic exercise group (AEG) and control group (CG). Physical Fitness was assessed by Six Minutes Walking Test (6MWT), Chair Sit and Reach Test (CSR), Five-Repetition Sit-To-Stand Test (FRSTST), Handgrip Strength Test (HST) and isokinetic and isometric knee strength tests. KOA symptoms and quality of life were assessed by self-reported questionnaires (Knee Injury and Osteoarthritis Outcome (KOOS), Brief Pain Inventory (BPI), Beck Depression Inventory (BDI), International Physical Activity Questionnaire (IPAQ), Weight and Lifestyle Inventory (WALLI). Body composition and morphology was measured by DXA scanner and waist, hip and thigh circumferences. Descriptive statistics and Pearson Correlation Coefficient were used for baseline analyses; Univariate Analyses of Covariance (ANCOVA) was used as primary analyses. Results: Final sample included 48 adults (BMI: 35.0±4.9 kg/m2; age: 55±7 years.), 23 in the CG and 25 in AEG. Regarding physical function, significant group effect was found for 6MWT, FRSTST (p<.001) and Isokinetic flexion peak torque, in both knees (p<.05). Regarding KOOS; BPI and BDI, significant group effect was found in all dimensions. Conclusion: PICO aquatic program was effective in improving KOA symptoms, physical fitness and health-related quality of life of its practitioners. Trial Registration: NCT01832545.<br>RESUMO: Introdução: O exercício aquático é considerado uma opção não farmacológica no tratamento e controlo dos sintomas da osteoartrose do joelho (OAJ). O principal objetivo deste estudo foi determinar a eficácia de um programa de 3 meses de exercício aquático nos sintomas, aptidão física e qualidade de vida de adultos com sobrepeso ou obesos com OAJ. Métodos: Os critérios de elegibilidade foram 40 ≤ idade ≤ 65 anos; IMC ≤ 28 Kg/m2 e diagnóstico clínico e radiológico de OAJ. Os participantes foram randomizados em grupo de exercício aquático (GEA) e grupo controlo (GC). Aptidão física foi avaliada pelos testes de Seis Minutos Marcha (6MM), Sentar e levantar da Cadeira 5X (SLC), Sentar e alcançar, Alcançar atras das costas, força de preensão manual e avaliação isométrica e isocinética da força dos músculos do joelho. Os sintomas e qualidade de vida foram avaliados por questionários de autorrelato: Questionário KOOS sobre o Joelho, Inventário Breve da Dor (IBD), Inventario de Depressão de Beck (IDB), Questionário Internacional de Atividade Física (IPAQ), Inventário do Peso e estilo de vida (IPEV). A composição corporal e morfologia foram avaliados por DEXA scanner e medidas de circunferência. Estatística descritiva, coeficiente de correlação de Pearson, análise Univariada de covariância (ANCOVA) e regressão linear múltipla foram os métodos estatísticos utilizados. Resultados: 48 adultos (IMC: 35.0±4.9 Kg/m2, idade: 55±7 anos) completaram o estudo, 23 no GC e 25 no EAG. Quanto à função física, foi encontrado efeito de grupo significativo no 6MM, SLC (p<.001), no pico de torque da força de joelho na flexão, em ambos os joelhos (p<.05). Efeito de grupo significativo foi encontrado nas dimensões do KOOS; IBD e IDB. Conclusão: O programa aquático PICO foi eficaz para promover a melhoria dos sintomas da OAJ, da aptidão física, estado psicológico e qualidade de vida relacionada com a saúde de seus praticantes. Registro de Clinical Trial: NCT01832545<br>FCT - Fundação para a Ciência e a Tecnologia

Knee osteoarthritis (OA) is a degenerative joint condition characterized by progressive joint pain, swelling, and loss of muscle and joint function for which there is no known cure. Current research indicates that the most important modifiable risk factor for the development and progression of knee OA is obesity, a condition that is increasingly common in older adults. Established treatment guidelines for knee OA recommend regular exercise for disease management. However, for obese patients weight-bearing exercise elicits large joint forces that can exacerbate symptoms and influence disease progression. Using a new anti-gravity treadmill capable of generating a lifting force called lower body positive pressure (LBPP), obese patients with knee OA can engage in regular physical activity while minimizing joint loading. The aim of this study was to assess the effect of a 12-week, anti-gravity treadmill walking (AGTW) program on knee pain and function in obese older adults with knee OA. The