Thesis (Ph. D.)--Oregon State University, 2007. / Includes bibliographical references (leaves 113-116). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (Ph. D.)--Oregon State University, 2007. / Includes bibliographical references (leaves 113-116).

Primary osteoarthritis (OA) is a late-onset, degenerative condition of synovial joints, and is the major cause of pain and disability in older persons. OA represents a significant disease burden and focus of research, especially as no disease-modifying therapies exist to manage the condition. The genetic influence to OA is complex and polygenic. The arcOGEN study, the most powerful genome-wide association study yet to investigate OA in humans, identified the 9q33.1 locus to be significantly associated with hip OA in females. TRIM32 lies within the 9q33.1 susceptibility locus and may have strong biological relevance to OA; it encodes a protein with E3 ubiquitin ligase activity. Sanger sequencing of TRIM32 in the youngest 500 female patients with hip OA from the arcOGEN study was performed to identify rare variants in TRIM32 that are associated with OA of the hip in females. Polymorphisms were identified in the proximal promoter, and 3’untranslated regions (3’UTR) of TRIM32 that are disproportionately represented in female patients with hip OA, compared to the control population. In vitro studies identified expression of TRIM32 in human femoral head cartilage; reduced expression of TRIM32 was also demonstrated in femoral head primary articular chondrocytes from patients with hip OA compared to control patients. Trim32 knockout resulted in increased aggrecanolysis in murine femoral head explants. Murine chondrocytes deficient in Trim32 also exhibited increased expression of markers of a mature chondrocyte phenotype in response to anabolic cytokine stimulation, and increased expression of markers of a hypertrophic chondrocyte phenotype upon catabolic cytokine stimulation. In vivo studies of joint degeneration in Trim32 knockout mice demonstrated increased cartilage degradation and tibial epiphyseal bone changes after surgically induced knee joint instability, compared to wild-type mice. Increased cartilage degradation and medial knee subchondral bone changes were also identified upon ageing of Trim32 knockout mice. These results further implicate TRIM32 in the genetic predisposition to OA, and indicate a role for TRIM32 in the joint degeneration evident in OA. These results support the further study of TRIM32 in the pathophysiology of OA and development of novel therapeutic strategies to manage OA.

背景：膝痹因勞損或年高，膝失精血充養，經氣不利等原因所導致並以膝部長期固定疼痛，活動時關節內有聲響等為主要表現的肢體屏病類疾病。多發於老年人, 西醫的膝骨性關節炎、退行性膝關節病、膝關節滑膜炎，髏骨軟他症等屬於該疾病的範疇。該疾病所導致的疼痛以及活動障礙嚴重影響了人們的生活質量，亦極大地增加了家庭以及社會負擔。中醫學認為膝痹是因為肝腎虧虛，精血不足，筋骨失養，風、寒、濕、熱等邪氣趁虛而人，阻滯經脈氣血所致。 目的：通過對近十二年文獻的研究，分析溫針治療膝痹的臨床療效，作用機制，以及評價當前文獻質量，反映國內外溫針治療膝痹的研究現狀，為進一步的研究提供思路和依據。 方法：採用計算機檢索國內外相關臨床研究文獻。中文文獻檢索數據庫為： 中國 期刊全文資料庫（ CNKI ），檢索主題詞為“溫針，’ ，“針灸療法，’，"溫針療法 ,“溫針灸， "膝"，“膝關節 。英文文獻檢索數據庫為PubMed ，檢索主題詞為 “ acupuncture and moxibustion ,“warm needling’,“warm acupuncture,“warming needle moxibustion , “arthralgia syndrome’,“ knee arthralgia,“knee osteoarthritis,“osteoarthritis of the knee",“osteoarthritis of knee join t , “degenerative arthritis of the knee" , 九enile knee osteoarthri ti s 。檢索年限為2005 至2016 年。 將篩選後的文獻進行樣本量，診斷標準，隨機方法，臨床分期，療效評價方法，幹預措施，幹預週期及遠期隨訪，不良反應及脫失率，文獻評價等方面的統計與比較。 結果： 多數文獻認為溫針治療膝屏有較好的療效，但日前國內溫針治療膝痹的文獻質量普遍不高，通過對近十二年來溫針治療膝蟬的臨床研究進行回顧，發現國內臨床研究在樣本量估算，隨機方法，分級、分期進行治療，診斷標準和療效評價標準’遠期療效隨訪，不良反應和脫失率，隨機對照試驗質量等方面存在一定問題。且在單一療法的評價方面尚缺乏較強的說服力。本次研究通過Meta 分析雖然可得出溫針較口服西藥與單純針刺的療效為佳，但由於納入研究的試驗數量有限, 文獻質量亦參差不齊，故所得出的結論有一定的侷限性。 結論：由於文獻質量存在一定的問題，故而單一療法的評價方面尚缺乏較強的說服力。為了進一步證明溫針治療膝痹的療效，需要開展更多的設計合理，執行嚴格的大樣本、多中心、高質量的隨機對照試驗，並且在試驗中應進行遠期療效觀察，詳細描述研究過程中的不良反應以及脫失率， J,,j、期提供更加全面可靠的臨床依據。溫針治療膝痹的機制研究方面尚未完善對溫針治療的影響因素如灸量選擇，針刺深度選擇等方面亦未達成共識，這些方面亦可以作為未來研究的發展方向。

通过检索2003年1月一2013年12月中国期刊全文数据库(CNKI)全部医学期刊，对所筛选出的55篇临床文献的操作方法、硏究过程和结论进行归纳和分析。 结果表明温针不但能起到针刺效果还能作用到深层组织温通经络，消炎镇痛；温针对所有四型的膝痹（风寒湿阻型、阳虚寒凝型、瘀血阻滞型和肾虚髓亏型）均有治疗的作用，但对阳虚寒凝型的作用较弱；温针治疗膝痹常用犊鼻和膝眼等局部穴位，并可结合辨证配1-2穴；针刺常用普通剌法，平补平泻；施以何种灸量，要根据患者的身体状况而定，一般2壮适中。 在文献中多用温针治疗与其他疗法进行对比，对比发现：温针缓解关节僵硬的作用明显；电针则侧重于抗炎镇痛；中频治疗可以解除软组织的粘连，同时修复损伤组织；局部阻滞能减小关节软骨间的摩擦，较快起效，减轻疼痛症状；口服中药可以从内而外的改善关节病变；西药口服能较快缓解疼痛和部分临床症状;推拿、康复、运动训练等疗法的配合，有助于缓解肌肉痉挛，同时减少膝关节软骨之间的压力等等。由于众多疗法起效的侧重方向不同，因此在临床治疗中，为了提高治愈率常将温针与电针、中频、局部阻滞、口服中药或西药等疗法联合应用。但采用何种疗法还要根据患者的实际情况，切勿使用过多种手法，增加患者的关节负担。 虽然温针治疗膝痹的作用已经得到较多的临床试验验证，但其作用机制的探讨仍然不足。接下来的硏究应注重临床硏究方法的改进，规范温针灸的操作过程，重视温针治疗膝痹的作用机制，从而提高温针治疗的膝痹的临床疗效和理论依据。 关键词：温针 膝痹 临床试验 综述文献

