joint disease

关节病
  • 文章类型: Journal Article
    目的:这项研究的目的是表征从有或没有自然发生的创伤后骨关节炎(PTOA)的马获得的血浆和滑液中的细胞外囊泡(EV)。
    方法:从有(n=6)和没有(n=6)PTOA的马的血浆和滑液中分离出EV。
    方法:对血浆和滑液EV的数量进行表征,尺寸,和表面标记。进行小RNA测序,和差异表达的microRNAs(miRNAs)进行了生物信息学分析,以确定推定的靶标并探索与特定生物过程的潜在关联。
    结果:与没有PTOA的马相比,来自具有PTOA的马的血浆和滑液样品具有明显更高的外泌体比例和更低的微泡比例。小RNA测序揭示了几种差异表达的miRNA,包括miR-144,miR-219-3p,血浆中的miR-199a-3l和miR-199a-3p,滑液EV中的miR-214和miR-9094。差异表达miRNA的生物信息学分析强调了它们在纤维化中的潜在作用,软骨细胞的分化,凋亡,和PTOA中的炎症途径。
    结论:我们已经确定了具有天然存在的PTOA的马的血浆和滑液EV的小的非编码特征的动态分子变化。这些发现可能有助于鉴定PTOA发病机制中的有希望的生物标志物,为了促进靶向治疗的发展,并帮助建立适当的PTOA翻译模型。
    OBJECTIVE: The objective of this study was to characterize extracellular vesicles (EVs) in plasma and synovial fluid obtained from horses with and without naturally occurring post-traumatic osteoarthritis (PTOA).
    METHODS: EVs were isolated from plasma and synovial fluid from horses with (n = 6) and without (n = 6) PTOA.
    METHODS: Plasma and synovial fluid EVs were characterized with respect to quantity, size, and surface markers. Small RNA sequencing was performed, and differentially expressed microRNAs (miRNAs) underwent bioinformatic analysis to identify putative targets and to explore potential associations with specific biological processes.
    RESULTS: Plasma and synovial fluid samples from horses with PTOA had a significantly higher proportion of exosomes and a lower proportion of microvesicles compared to horses without PTOA. Small RNA sequencing revealed several differentially expressed miRNAs, including miR-144, miR-219-3p, and miR-199a-3l in plasma and miR-199a-3p, miR-214, and miR-9094 in synovial fluid EVs. Bioinformatics analysis of the differentially expressed miRNAs highlighted their potential role in fibrosis, differentiation of chondrocytes, apoptosis, and inflammation pathways in PTOA.
    CONCLUSIONS: We have identified dynamic molecular changes in the small noncoding signatures of plasma and synovial fluid EVs in horses with naturally occurring PTOA. These findings could serve to identify promising biomarkers in the pathogenesis of PTOA, to facilitate the development of targeted therapies, and to aid in establishing appropriate translational models of PTOA.
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  • 文章类型: Letter
    暂无摘要。
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  • 文章类型: Journal Article
    关节病通常需要连续监测关节状况,通常使用磁共振(MR)或超声(US)成像进行。US成像通常是首选的筛查或诊断工具,因为它快速且便宜。然而,传统的2-DUS在比较检查之间的成像结果方面的能力有限,这是因为其对操作者的依赖性以及与在相同位置和方向重复成像相关的挑战.几个成像会话之间的比较对于评估关节状况的间隔进展至关重要。我们提出了一种用于踝关节评估的新型3-DUS扫描仪,可以通过启用3-D成像来部分克服这些问题。这里,我们(i)介绍了3-D美国脚踝扫描仪系统的设计,(ii)验证系统的几何重构精度,(iii)提供健康志愿者脚踝的初步图像,(iv)将3-DUS成像结果与MR成像进行比较。3-D脚踝扫描仪由一个装满水的浴缸组成,例如,线性US探针附接到桶的壁,以及使US探针围绕桶的中心旋转360°的机动单元。当探头旋转时,3-DUS图像由位于浴缸中间的患者的脚踝形成。美国探头高度,从浴缸中心的角度和距离可以调整。使用两个测试体模在不同探头角度的每个坐标方向上验证了系统的重建精度。使用由许多间距已知的Ø200-µm尼龙线和带有加工凹槽的金属杆组成的体模在水平和垂直方向上进行验证,分别。通过对具有已知体积的两个嵌入球体的琼脂体模进行成像并将分割的球体体积和表面积与预期进行比较来进行体积重建准确性验证。获得了五名健康志愿者的两个脚踝的三维US和MR图像。在两种成像方式中对胫骨远端和距骨近端进行了分割,并使用95%Hausdorff和平均表面距离比较了这些分割的表面。在所有坐标方向和几个探头角度上观察到的平均线性测量误差为2.98%。平均测量体积测量误差为3.45%。志愿者研究揭示了3-D脚踝扫描仪图像中存在的联合评估的有用特征,如接头间距,胫骨远端和距骨近端。3-DUS和MR图像中平均95%Hausdorff和分割之间的平均表面距离为5.68±0.83和2.01±0.30mm,分别。在这个概念验证研究中,3-DUS踝关节扫描仪能够可视化踝关节特征,这对关节评估很有用.