alternate hypothesis was that there would be a difference between Knee Injury and Osteoarthritis Outcome Score (KOOS) results before and after the anti-gravity treadmill walking program. A group of 25 participants with a mean (SD) age of 64.2 (6.1) years and BMI of 33.0 (6.8) kg/m2 completed AGTW twice per week for 12 weeks at a body weight percentage that minimized knee pain. Knee symptoms and function (KOOS), knee pain during full weight-bearing treadmill walking (FTW), isokinetic quadriceps and hamstring muscle strength, cardiovascular fitness (YMCA submaximal cycle ergometer test), general health status (SF-12), and activity level (average daily pedometer readings) were assessed at baseline and following the completion of the 12-week program using paired t-tests and Wilcoxon signed rank sum tests (α = 0.05). Improvements between baseline and outtake were found in all KOOS subscales, as well as hamstring and quadriceps thigh muscle strength. Knee pain during full FWB and AGTW decreased following the 12-week program. No significant differences were found in cardiovascular fitness, SF-12 scores, or average daily pedometer readings. The results of this study suggest that anti-gravity treadmill walking increases thigh muscle strength, reduces knee pain, and increases functional capacity during daily activities, including FTW in older, obese individuals with knee OA. Anti-gravity treadmill technology has the potential to improve the health and functional capacity of at-risk knee OA individuals, and advance current methods of rehabilitation and long-term management of chronic symptomatic knee OA.

Research Doctorate - Doctor of Philosophy (PhD)<br>Musculoskeletal conditions, including osteoarthritis of the knee or hip and spinal pain, are leading causes of global disability. Despite this, evidence suggests that the vast majority of patients with osteoarthritis and spinal pain do not receive care that is consistent with evidence-based clinical practice guidelines, including encouragement to engage in physical activity and support to lose weight. Two key barriers to the provision of guideline-recommended care are concerned with the accessibility of such care, and scalability of existing clinical models of care. Telephone-based models of care are a promising option to support patients with musculoskeletal conditions. While a number of trials investigating the use of telephone-based interventions for osteoarthritis and spinal pain have been published there remains uncertainty about the effectiveness and cost-effectiveness of telephone interventions for patients in this population group. In Chapter Two, a systematic review was conducted to assess the effectiveness of telephone-based interventions to support patients with osteoarthritis and spinal pain on pain intensity and disability. Seven electronic databases were searched for randomised controlled trials (RCTs) and non-randomised controlled trials that aimed to test the effectiveness of telephone-based interventions for patients with osteoarthritis and spinal pain. Twenty-three studies with a total of 4,994 participants were included. All included studies examined interventions focused on supporting self-management and providing education in addition to a range of intervention targets, for example, physical activity. The review found moderate-quality evidence that telephone-based interventions reduce pain intensity (n = 5 trials, n = 1,357 participants, standardised mean difference (SMD) -0.27, 95%CI:-0.53 -0.01, Tau2 = 0.06, I2 = 74%) and disability (n = 7 trials, n = 1,537 participants, SMD -0.21, 95%CI: -0.40 to -0.02, Tau2 = 0.03, I2 = 56%) compared to usual care. There was moderate-quality evidence that telephone plus face-to-face interventions are no more effective than face-to-face interventions alone. The results highlight the potential for telephone-based services to support osteoarthritis and spinal pain patients to access better quality care. All clinical practice guidelines for osteoarthritis recommend weight loss as a core treatment for patients with knee osteoarthritis. Despite these recommendations, few overweight patients with knee osteoarthritis receive care to support weight loss. There is evidence to support telephone-based approaches in achieving modest weight loss among overweight participants in the general