Residual dysfunction after a fracture of the distal radius is most often mild but may give rise to significant impairment especially in the younger active population. The symptoms often manifest around the distal ulna when loading the hand or rotating the forearm. In this region are found articular and soft tissue connections running from the distal ulna to the distal radius as well as to the ulnar side of the carpus. The aims of this thesis were to investigate the effects of distal radius fractures on the structures about the distal ulna and to what extent malunion and ulnar soft tissue lesions affect function. Both patients and cadaver specimens were used in the five different studies. In a retrospective study of 17 malunited distal radius fractures supination impairment improved significantly by correction of the skeletal malunion. This highlights the importance of distal radioulnar joint congruity for forearm rotation in a subset of cases. The pathomechanisms of injury to the triangular fibrocartilage complex (TFCC) were studied. In a cadaveric distal radius fracture model different restraining properties and injury patterns were investigated. Similar patterns of injury were then observed in 20 patients with a displaced distal radius fracture. It was found that a TFCC injury can be expected with dorsal displacement of the distal radius fragment of 32o or more from the anatomically correct position. The distribution of a TFCC injury apparently differs depending on the size of an associated ulnar styloid fracture. In cases of an intact ulnar styloid or a concomitant tip fracture (Type 1) the first stage of injury seems to be extensor carpi ulnaris subsheath separation from the distal ulna and the dorsal radioulnar ligament. Thereafter follows a disruption of the deep insertions into the fovea of the ulna starting from the palmar and extending dorsally and radially. An extensive injury can be detected with a novel non-invasive test called the ‘bald ulnar head test’, which is performed under anaesthesia. Diagnosis of an acute TFCC injury is difficult using non-invasive methods. In a prospective study of 48 patients, CT scanning to detect pathologic subluxation was found to be of little use in both acute and chronic cases, and is therefore not endorsed on this indication. A radioulnar stress test, which in previous studies has correlated well to a deep TFCC injury, was found to be highly reliable but not to correspond with significant disability in self-administered questionnaires of functional outcome two years or more after injury. This indicates that the subset of patients possibly benefiting from acute repair must be identified by other means.

La morphologie des os humains varie en fonction du sexe, de l'âge et de l'ethnie. Cette variabilité de l'anatomie humaine peut aider à déterminer le sexe, l'âge et l'ethnie. Les outils utilisés pour de telles analyses sont classiquement des méthodes ostéométriques (longueur, angle, rapport de longueur) qui peuvent être sujettes à des biais d'analyse ou d'interprétation. L'analyse morphométrique géométrique 3D (MG) permet de limiter ces biais. Elle étudie et compare la forme d'un ou plusieurs objets en éliminant les effets liés à la taille de celui-ci. Nous n'avons pas retrouvé d'analyse du dimorphisme sexuel, ethnique et lié à l'âge de l'extrémité distale du fémur à l'aide de cette méthode. Le fémur est pourtant un des plus gros os du corps et il est souvent bien conservé dans les restes humains. L'objectif de ce travail était de montrer qu'il existe une différence de forme du fémur distal en fonction de l'âge, du sexe et de l'ethnie visualisable grâce à MG. Nous avons réalisé une MG de 482 scanners d'extrémité distale de fémur de sujets vivant dans le sud de la France et dans la région de Chongqing (chine). Les sujets présentant une pathologie osseuse ou articulaires ont été exclus. Dix landmarks ont été positionnés sur des reconstructions tridimentionelles. Nous avons également réalisé une analyse ostéométrique " classique " en plus de MG afin d'évaluer la vraisemblance de nos résultats. Les données ont été analysées par deux observateurs à deux temps différents. Nous avons calculé pour chaque landmark la variabilité inter et intraobservateur. Les landmarks choisis permettaient de caractériser la forme de l'extrémité distale du fémur. La première étape a consisté en la réalisation d'une analyse généralisée procrustre (GPA). Les coordonnées dans l'espace des landmarks ont été analysées en utilisant