    Joint arthropathies often require continuous monitoring of the joint condition, typically performed using magnetic resonance (MR) or ultrasound (US) imaging. US imaging is often the preferred screening or diagnostic tool as it is fast and inexpensive. However, conventional 2-D US has limited capability to compare imaging results between examinations because of its operator dependence and challenges related to repeat imaging in the same location and orientation. Comparison between several imaging sessions is crucial to assess the interval progression of joint conditions. We propose a novel 3-D US scanner for ankle joint assessment that can partially overcome these issues by enabling 3-D imaging. Here, we (i) present the design of the 3-D US ankle scanner system, (ii) validate the geometric reconstruction accuracy of the system, (iii) provide preliminary images of healthy volunteer ankles and (iv) compare 3-D US imaging results with MR imaging. The 3-D ankle scanner consists of a tub filled with water, a linear US probe attached to the wall of the tub and a motorized unit that rotates the US probe 360° around the center of the tub. As the probe rotates, a 3-D US image is formed of the ankle of the patient positioned in the middle of the tub. US probe height, angle and distance from the tub center can be adjusted. The reconstruction accuracy of the system was validated in each of the coordinate directions at different probe angles using two test phantoms. A phantom consisting of numerous Ø200-µm nylon threads with known spacing and a metal rod with machined grooves was used for validation in the horizontal and vertical directions, respectively. The volumetric reconstruction accuracy validation was performed by imaging an agar phantom with two embedded spheres of known volumes and comparing the segmented sphere volume and surface area with the expected. Three-dimensional US and MR images of both ankles of five healthy volunteers were acquired. Distal tibia and proximal talus were segmented in both imaging modalities and the surfaces of these segmentations were compared using the 95% Hausdorff and mean surface distances. The observed mean linear measurement error in all the coordinate directions and over several probe angles was 2.98%. The mean measured volumetric measurement error was 3.45%. The volunteer study revealed useful features for joint assessment present in the 3-D ankle scanner images, such as joint spacing, distal tibia and proximal talus. The mean 95% Hausdorff and mean surface distances between segmentations in 3-D US and MR images were 5.68 ± 0.83 and 2.01 ± 0.30 mm, respectively. In this proof-of-concept study, the 3-D US ankle scanner enabled visualization of the ankle joint features that are useful for joint assessment.
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  • 文章类型: Journal Article
    评价运动锻炼和患者教育对未接受手术的髋关节发育不良患者的可行性和可接受性。
    可行性研究。
    参与者接受了为期6个月的运动指导和患者教育。可行性涵盖招聘,保留,和变化机制(MC)。用髋关节和腹股沟结果评分(HAGOS)测量MC,肌肉力量测试,Y平衡试验,和跳跃距离测试(HDT)超过六个月。可接受性涵盖依从性,期望,感知,好处,和伤害。
    32人中有30人被招募(平均年龄:30岁);6人失去随访。24名参与者平均改善了11(95CI:5-17)HAGOS痛点,所有分量表的改善均为1-11分.平均髋关节外展强度提高了0.2(95CI:0.04-0.4)Nm/kg,类似于屈伸。Y平衡测试中值改进:前:70(IQR:64-74)至75(IQR:72-80)厘米;后内侧:104(IQR:94-112)至119(IQR:112-122)厘米,后外侧:98(IQR:89-109)至116(IQR:108-121)厘米(p<.001)。HDT的中位数改善为:37(IQR:30-44)至52(IQR:45-58)厘米(p<.001)。参与者参加了84%的预定会议(1,581:1,872),期望得到满足,和感知的特点是锻炼自我效能高。报告了好处,没有严重危害。
    髋关节发育不良患者愿意被招募进行锻炼和患者教育,可接受的保留。通过疼痛的改善观察到MC,强度和功能具有较高的运动接受度和患者教育干预。因此,进行全面随机对照试验似乎是可行的.