population. Similarly, telephone-based interventions have been found to be effective in addressing behavioural determinants of weight, diet and physical activity in the general population. However, there are no previous studies primarily focused on the provision of weight loss care via telephone for patients with knee osteoarthritis. Chapters Three and Four presents an a priori protocol and statistical analysis plan for a high-quality pragmatic RCT testing the effectiveness of referring patients with knee osteoarthritis, who are overweight or obese, to an existing non-condition specific telephone-based weight loss intervention. Eligible patients (n=120) were randomly allocated to receive the weight loss intervention or usual care. Chapter Five presents the results of the trial and showed that there were no differences between groups for knee pain intensity over 6 months (area under the curve, mean difference 5.4, 95%CI: -13.7 to 24.5, p=0.58; equivalent to a 0.2 point difference on the pain intensity numerical rating scale 95%CI: -0.53 to 0.94) or weight change (the hypothesised mechanism to reduce pain intensity) at 6 months (self-reported weight; mean difference -0.4, 95%CI: -2.6 to 1.8, p=0.74). These results suggest that among patients with knee osteoarthritis who are overweight, telephone-based weight loss support, provided using an existing weight loss intervention might not adequately support patients with knee osteoarthritis to reduce knee pain intensity or weight. Given the scarce resources in healthcare, policy-makers are increasingly requiring evidence of economic value for healthcare interventions to make informed decisions about how to allocate resources. Therefore, undertaking economic evaluations of knee osteoarthritis management approaches is important. Chapter Six presents an economic evaluation of the RCT presented in Chapters Three, Four and Five. Quality-adjusted life years (QALYs) was the utility measure of effect and pain intensity, disability, weight, and BMI were the clinical measures of effect. Costs included intervention costs, healthcare utilisation costs (healthcare services and medication use) and absenteeism costs due to knee pain, collected using a patient self-reported inventory. The primary cost-effectiveness analysis was performed from the societal perspective, which accounted for a range of cost categories (intervention costs, healthcare utilisation costs and absenteeism costs due to knee pain). Mean cost differences between groups (intervention minus control) were $493 (95%CI: -3513 to 5363) for healthcare costs, $-32 (95%CI: -73 to 13) for medication costs, and $125 (95%CI: -151 to 486) for absenteeism costs. The total mean difference in societal costs was $1197 (95%CI: - 2887 to 6106). For QALYs and all clinical measures of effect, the probability of the intervention being cost-effective compared with usual care was less than 0.36 at all willingness-to-pay values. These findings suggest from a societal perspective referral to an existing non-condition specific telephone-based weight loss service was not a cost-effective relative to usual care for quality-adjusted life years (QALYs). Whilst the studies included in this thesis have advanced the evidence-base regarding the effectiveness of telephone-based interventions for the delivery of recommended care for patients with osteoarthritis and spinal pain, there remain a number of aspects that require further investigation. Specifically, although the systematic review found that telephone-based interventions should be considered for the management of osteoarthritis and spinal pain, the referral of patients with knee osteoarthritis patients who were overweight or obese to an existing telephone weight loss service was neither effective nor cost-effective despite offering a scalable, accessible option for the delivery of weight loss care. Given the high prevalence of osteoarthritis, and that excess weight is a key driver for the onset and progression of this condition; a dedicated line of research to understand how to best deliver weight loss support at scale is warranted. This research should focus on how to best integrate and optimise scalable, effective weight loss interventions into clinical practice; such that clinicians can embed this care into routine practice and improve outcomes for patients with osteoarthritis.