Orientadores: Sergio Roberto Peres Line, Paulo Sergio Flores Campos / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-09T19:33:47Z (GMT). No. of bitstreams: 1 Campos_MariaIsabelaGuimaraes_D.pdf: 3191665 bytes, checksum: ffbd544df321690468c5974728a9d0a8 (MD5) Previous issue date: 2007 / Resumo: O objetivo deste estudo foi investigar a ocorrência dos polimorfismos IL-1A (-889C/T), IL-1B (-511C/T), IL-1B (+3953C/T), IL-1RN VNTR (intron 2), IL-6 (-174G/C) e TNF-A (-308G/A) em 92 pacientes com sinais imaginológicos de alterações degenerativas da ATM e em 102 indivíduos controles. O DNA dos voluntários foi extraído a partir de células epiteliais da mucosa bucal e submetido às técnicas de PCR (reação em cadeia da polimerase) e RFLP (polimorfismo no comprimento do fragmento de restrição) para a detecção dos possíveis alelos. Os produtos do PCR/RFLP foram analisados em géis de poliacrilamida a 10%, corados por prata. Os polimorfismos foram analisados individualmente e sob a forma de haplótipos. O programa Arlequin (ver. 3.01) foi utilizado para calcular o desequilíbrio de ligação entre os loci polimórficos da IL-1 e determinar seus possíveis haplótipos. Adicionalmente, um questionário foi aplicado aos voluntários para investigar a presença de fatores locais e sistêmicos associados a DTMs. Os dados do questionário, bem como, as freqüências alélicas, genotípicas e haplotípicas foram comparadas entre os dois grupos com auxílio do teste qui-quadrado (p<0,05). O método de Mantel-Haenszel foi utilizado para o cálculo de odds ratio (OR), com intervalo de confiança (IC) a 95% para estimar o risco de cada fator avaliado na ocorrência da doença. As análises estatísticas foram realizadas com auxílio do programa Epi Info (ver. 6.04). Estresse e/ou ansiedade (p=0,001), uso freqüente de ansiolíticos ou antidepressivos (p=0,000), hábitos parafuncionais (p=0,000), histórico de trauma facial (p=0,005), queixas constantes de dores em outras articulações (p=0,000), presença de alterações sistêmicas (p=0,000) e histórico de familiares com DTM (p=0,000) se mostraram significativamente mais freqüentes nos pacientes do grupo teste. Considerando o polimorfismo IL-1B (+3953C/T), o alelo C e genótipo C/C mostraram maior ocorrência no grupo teste do que no controle (p=0,000), aumentando em 3,24 e 6,35 vezes o risco de desenvolvimento de DTM, respectivamente. A presença do genótipo C/T do polimorfismo IL-1A (-889C/T) aumentou em aproximadamente 1,87 vezes o risco em desenvolver DTM. Os loci polimórficos IL-1B (+3953C/T), IL-1A (-889C/T) e IL-1RN se mostraram em desequilíbrio de ligação e foram analisados simultaneamente, demonstrando que indivíduos portadores do respectivo haplótipo TC1 apresentaram-se 0,11 vezes mais protegidos em desenvolver DTM. Considerando o polimorfismo IL-6 (-174G/C), indivíduos portadores do alelo C e do genótipo C/G apresentaram um risco 1,60 e 1,98 vezes maior em desenvolver DTM, respectivamente. O presente estudo mostra que polimorfismos nos genes da IL-1 e IL-6 estão associados ao desenvolvimento de DTMs na população estudada e corrobora evidências anteriores de que fatores psicológicos, locais e sistêmicos devem atuar em conjunto no desenvolvimento de DTMs / Abstract: The aim of this study was to investigate the occurrence of IL-1A (-889C/T), IL-1B (-511C/T), IL-1B (+3953C/T), IL-1RN VNTR (intron 2), IL-6 (-174G/C) and TNF-A (-308G/A) polymorphisms in 92 patients with degenerative changes of temporomandibular joint. Control group comprised 102 healthy individuals. Genomic DNA was obtained from oral mucosa cells and polymorphisms were identified by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). Restriction products were visualized by electrophoresis on vertical 10% polyacrylamide gels, followed by silver staining. The Arlequin software (ver.3.01) was used to determine haplotype frequencies and linkage disequilibrium among the IL-1 polymorphic sites. The polymorphisms were analyzed individually and in haplotypes. In addition, a questionnaire was answered by