    To evaluate the feasibility and acceptability of exercise and patient education for patients with hip dysplasia not receiving surgery.
    Feasibility study.
    The participants received exercise instruction and patient education over six months. Feasibility covered recruitment, retention, and mechanisms of change (MC). MC were measured with Hip and Groin Outcome Score (HAGOS), muscle strength tests, Y-balance test, and hop for distance test (HDT) over six months. Acceptability covered adherence, expectations, perceptions, benefits, and harms.
    Thirty of 32 were recruited (median age: 30 years); six were lost to follow-up. Twenty-four participants improved by a mean of 11 (95%CI: 5-17) HAGOS pain points, improvements in all subscales were 1-11 points. Mean hip abduction strength improved 0.2 (95%CI: 0.04-0.4) Nm/kg, similar to flexion and extension. Median Y-balance test improvements: anterior: 70 (IQR: 64-74) to 75 (IQR: 72-80) centimetres; posteromedial: 104 (IQR: 94-112) to 119 (IQR: 112-122) centimetres and posterolateral: 98 (IQR: 89-109) to 116 (IQR: 108-121) centimetres (p < .001). Median improvement in HDT was: 37 (IQR: 30-44) to 52 (IQR: 45-58) centimetres (p < .001). Participants adhered to 84% of scheduled sessions (1,581:1,872), expectations were met, and perceptions were characterized by high self-efficacy for exercise. Benefits were reported with no serious harms.
    Patients with hip dysplasia are willing to be recruited for exercise and patient education, with acceptable retention. MC were observed through improvements in pain, strength and function with high acceptance of the exercise and patient education intervention. Thus, it seems feasible to conduct a full-scale randomised controlled trial.
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  • 文章类型: Journal Article
    目的:遗传性血色素沉着病是一种遗传性疾病,由人类稳态铁调节蛋白(HFE)基因的几种已知突变引起。铁的异常积累导致类似于骨关节炎(OA)的关节疾病,但出现在相对较年轻的年龄,并伴有肝硬化,糖尿病,对其他器官的伤害。血清转铁蛋白饱和度和铁蛋白水平升高是血色素沉着症的已知标志物,具有高阳性预测值。
    方法:我们回顾性分析了2,035例因OA而接受膝关节置换术的患者的铁研究。
    结果:没有患者出现HFE基因C282Y,S65C,或H63D突变测试。总的来说,男性队列中的18名患者(2.96%)和女性队列中的51名患者(3.58%)在病理上增加了铁蛋白水平,这可能表明血色素沉着病。7例患者(0.34%)的血清转铁蛋白饱和度高于45%。
    结论:骨科对该疾病的诊断意识较低,需要改进。接受膝关节置换术的骨关节炎患者应通过铁研究常规筛查血色素沉着症,并在需要时进行基因检测。证据水平:III级——回顾性队列研究。引用这篇文章:BoneJtOpen2021;2(12):1062-1066。
    OBJECTIVE: Hereditary haemochromatosis is a genetic disorder that is caused by several known mutations in the human homeostatic iron regulator protein (HFE) gene. Abnormal accumulation of iron causes a joint disease that resembles osteoarthritis (OA), but appears at a relatively younger age and is accompanied by cirrhosis, diabetes, and injury to other organs. Increased serum transferrin saturation and ferritin levels are known markers of haemochromatosis with high positive predictive values.
    METHODS: We have retrospectively analyzed the iron studies of a cohort of 2,035 patients undergoing knee joint arthroplasty due to OA.
    RESULTS: No patients had HFE gene C282Y, S65C, or H63D mutations testing. In total, 18 patients (2.96%) of the male cohort and 51 (3.58%) of the female cohort had pathologically increased ferritin levels that may be indicative of haemochromatosis. Seven patients (0.34%) had serum transferrin saturation above 45%.