The ability to estimate body mass from human skeletal remains with a high degree of accuracy would be significant for the identification of identifying unknown individuals in a forensic anthropology context, documenting secular change in modern populations, and evaluating any prevalence in prehistoric populations. Modern research investigating body mass incorporates one of two models: morphometric and biomechanical. The morphometric model views the body as a cylinder, where weight estimates are gathered from extreme points such as the breadth of the pelvis. In contrast, the biomechanical model incorporates engineering principles and biology to understand the effects of mass on the human skeleton. Only the biomechanical model can accommodate extremes in body mass, such as those exhibited by modern populations. This study examined the accuracy of estimating body mass (obesity in particular) from human skeletal remains using a suite of traits shown to be significant in previous studies, including documented biomechanical analysis of obese individuals involving gait and sit-to-stand (STS) movements. It was hypothesized that using a combination of methods, body mass could be estimated with a high degree of accuracy. Using a large skeletal sample (n = 191), composed of male and females with documented age, weight, and height, the following three variables were examined: (1) the spinal manifestation of diffuse idiopathic skeletal hyperostosis (DISH), (2) osteoarthritis (OA) of the tibiae, and (3) external femoral dimensions. These were then subject to statistical tests. Spearman's rank-order correlation and Mann-Whitney U tests showed significant relationships between DISH and obesity in females (p<.05), but not for males. The presence and severity of OA of the medial condyles were also significantly related to BMI in females (p<.05). In males, the relationship between BMI and OA was only significant on the condyles of the right tibiae (p<.05). Finally, ANOVA and Pearson's product-moment correlation tests were performed to evaluate the cross-sectional dimensions of the femur. The effect of age, stature, and BMI were also examined. ANOVA results showed a significant effect between BMI and M-L cross-sectional dimensions among both sexes (p<.05). Initial Pearson's tests performed separately on males and females showed no significant correlations; however, after the sexes were pooled, small to moderate negative correlations between the M-L/A-P ratio along the diaphysis of the femur and BMI were found. Finally, multiple regression analyses were performed. The models for both sexes with all ten variables was statistically significant for BMI. The final accuracy rate was 78.48% for females and 84.37% for males. The primary goal of this study was to evaluate Moore's (2008) body mass estimation study. In this investigation, however, all dimensions of the femur were performed using an osteometric board and sliding calipers following the guidelines used by Agostini and Ross (2011). The results of this study paralleled many of the observations seen in previous studies, particularly the M-L lateral widening of the femur. Future research should continue to examine the relationship of DISH and OA with body mass, particularly regarding the varying manifestations between the sexes and confounding factors such as age.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina<br>Introdução: A gonartrose é uma das causas mais comuns de incapacidade após a quarta década de vida, com a prevalência aumentando com a idade. O sobrepeso e a obesidade são fatores-chave para o desenvolvimento e progressão da gonartrose, o que justifica fortemente a recomendação de perda de peso nesses casos. No entanto, apenas alguns dos doentes que apresentam concomitantemente excesso de peso e gonartrose têm apoio na implementação de medidas para perder peso. É, pois, necessário clarificar o impacto de estratégias não-cirúrgicas de perda de peso nestes doentes.Objetivo: Avaliar os efeitos de medidas não-cirúrgicas para perda de peso ao nível da dor, incapacidade funcional e qualidade de vida em doentes com sobrepeso ou obesos diagnosticados com gonartrose.Métodos: Foram pesquisados ensaios clínicos randomizados (ECR) publicados até 21 de Novembro de 2018 nas bases de dados Cochrane, Pubmed, EMBASE e PEDro comparando intervenções conservadoras para perda de peso com intervenções de controle ativo ou inativo (cuidado usual, somente exercício, nenhuma intervenção). Dois revisores extraíram os dados de forma independente. Diferenças médias padronizadas (DMP) de estudos individuais foram agrupadas através de meta-análise para expressar o tamanho do efeito (TE) do tratamento. Foi avaliado o risco de viés para cada estudo e a qualidade dos resultados foi classificada seguindo a abordagem Grading of Recommendations, Assessment, Development and Evaluation (GRADE).Resultados: