No description available.

No description available.

No description available.

The aim of this programme of work is to characterize the relevance of joint hypermobility and autonomic symptoms, particularly orthostatic intolerance, to clinical psychopathology. Joint hypermobility is a widespread, poorly recognized, connective tissue condition. Affected individuals are reportedly overrepresented among panic or anxiety disorders, irritable bowel syndrome, fibromyalgia, and chronic fatigue. Dysfunction or dysregulation of the autonomic nervous system, typically postural tachycardia syndrome is often found. Structural differences in amygdala have been reported in association with joint hypermobility. The relevance of hypermobility and autonomic dysfunction to general psychiatric conditions is currently poorly understood.

No description available.

No description available.

Four studies were conducted in this PhD aiming to evaluate knee joint loading assessed by calculating knee contact forces (KCF) using a musculoskeletal modeling workflow during common daily-living activities as walking and more demanding tasks, in individuals with varying levels of medial knee osteoarthritis (OA) severities. In study I, KCF were calculated and its relations with knee external knee adduction moments (KAM) and/or flexion moments (KFM) assessed during the stance phase of gait. Knee loading was evaluated in individuals with early medial knee OA, classified based on early joint degeneration on MRI and compared to individuals with established medial knee OA and healthy subjects. The effect of using an anatomical versus a functional axis of rotation (FAR) on KAM in healthy subjects and patients with knee OA was investigated in study II. In addition, this study reports KAM for models with FAR calculated using weight-bearing and non-weight-bearing motion. Study III calculates KCF and contact pressures during gait and step-up-and-over tasks in subjects with early knee OA and those with established knee OA compared to healthy subjects using a multi-body knee model with articular cartilage contact, 14 ligaments, and 6-DoF tibiofemoral and patellofemoral joints. Finally, study IV assessed trunk kinematics, KCF and knee contact pressures in individuals with medial knee OA during different stair negotiation strategies: step-over-step (SOS) at controlled speed, and also SOS at self-selected speed and step-by-step (SBS). This PhD contributed to, firstly, describe the importance of calculating the KCF in both medial and lateral knee compartments to better assess loading changes in individuals with varying levels of medial knee OA severities, especially those with early knee OA, during gait. The medial KCF provided a more sensitive metric to knee joint loading than external KAM or total KCF. Secondly, KAM was shown to be sensitive to the knee axis of rotation, indicating that differences between subject groups might be heavily dependent on the knee axis definition. Finally, different mechanisms used by these patients were identified during gait versus step/stair activities when compared to healthy subjects. Stair negotiation forced the use of compensatory mechanisms in patients with knee OA while gait did not.

Skeletal muscle atrophy due to disuse is a widespread problem arising from many situations including clinical immobilisation due to injury or disease. As individuals age, the universally observed loss of muscle mass and function known as sarcopenia compounds this problem leading to a significant reduction in locomotor ability and quality of life for sufferers. Recently there has been much work investigating ways to mitigate muscle mass loss in immobilised limbs and to aid in recovery in the post immobilisation phase. Much focus has been placed on recovery protocols based upon either resistance training, nutritional supplementation, or both. In study 1 we report an extensive data set describing in detail skeletal muscle adaptations in structure and function in response to both disuse (ULLS) and retraining. The results indicate that, 1) the loss of muscle force with 3-week unloading in humans is mostly explained by muscle atrophy and a decrease in myosin content and, 2) all the neuromuscular changes induced by this model of disuse can be fully restored after a resistance training intervention of equal duration Study 2 tests the hypothesis that increasing amino acid leucine availability by nutritional supplementation will increase muscle protein synthesis in immobilised muscle and result in mitigating the loss of lean muscle mass. In fact, we found that leucine supplementation alone was not sufficient to maintain muscle mass during 3 weeks of unilateral lower limb suspension. Study 3 examined the effect of leucine supplementation on muscle mass gains during an active recovery training program of muscles previously subjected to ULLS. Despite low participant numbers, the data suggest that leucine supplementation had no effect on the extent to which muscle recovered post ULLS. Study 4 investigates the role of training and immobilization in sarcopenia and discusses the potential of using ultrasound imaging to develop an image based biomarker of sarcopenia. Cross sectional data from both young and old individuals subjected to different loading conditions are analysed in this study. Life-long training appears to slow down the process of sarcopenia whilst periods of disuse due to injury or disease worsen the condition. The change in muscle fibre geometry exhibited in sarcopenia and disuse atrophy could potentially act as a convenient and inexpensive indicator of the onset of sarcopenia.

Genetic defects occurring in the sedlin gene, a conserved component of TRAPP complex, cause Spondyloepiphyseal Dysplasia Tarda (SEDT), a rare progressive condition characterised by impaired chondrogenesis resulting in short stature, flattening of the vertebrae, and premature osteoarthritis. The role of sedlin in the pathogenesis of SEDT disease so far is still unknown. Prompted by the consideration that sedlin is ubiquitously expressed but that sedlin mutations cause cartilaginous-restricted dysfunctions, I hypothesized that sedlin might exert a role in membrane trafficking generally but in particular in the transport of chondrocyte- specific cargoes, such as type II procollagen (PCII). This hypothesis was reinforced by the fact that mutations in PCII give rise to autosomal dominant forms of spondyloepiphiseal dysplasia. I tested this hypothesis by analyzing the involvement of sedlin in the transport of different classes of secretory cargoes and found that sedlin is selectively required for PCII to exit the ER, while it is not essential for ER exit of small soluble and membrane-associated cargoes. I have also identified the molecular mechanism underlying this role of sedlin in its ability to bind the GTPase Sarl and to control the membrane-cytosol cycle of Sarl itself and of the COPIl coat complex at the level of the ER exit sites. Sedlin depletion and/or mutation in SEDT patients slows down the Sar1 cycle and prolongs the membrane association of Sar1-GTP at the ER exit sites, thus inducing constriction and premature fission of nascent carriers which fail to incorporate the large PC protofibrils but are still competent for smaller secretory cargoes. All together these findings provide new insights not only into understanding the role of sedlin but also shed new light on the molecular mechanisms underlying the onset of the SEDT disease.