    CONCLUSIONS: The awareness for the diagnosis of this disorder in Orthopaedics is low and needs improvement. Osteoarthritic patients undergoing knee arthroplasty should be routinely screened for haemochromatosis by iron studies and referred to genetic testing when needed. Level of evidence: Level III - Retrospective cohort study. Cite this article: Bone Jt Open 2021;2(12):1062-1066.
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  • 文章类型: Journal Article
    UNASSIGNED: Hemophilia is characterized by the development of joint bleeds that cause long-term joint damage (hemophilic arthropathy). Joint damage leads to disability and affects psychosocial aspects in patients with hemophilia.
    UNASSIGNED: To compare the clinical situation, perception of disease and quality of life, and coping strategies in adult patients with hemophilia in El Salvador and Spain.
    UNASSIGNED: In this comparative clinical study, 43 patients with hemophilia aged between 18 and 50 years old from Spain and El Salvador participated. After obtaining the patients\' consent, they completed the Illness Perception Questionnaire-Revised (IPQ-R), Hemophilia-QoL and Inventory of Coping strategies questionnaires. Joint status was assessed using the Hemophilia Joint Health Score and based on a record of clinical and treatment data.
    UNASSIGNED: Hemophilia patients from Spain showed an improved perception of quality of life (p <0.05), although there were only differences in the self-criticism variable (p = 0.04) for coping strategies. Joint damage and age correlated (p <0.05) negatively with perception of disease, perceived quality of life and coping strategies in both populations. There were differences (p <0.05) between the two populations based on HIV and HCV coinfections in perception of disease and perceived quality of life.
    UNASSIGNED: Patients with hemophilia in El Salvador exhibit a poorer perception of disease and quality of life. Despite differences in access to treatment from one country to the other, there is no difference in coping with the disease. Older patients are better able to adapt to the disease.
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  • 文章类型: Journal Article
    这项观察性研究评估了boswellia,姜黄,和红藻提取物在膝骨关节炎(KOA)患者中的应用。鉴于对骨关节炎以患者为中心的护理的兴趣与日俱增,通过患者报告的预后指标(PROMs)进行疗效评估:患者可接受症状量表(PASS),最小临床重要性改善(MCII)患者总体变化印象(PGIC),和Lequesne算法功能指数(LAFI)。患者还完成了关于疼痛质量的17个项目的列表。
    单侧或双侧KOA疼痛的患者必须每天服用1-4粒含有乳香的膳食补充剂,姜黄,和红藻提取物90天。患者在第0天(基线)完成PROM,10、20、30、60和/或90。
    共有118名患者[女性:69.5%;年龄:62.9(9.5)岁,平均(SD)]纳入研究,并服用至少一粒胶囊。平均(SD)随访时间为100.7(54.9)天。第90天疼痛缓解最大:64.5%的患者为应答者(PASS阳性);68.8%和58.4%的MCII和PGIC评分表明积极效果(评分≥3)或整体改善(评分≥5);73.3%(基线为47.5%)轻度/中度残疾(LAFI评分<8);55.2%的疼痛强度(VAS)有意义的降低(-30%),35.1%(基线为59.2%)服用镇痛药作为补充治疗。第一次PASS改变的中位时间为34天。疼痛强度(VAS),以及两个疼痛特征(即,“刺痛”和“广泛疼痛”),是与第30天无应答相关的独立因素。根据疼痛特征分离出四组反应者,一个集群表现出更高的响应率。
    这项初步研究的结果表明,boswellia,姜黄,和测试的红藻提取物可以改善KOA患者。除了这些结果,这项研究表明,PROM和特定疼痛定性描述符对于准确评估疼痛状态下的膳食补充剂方法的重要性.
    UNASSIGNED: This observational study evaluated a combination of boswellia, turmeric, and red algae extracts in patients with knee osteoarthritis (KOA). Given the growing interest in patient-centered care in osteoarthritis, effects were assessed by an arsenal of patient-reported outcome measures (PROMs): Patient Acceptable Symptom Scale (PASS), Minimal Clinically Important Improvement (MCII), Patient Global Impression of Change (PGIC), and Lequesne algofunctional index (LAFI). Patients also completed a list of 17 items on pain quality.
    UNASSIGNED: Patients with painful unilateral or bilateral KOA had to take 1-4 capsules per day of a dietary supplement containing boswellia, turmeric, and red algae extracts for 90 days. Patients completed PROMs on Days 0 (baseline), 10, 20, 30, 60, and/or 90.