Foram identificados 11 ECR elegíveis para inclusão. Todos os ensaios incluídos apresentaram risco de viés pouco claro. A qualidade dos resultados foi de alta a muito baixa. Dados agrupados apoiaram o uso de medidas não-cirúrgicas para perda de peso para melhorar a incapacidade auto- referida (TE = 0,33, IC 95% 0,17 a 0,49; p < 0,001; evidência de alta qualidade), o desempenho no teste funcional de caminhada (TE = 0,16; IC 95% 0,01 a 0,31; p = 0,031; evidência de alta qualidade), a qualidade de vida física (TE = 0,33, IC 95% 0,18 a 0,48, p < 0,001, evidência de alta qualidade) e a gonalgia (TE = 0,52, 95% IC 0,25 a 0,80; p < 0,001; evidência de qualidade moderada). Não houve fortes evidências de que intervenções conservadoras para perder peso tenham efeito benéfico na qualidade de vida mental (p = 0,58; evidência de baixa qualidade) nem no teste de subir escadas (p = 0,19; evidência de qualidade muito baixa).Discussão/Conclusão: Evidência de alta qualidade sugere que as intervenções conservadoras para a perda de peso fornecem benefícios (embora modestos) quanto à incapacidade funcional (auto-referida e teste funcional da caminhada) e qualidade de vida física. Evidência de qualidade moderada suporta um efeito positivo notório na melhoria da gonalgia. São necessários mais ensaios clínicos bem estruturados que testem os efeitos de intervenções não-cirúrgicas de perda de peso, particularmente no teste funcional de subir escadas e na qualidade de vida mental, onde a evidência de melhoria não é clara.<br>Introduction: Knee osteoarthritis (OA) is found mostly in people over 45 years old and is one of the common causes of disability after the fourth decade of life, with prevalence increasing with age. Being overweight is a key ingredient for knee OA and obesity is an established risk factor for development and progression of knee OA. Therefore, clinical guidelines strongly recommend conservative weight loss as primary management of concomitant weight excess and knee osteoarthritis (OA). Despite those recommendations, only few overweight patients with knee OA have support for weight loss management and there is still a need to understand the most recent evidence of the impact of nonsurgical weight loss strategies in obese or overweight patients with knee OA.Objective: To assess the effects of nonsurgical weight loss interventions on pain, physical function and quality of life in overweight or obese patients diagnosed with knee OA.Methods: Cochrane Library, Pubmed, EMBASE and PEDro were searched for randomized controlled trials (RCTs) published prior to November 21, 2018. RCTs comparing nonsurgical (conservative) weight loss interventions with an active or inactive control intervention (usual care, only exercise, no intervention) were selected. Two review authors independently extracted data. Standardized mean differences (SMDs) of individual studies were pooled using both random and fixed-effects meta-analysis (depending on the existence or not of heterogeneity, respectively) to express treatment effect sizes (ES) from the end of the treatment. The Cochrane tool was used to assess risk of bias for each study and the quality of evidence across studies was evaluated following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results: We identified eleven RCTs eligible for inclusion. All included trials had unclear risk of bias as no strategies were reported to address the issue of incomplete blinding. The quality of evidence for outcomes, using GRADE approach, ranged from high to very low. Pooled data supported the use of nonsurgical weight loss intervention compared with control for improving knee pain (Effect Size (ES) = 0.52, 95% Confidence Intervals (CI) 0.25 to 0.80; p < 0.001; moderate quality evidence), self-reported disability (ES = 0.33, 95% CI 0.17 to 0.49; p < 0.001; high quality evidence), 6MWT (ES = 0.16; 95% CI 0.01 to 0.31; p = 0.031; high quality evidence) and physical quality of life (ES = 0.33, 95% CI 0.18 to 0.48; p < 0.001; high quality evidence). There was no strong evidence that the intervention has an effect in timed stair climb test performance (ES = 0.27, 95% CI -0.13 to 0.67; p = 0.19; very low quality evidence) neither in mental quality of life (ES = 0.05, 95% CI -0.12 to 0.21; p = 0.58; low quality evidence).Discussion/Conclusion: High-quality evidence suggests that nonsurgical weight loss interventions provide benefit, even though small, in terms of self-reported disability, performance on 6MWT and physical quality of life. Also, moderate quality evidence supports a moderate positive effect of weight reduction interventions in the improvement of knee pain. Further powered well-designed clinical trials testing the effects of nonsurgical weight loss interventions are required, particularly on timed stair climb test and mental quality of life, where evidence of improvement is unclear.