volunteers in order to assess the presence of local and systemic factors associated to TMDs. Data of the questionnaires, frequencies of alleles, genotypes and haplotypes were compared between the two groups using the chi-squared test (p<0.05). The odds ratio (OR) was calculated with 95% confidence intervals (CI) to estimate the relative risk of each factor on the disease occurrence. The statistical analyses were performed using Epi Info software (ver. 6.04). Stress and/or anxiety (p=0.001), frequent usage of anxiolytic or antidepressant drugs (p=0.000), oral parafunctions (p=0.000), history of facial trauma (p=0.005), presence of systemic diseases (p=0.000), complaints of pain in other joints (p=0.000) and history of relatives with TMD (p=0.000) were significantly more frequent in patients of test group. For the IL-1B (+3953C/T) polymorphism, allele C and genotype C/C were significantly frequent in patients of test group (p=0,000), showing 3,24- and 6,35-folds increased risk for TMD development, respectively. Individuals with genotype C/T of IL-1A (-889C/T) polymorphism showed a 1,87-folds increased risk for TMD development. The polymorphisms IL-1B (+3953C/T), IL-1A (-889C/T) and IL-1RN were in linkage disequilibrium and were analyzed in haplotypes. The respective haplotype TC1 showed a protective effect increased in 0,11-folds. Individuals with allele C and genotype C/G of IL-IL-6 (-174G/C) polymorphism showed a 1,60- and 1,98-folds increased risk for TMD development, respectively. The present study shows that IL-1 and IL-6 polymorphisms are associated with development of TMDs in the studied population and corroborates previous evidences that psychological, local and systemic factors should act in combination to promote development of TMDs / Doutorado / Histologia e Embriologia / Doutor em Biologia Buco-Dental

INTRODUCTION: Altered neuromuscular control and knee joint instability are commonly observed in populations with knee osteoarthritis (OA). Since knee OA is more prevalent in females, sex-related differences in muscle activation and movement strategies during activities of daily living (ADL) are theorized to be a contributing factor to the increased prevalence in females. PURPOSE: The aims of this thesis were: 1) identify sex differences in joint dynamics and muscle activation patterns in older adults with knee OA and healthy older adults; and 2) investigate whether differences in co-activation and dynamic knee joint stiffness exist between sexes in an OA and healthy populations. For both aims, squatting tasks were evaluated because it is a common and critical component in ADLs. METHODS: Thirty healthy individuals (15 females) and thirty individuals with knee OA (15 female) performed three two-legged squats at a self-selected pace on two force platforms. Hip, knee, and ankle sagittal and frontal plane joint angles, moments and powers were calculated and electromyography (EMG) of eight muscles crossing the knee joint was recorded for the test (OA affected or dominant) limb. Maximum voluntary isometric contractions were used to normalize the EMG data. Co-activation indices for six antagonist muscle pairings and dynamic knee joint stiffness (DKJS) were calculated for the acceleration and deceleration phases of squat descent and ascent. Two-way ANOVAs (Sex X OA status) were used to characterize differences in muscle activation patterns and movement strategies. RESULTS: For aim 1, decreased hip, knee and ankle sagittal plane range of motion was identified in the OA participants, with females showing the greater deficits compared to the males. Males with OA implemented a hip dominant strategy by increasing hip joint moments and decreasing knee joint moments compared to the females. Indifferent of joint status, females performed the squat with more hip adduction compared to males. Females with OA demonstrated greater hip adduction and knee valgus angles throughout the squat, contributing to the decrease in the frontal plane range of motion. Additionally, hip joint power was lower in all female participants compared to males while knee joint power was lower in the OA participants. For aim 2, females with OA, and to lesser extent males with OA had greater DKJS around peak knee flexion