    UNASSIGNED: A total of 118 patients [female: 69.5%; age: 62.9 (9.5) years, mean (SD)] were included in the study and took at least one capsule. Mean (SD) follow-up duration was 100.7 (54.9) days. Pain relief was maximal on Day 90: 64.5% of patients were responders (positive PASS); 68.8% and 58.4% had MCII and PGIC scores indicating positive effect (score ≥3) or global improvement (score ≥5); 73.3% (versus 47.5% at baseline) were mildly/moderately disabled (LAFI score <8); 55.2% had meaningful decrease (-30%) in pain intensity (VAS), 35.1% (versus 59.2% at baseline) took analgesics as supplementary treatment. Median time to the first PASS change was 34 days. Pain intensity (VAS), as well as two pain characteristics (ie, \"Stabbing pain\" and \"Widespread pain\"), were independent factors associated with non-response on Day 30. Four clusters of responders were isolated according to pain characteristics, with one cluster exhibiting a higher responder rate.
    UNASSIGNED: The results of this preliminary study suggest that the combination of boswellia, turmeric, and red algae extracts tested could improve KOA patients. Beyond these results, this study showed the importance of PROMs and specific pain qualitative descriptors for the accurate evaluation of dietary supplement approaches in painful conditions.
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  • 文章类型: Journal Article
    背景:嗜血关节病的特征是关节受限。血友病患者中受影响最大的关节之一是膝盖。
    目的:本研究评估了手工疗法和被动肌肉伸展运动对血友病性膝关节病患者减少关节积血和疼痛频率、改善关节健康和活动范围的有效性。
    方法:将28例血友病性膝关节病患者随机分为实验组或对照组(无干预)。手动治疗包括关节牵引和滑翔动作,除了被动的肌肉拉伸。干预包括一次60分钟,每周两次,为期12周。我们评估了膝关节积血的频率(自我报告),关节健康(血友病关节健康评分),运动范围(测角)和感觉到的膝关节疼痛(视觉模拟量表)。在干预结束时和12周随访期后进行基线评估。
    结果:与对照组相比,实验组的关节积血频率显着下降(F=11.43;P<.001)。与对照组相比,实验组在关节健康变量方面一直有更好的结果(F=13.80;P<.001),膝关节屈曲运动范围(F=24.29;P<.001)和伸展丧失(F=8.90;P<.001),和感知疼痛(F=49.73;P<.001)。
    结论:使用关节牵引和滑翔动作的手动疗法,除了被动的肌肉伸展,减少血友病患者关节积血的频率。被动肌肉伸展运动的手动疗法可改善关节健康,运动范围和感知的关节疼痛。
    BACKGROUND: Haemophilic arthropathy is characterized by joint restrictions. One of the most affected joints in haemophilia patients is the knee.
    OBJECTIVE: This study evaluates the effectiveness of manual therapy and passive muscle stretching exercises for reducing the frequency of hemarthrosis and pain and improving joint health and range of motion in patients with haemophilic knee arthropathy.
    METHODS: Twenty eight patients with haemophilic knee arthropathy were randomized to an experimental group or to a control group (without intervention). Manual therapy sessions included joint traction and gliding manoeuvers, in addition to passive muscle stretching. The intervention included one 60-minute with two weekly sessions over a 12-week period. We evaluated the frequency of knee hemarthrosis (self-reporting), joint health (Hemophilia Joint Health Score), range of motion (goniometry) and perceived knee pain (visual analogue scale). A baseline evaluation was performed at the end of the intervention and after a 12-week follow-up period.
    RESULTS: The frequency of hemarthrosis dropped significantly in the experimental group compared to the control group (F = 11.43; P < .001). Compared to the control group, the experimental group had consistently better results in the variables for joint health (F = 13.80; P < .001), range of motion in knee flexion (F = 24.29; P < .001) and loss of extension (F = 8.90; P < .001), and perceived pain (F = 49.73; P < .001).
    CONCLUSIONS: Manual therapy using joint traction and gliding manoeuvers, in addition to passive muscle stretching, reduces the frequency of hemarthrosis in patients with haemophilia. Manual therapy with passive muscle stretching exercises improves joint health, range of motion and perceived joint pain.