Background: Affecting approximately one in four adults over the age of 50 years in the UK, knee pain is a leading cause of disability in the elderly and bears a significant economic cost. Despite the plethora of studies that have investigated the factors associated with the onset of knee pain and osteoarthritis (OA) in the sedentary population, relatively little is known about the prevalence and factors associated with musculoskeletal pain and OA in an athletic sporting population. Objectives: This study aimed to: (1) describe the injury patterns, the prevalence of pain, and OA in Great Britain’s (GB) Olympians; (2) determine in GB Olympians aged 40 years and older the risk of pain and OA at three joints - the hip, knee and the lumbar spine; and (3) identify the individual risk factors associated with joint pain and OA in GB Olympians aged 40 years and older. Methods: This was a cross-sectional study design with an internal nested-case control study. A web-based and / or paper questionnaire was distributed by email and / or post to 2742 GB Olympians living in 30 different countries. The questionnaire was used to collect data on risk factors associated with the onset of pain and OA. The presence of OA was defined by a self-reported physician-diagnosis. Pain was self-reported using a body manikin, and defined as pain in or around the selected joint on most days for at least one month. The most severe limb was selected as the index joint for data analysis, if bilateral. Three separate models of binary logistic regression were constructed to examine the covariates that were associated with pain at the hip, knee, and the lumbar spine. A further three models were constructed to examine the covariates associated with OA at the aforementioned joints. Covariates were identified for analysis, and those that were associated with pain or OA (P < 0.25) were purposefully fitted into a multivariable regression model. The final regression models were constructed by refitting, one at a time, the covariates that had previously been excluded until all of the covariates and interactions that were clinically relevant or significant at traditional levels (P < 0.05) were included. Relative risk (RR) was estimated using odds ratio (OR), and confounding factors were adjusted (aOR) using logistic regression. The Faculty of Medicine and Health Sciences Research Ethics Committee at the University of Nottingham approved the study. Results: The response rate was 26%, with 714 returns achieved between the 22nd of May 2014 and the 31st of January 2015. The questionnaires were returned from GB Olympians living in 15 different countries, including the UK. The age of the GB Olympians recruited ranged from 19 to 97 years, with a mean age of 58.76 + 16.79 years. Fifty-seven per cent of those recruited were male (n = 405) and 43% were female (n = 309). The age of male GB Olympians recruited ranged from 22 to 97 years, with a mean age of 63.00 + 16.30 years. The age range of female GB Olympians recruited ranged from 19 to 93 years, with a mean age of 53.20 + 15.78 years. A total of 821 significant injuries were reported, resulting in an injury rate of 1150 significant injuries per 1000 registered GB Olympians, with 62% reporting they had sustained at least one significant injury (n = 441). Cartilage injuries, joint sprain (injury of joint and / or ligaments), and ligament ruptures were prominent in those with knee pain and knee OA. Intervertebral disc injuries, contusions and joint related injury were common in those with pain and OA at the lumbar spine. Pain was most prevalent at the lumbar spine (32.7%), knee (25.6%), hip (23.0%), and the ankle (14.1%). Osteoarthritis was most prevalent at the knee (14.2%), hip (11.1%), lumbar spine (5.0%), and the ankle (1.3%). Female gender and older age were significantly associated with lumbar spine OA, and older age and a previous significant hip injury were significantly associated with the prevalence of hip OA. Ageing and body mass index (BMI) (kg/m2), a previous significant knee injury and early-life (20-29 years) generalised joint hypermobility (GJH) (Beighton > 4/9) were found to be significantly associated with the prevalence of knee OA. The strongest factors associated with knee pain were a prior significant knee injury, early-life (20-29 years) varus knee alignment, competing in weight-bearing loading sports, widespread pain, and a higher body mass index (kg/m2). Factors associated with hip pain included a previous significant hip injury and competing in weight-bearing loading sports. A one-unit increase in age and BMI (kg/m2), and a prior significant lumbar spine injury were significantly associated with lumbar spine pain. A one-unit increase in physical well-being was significantly associated with a lower prevalence of pain at the hip and knee. Conclusion: This study found that: 1) injury appeared to be constantly the strongest risk factor for pain at the knee, hip and the lumbar spine, as well as OA at the hip and knee; 2) in GB Olympians aged 40 years and older, the knee was most likely affected by OA, and the lumbar spine by pain; 3) participation in weight-bearing loading sports was associated with hip and knee pain, but not hip and knee OA; and 3) generalised joint hypermobility (Beighton > 4/9) appeared to be not a risk factor for injury, and nor was it a risk factor for all joint pain/OA, except OA at the knee joint. Female GB Olympians with early-life GJH were more vulnerable to knee OA than their male counterparts. Future research is needed to help determine whether or not GJH is a risk factor associated with the onset of knee OA in the general population, particularly among females. As one of the few modifiable risk factors, joint injury prevention should be part of the future initiatives to reduce the risk of OA, along with maintaining a healthy body weight.