compared to the healthy participants. Co-activation indices revealed sex differences in neuromuscular control: Females with knee osteoarthritis had higher muscle activation magnitude and co-activation of antagonistic muscles, whereas the males used a more selective increase in hamstring co-activation and more balanced quadriceps-hamstring recruitment. CONCLUSION: Two-legged squats were able to detect sex and OA related functional deficits at the knee and adjacent hip and ankle joints. OA had a greater effect on the movement and neuromuscular control in females than males and the squat identified specific deficiencies that can be targeted for rehabilitation.

The pathogenesis of osteoarthritis (OA) is complex, but likely involves destruction of articular cartilage by endogenous enzymes (Dingle 1979). Factors controlling this are not well understood. Cetabolin, a 21,000 molecular weight peptide structurally end functionally related to interleukin-1, stimulates living but not killed chondrocytes in vitro to degrade their matrix (Fell and Jubb 1977, Saklatvala et al. 1983), suggesting it is not itself a degradative enzyme but functions as a control factor. The work in this thesis investigated the possible role of cetabolin in the pethogenesis of OA by measuring catabolin production by cultures of synovium excised from the canine anterior cruciate ligament transection model of OA. Normal cenine synovium in culture was shown to produce a factor which can stimulate the release of glycoseminoglycens from living cenine articular cartilage in culture. The total emount of cetebolin produced by cultures of synovium from experimentally induced OA synovium is statistically significantly greater (p<0.05) than that produced by normal synovium. When calculated per gram of synovium, there was no statistically significant difference. This suggests that a possible role for cetebolin in the pathogenesis of OA might be related to the degree of synovial hypertrophy. / Medicine, Faculty of / Graduate

Osteoarthritis (OA) is the most common type of joint disease that affects nearly 5 million people in Canada alone. OA involves degenerative processes affecting the integrity of articular cartilage, a thin soft tissue at the surface of subchondral bones in joints that facilitates smooth and friction less movement. This disease also affects the other tissues of the joint, including the synovium and its resident cells the fibroblast-like and macrophage-like synoviocytes. Consequences of this pathology include painful movement and stiff joints resulting in loss of range of motion. A broad number of factors may contribute to the development of OA, including obesity, injuries, infections, genetic predispositions and aging. Although there are a number of medications used for the treatment of OA, these only serve to manage its symptoms. An actual cure is yet to be developed. Inorganic polyphosphate (polyP) has previously been identified as a potentially interesting biomolecule for the treatment of OA because of its ability to stimulate tissue formation by chondrocytes - the cells found in the articular cartilage. In this thesis, we first aimed to evaluate the potential of polyP as a therapeutic for joint diseases such as OA further, by characterizing its effects on a number of cell processes (e.g., proliferation, metabolic activity, migration, matrix accumulation) in fibroblast-like synoviocytes (FLS) - specialized cells found in the synovium encapsulating the synovial joints. The synovium is an important tissue for joint physiology and OA pathogenesis; it is thus essential that any therapeutic introduced in the joint not impact this tissue negatively. These studies showed that polyP significantly inhibits FLS proliferation. This effect is interesting in the context of OA as FLS proliferation is associated with progression of the disease. PolyP also increased FLS migration rate and caused changes in metabolic activity, although the trends were inconsistent over time. We also optimized a new protocol for the synthesis of sub-micron calcium-polyP particles. Nanoparticle drug delivery for OA treatment has been gaining importance in recent years as a way to access the cells in cartilage through the small pores in the extracellular