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    文章类型: Journal Article
    OBJECTIVE: Temporomandibular disorder (TMD) is believed to be co-morbid with rheumatologic conditions such as Osteoarthritis (OA). We determine 30-day prevalence and cumulative incidence, and risk factors for facial pain in a cohort of subjects who either had or were at risk of developing symptomatic radiographic knee osteoarthritis (SRKOA).
    METHODS: Poisson regression models examined whether age, sex, race, Center for Epidemiologic Studies-Depression Scale (CES-D) score, number of painful joints, and presence of SRKOA were risk factors for facial pain in 4,423 subjects at baseline and in 3,472 subjects at 24 and/or 48 months follow-up.
    RESULTS: At baseline, 30-day period prevalence of facial pain was 9.25%; and 30-day cumulative incidence at 24-months and at 48-months was 5.9% and 4.9%, respectively. Factors associated with prevalence and incidence of facial pain were: younger age, female sex, (CES-D) score, and a larger number of painful joints. For each increase in age of one year, the incidence of facial pain decreased by 1%. Women had a 96% higher incidence than men, and each unit increase of (CES-D) score was associated with a 2% increase in the incidence of facial pain. For every additional painful joint, there was a 21% increase in the incidence of facial pain. Subjects with SRKOA had a 33% increase in the incidence of facial pain compared to those with risk factors for SRKOA.
    CONCLUSIONS: OA and TMD share several risk factors. The risk factors identified in cross-sectional analysis of prevalence are similar to those identified in longitudinal analysis on incidence.
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  • 文章类型: Journal Article
    肘关节病是血友病患者的特征。关节病表现为运动范围减小,疼痛,失去力量和肌肉萎缩,和轴向变化。目的是评估血友病肘关节病患者的两种物理治疗方案的安全性,该方案将手动治疗和家庭锻炼与教育课程相结合。
    这是一项随机研究,涉及27名患有肘部血友病性关节病的患者,平均年龄为34.48岁(SD:12.99)。被随机分配到手动治疗组,教育组和对照组。物理治疗方案是:通过关节牵引进行手动治疗,被动肌肉伸展和本体感觉神经肌肉促进;和教育会议和日常家庭锻炼。这项研究持续了12周,手动治疗组每周两次,教育组每两周一次,每天进行家庭锻炼。测量的变量是肘部的运动范围,肱二头肌力量,手臂的圆周,和肘部疼痛。
    手法治疗改善了手臂的周长,屈肘和肘部疼痛。六个月后,MT组仍然享有改善。在教育方面有改进,但并不重要,在测量的变量中。
    两种物理疗法均未引起肘关节积血。手动治疗改善了手臂的运动范围和周长,并减轻慢性肘关节病血友病患者的疼痛。在治疗期间或随访期间没有记录到关节积血。需要更大的随机临床试验来证实这项研究的结果。
    (NCT02198040)。2014年7月22日注册,追溯注册。
    Elbow arthropathy is characteristic in patients with hemophilia. Arthropathy is manifested by decreased range of motion, pain, loss of strength and muscular atrophy, and axial changes. The objective is to evaluate the safety of two physiotherapy programs combining manual therapy and home exercises with educational sessions in patients with hemophilic elbow arthropathy.
    This is a randomized study with 27 patients with elbow hemophilic arthropathy with a mean age of 34.48 (SD: 12.99) years, were randomised to Manual Therapy group, educational group and control group. The physiotherapy programmes were: manual therapy through joint traction, passive muscles stretching and proprioceptive neuromuscular facilitation; and educational sessions and daily home exercises. The study lasted for twelve weeks, with two sessions a week in manual therapy group and one session every two weeks with daily home exercises in educational group. The variables measured were range of motion of elbow, biceps strength, circumference of arm, and elbow pain.
    The treatment with manual therapy improved the circumference of arm, flexion elbow and elbow pain. Six months later, MT group still enjoyed improved. In the educational group there were improvements, but not significant, in the measured variables.
    Neither of the two physiotherapy interventions caused elbow hemarthrosis. The treatment with manual therapy improved the range of movement and circumference of arm, and lessened pain in hemophilic patients with chronic elbow arthropathy. No hemarthrosis was recorded during treatment or during the follow-up period. Larger randomized clinical trials are required to confirm the results of this study.
    ( NCT02198040 ). Registered 22 July 2014, retrospectively registered.
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