Orientação: António João Labisa da Silva Palmeira<br>Objetivo – Esta dissertação tem como objetivos a realização de uma Revisão rápida e Sistemática de Literatura, que por sua vez tem por objetivo analisar a relação entre factores motivacionais e barreiras para a prática de atividade física e os níveis de atividade física em adultos com dor no joelho por osteoartrite, e a realização de um estudo observacional transversal que tem por objetivo efetuar a análise da associação entre problemas relacionados com o joelho por osteoartrite e dor neuropática com os níveis de atividade física e a motivação para a prática de atividade física em adultos em manutenção da perda de peso. Método – Para a realização da Revisão rápida e Sistemática de Literatura foram utilizadas as seguintes bases de dados: PubMed, b-On e Google Académico. Foram considerados critérios de inclusão e de exclusão, que através de um processo de triagem permitiram incluir nesta revisão cinco estudos elegíveis, que incluíram no total 1986 participantes. Para a obtenção de dados e consequente realização do estudo observacional transversal foi efetuada uma análise secundária dos dados do estudo controlado randomizado Navigating to a Healthy Weight (NoHoW). Estes dados foram auto-reportados em quatro questionários validados para português e recolhidos pelos investigadores do estudo NoHoW, aos 18 meses. No estudo observacional transversal, prepararam-se os dados e obteve-se uma amostra (n = 961), dos quais 67.95% eram mulheres, a idade média foi de 45.90 anos (dp 11.49) e o IMC inicial médio foi de 29.06 kg/m² (dp 4.95). Resultados – Na Revisão rápida e Sistemática de Literatura, a dor no joelho foi uma barreira significativamente associada à atividade física (AF) moderada a vigorosa adequada (que cumpre as recomendações para a prática de AF), como também a falta de motivação, medo de cair ou medo de lesões. A prática de AF foi maior nos indivíduos com motivação. Foram encontradas associações estatisticamente significativas entre a redução da dor, melhorias na função física e na rigidez com a prática de AF e com a adesão à AF. Factores motivacionais, para aderir e permanecer a praticar AF foram: querer melhorar a função física, aliviar a dor ou artrite e desfrutar do exercício. No estudo observacional transversal verificou-se que ter maior intensidade de dor no joelho foi preditiva de menos AF vigorosa e menos tempo a caminhar. Possuir mais motivação controlada foi preditiva de menos tempo a caminhar e mais tempo sentado/a. Em contrapartida, ter melhor função física nas atividades da vida diária foi preditiva de mais tempo a caminhar. Possuir mais motivação autónoma foi preditiva de mais AF vigorosa e de menos tempo sentado/a. Conclusões – A Revisão rápida e Sistemática de Literatura e o estudo observacional transversal obtiveram resultados concordantes. A dor no joelho (intensidade) e a falta de motivação (motivação controlada) foram factores que levaram à diminuição dos níveis de AF. Ter motivação (motivação autónoma) foi um factor que levou ao aumento dos níveis de AF.<br>Objective - This dissertation aims to carry out a quick Systematic Literature Review, which aims to analyse the relationship between motivational factors and barriers to the practice of physical activity and the levels of physical activity in adults with knee pain due to osteoarthritis, and conducting a cross-sectional observational study that aims to analyse the association between problems related to the knee due to osteoarthritis and neuropathic pain with levels of physical activity and the motivation to practice physical activity in adults in maintaining weight loss. Method - To carry out this quick Systematic Literature Review, the following databases were used: PubMed, b-On and Google Scholar. Inclusion and exclusion criteria were considered, through a screening process that allowed to include in this review five eligible studies, which included a total of 1986 participants. To obtain data and consequent conduct of the cross-sectional observational study, a secondary analysis of the data from the randomized controlled study Navigating to a Healthy Weight (NoHoW) was performed. These data was self-reported in four questionnaires validated for Portuguese and collected by the researchers of the NoHoW study, at 18 months. In the observational cross-sectional study, data was prepared and a sample was obtained (n = 961), of which 67.95% were women, the mean age was 45.90 years (sd 11.49) and the initial BMI average was 29.06 kg/m² (sd 4.95). Results - In this quick Systematic Literature Review, knee pain was a barrier significantly associated with moderate to vigorous physical activity (PA) (by recommendations for PA practice), as well as lack of motivation, fear of falling or fear of injury. The practice of PA was higher in individuals with motivation. Statistically significant associations were found between pain reduction, improvements in physical function and stiffness with the practice of PA and adherence to PA. Motivational factors to adhere and continue to practice PA was wanting to improve physical function, relieving pain or arthritis and enjoying exercise. In the cross-sectional observational study, it was found that higher intensity knee pain was predictive of less vigorous PA and less time to walk. Having more controlled motivation was predictive of less time walking and more time sitting. In contrast, having a better physical function in the activities of daily living was predictive of more time walking. Higher autonomous motivation was predictive of more vigorous PA and less sitting time. Conclusions – This quick and Systematic Literature Review and the observational cross sectional study obtained concordant results. Knee pain (intensity) and lack of motivation (controlled motivation) were factors that led to a decrease in PA levels. Being motivated (autonomous motivation) was a factor that led to increased levels of PA.