matrix (ECM) and increase drug retention time in the joint. The calcium-polyP particles were synthesized by drop-wise addition of polyP into a calcium solution at controlled pH, drop rate and mixing rate. Particles size and stability before and after sterilization were measured by dynamic light scattering. We showed that the addition of sodium citrate dihydrate as a capping agent largely prevented particle agglomeration and increased particle stability. Control over particle size, particularly in the nanometer scale, remains to be achieved; however, this work is a first step towards the development of polyP delivery systems for the treatment of OA.

Knee osteoarthritis (OA) is a debilitating and costly chronic health condition affecting approximately 10% of Canadians. Total Knee Arthroplasty (TKA) is an effective procedure restoring quality of life and providing pain relief for patients with knee OA. The benefits of TKA are well established for patients with knee OA, but determining those who would most benefit is a challenging task. Physical functioning in patients with knee OA has been shown to be a key factor for appropriateness for TKA. The Lower Extremity Functional Scale (LEFS) and the Oxford Knee Score (OKS) are two patient-reported outcome measures (PROMs) measuring physical function that can be utilized to assist health care professionals in determining the need for TKA among this population. The LEFS is a regional PROM consisting of 20 questions asking about activities relating to lower extremity functioning. Questions are scored on a 5-point descriptive scale from 0 (extreme difficulty or unable to perform the activity) to 4 (no difficulty) with a total score of 80. Higher scores represent higher functioning. The OKS is a site-specific PROM that asks questions about pain and function and consists of 12 items ranked on a 5-point descriptive scale. Scores range from 1 to 5 (total score of 60) for each item with lower scores representing higher function. The purpose of this thesis was to determine the diagnostic accuracy for the LEFS and the OKS for determining appropriateness for TKA in people with primary knee OA. The hypothesis for the current study was that the LEFS would have higher diagnostic accuracy for appropriateness for TKA compared to the OKS. A cross-sectional retrospective study of patients with knee OA attending a Regional Joint Assessment Program (RJAP) from January to September 2013 was conducted. Classification of appropriateness for TKA was determined by the attending orthopedic surgeon’s decision at the end of the assessment. Diagnostic accuracy for the OKS and the LEFS were determined using the area under the curve (AUC) of the receiver operator characteristic (ROC) curve. Cut-off scores were calculated for both outcome measures. Four hundred and twenty one patients eligible for the study (41.8% males; 66.9 years old) completed the OKS and the LEFS. The diagnostic accuracy for the OKS and the LEFS was determined using the AUC of the ROC curve for each patient-reported measure using Stata ® version 12.1. The cut-off scores were determined as the point on the ROC curve yielding the best sensitivity and specificity for the two outcome measures. The results showed the LEFS did not have higher diagnostic accuracy (LEFS AUC = 0.686 (95% CI = 0.636 – 0.736); OKS AUC = 0.674 (95% CI = 0.623- 0.724)) for determining appropriateness for TKA in patients with primary knee OA in isolation. The best cut-off score for those deemed appropriate for TKA among patients with knee OA was 26 out of 80 LEFS points and 42 points out of 60 OKS points. The results of this thesis agree with previous research reporting that decision-making regarding the need for TKA in patients with knee OA is multi-factorial. Our data confirm that this decision cannot be based on patient-reported physical function alone. Factors other than or in addition to patient-reported lower limb physical functioning should be considered when determining which patients with knee OA would most benefit from TKA. Further research evaluating these factors is warranted to improve triage services for patients with knee OA most likely to benefit from TKA. / Thesis / Master of Science Rehabilitation Science (MSc)