une analyse en composant principal (PCA). Une analyse discriminante a permis de vérifier le pourcentage de cas dans lequel le sexe, l'âge ou l'ethnie estimés étaient les bons. GPA retrouve une différence de forme statistiquement significative entre les sexes, en fonction de l'âge et entre les ethnies. PCA retrouve une différence de forme en fonction de l'âge, du sexe ou de l'ethnie qui représente respectivement 54,4 ;58,6 et 61,9% de la variabilité observée. Les taux d'assignement correct avec cette méthode étaient de 80% (âge) ; 77,3% (sexe) et 82 % (l'ethnie). L'analyse ostéométrique " classique " retrouvait des valeurs comparables à celles retrouvées dans la littérature. Le pourcentage d'erreur intra et inter observateur pour l'ensemble des landmarks n'excédait jamais 2%. Nous avons démontré que l'analyse MG du fémur distal permettait de mettre en évidence une variabilité en fonction du sexe, de l'âge et de l'ethnie de ce segment osseux. La reproductibilité élevée et la vraisemblance des résultats valident notre méthodologie. Cette différence de forme a des retombées directes en anthropobiologie mais aussi en orthopédie. Cette méthode d'assignation ne donne pas de résultats suffisamment précis pour être utilisée seule. Cependant, elle a l'avantage de pouvoir être utilisée dans des contextes d'autopsie virtuelle ou in vivo. Par ailleurs, par la présente étude nous réactualisons les données morphométriques de population contemporaine du sud de la France et aussi de la région de Chongqing en chine. Cette méthodologie adéquate et reproductible va permettre de réaliser des comparaisons diachroniques ainsi qu'inter ethnique. La validation de l'utilisation d'examen d'imagerie médicaux ouvre un champ nouveau en anthropologie physique. En ce qui concerne l'aspect orthopédique, cette variabilité questionne sur la nécessité ou non d'implant spécifique et surtout sur la nécessité de réévaluer de manière régulière la forme des prothèses de genou. / The shape of human bones varies based on age, sex and ethnicity. This variability in human anatomy can be used to determine a person's age, sex and ethnicity. Historically, the tools used for such analyses are osteometric methods (length, angle, length ratio) that can be plagued by analysis or interpretation biases. Three-dimensional geometric morphometric analysis (3D GM) can limit the impact of these biases. It is used to describe and compare the general shape of one or more objects by eliminating any size-related effects. To the best of our knowledge, this method has never been used to analyse the sexual dimorphism, ethnicity-related and age-related differences in the distal femur. The femur is one of the longest human bones and is often well preserved in human remains. The goal of this study was to demonstrate differences in the shape of the distal femur according to age, sex and ethnicity using GM. We carried out 3D GM on 482 CT scans of the distal femur of adults living in the South of France and in the Chongqing region of China. Subjects with bone or joint pathologies were excluded. Ten landmarks were defined on 3D reconstructions of the distal femur. A standard osteometric analysis was performed in addition to the GM analysis to evaluate the plausibility of our results. The data were analysed by two observers at two different times. This allowed us to calculate the inter- and intra-observer variability for each landmark. The chosen landmarks were used to characterise the shape of the distal femur. The first step consisted of a generalized Procrustes analysis (GPA). The landmarks' coordinates in space were analysed using a principal component analysis (PCA). A discriminant analysis was performed to determine the percentage of cases in which the sex, age or ethnicity was correctly estimated. The GPA found a statistically significant difference in the distal femur shape between different sexes, ethnicity groups and age groups. The PCA found that age, sex and ethnicity accounted for 54.4%, 58.6% and 61.9% of the observed variability in distal femur shape, respectively. Using this method, 80% of cases were assigned the correct age, 77.3% the correct sex and 82% the correct ethnic group. The results of the osteometric analysis were comparable to published values. The percentage error for the intra- and interobserver comparisons for all the landmarks was always less than 2%. In this study, MG analysis of the distal femur revealed age-related, sex-related and ethnicity-related variability in the distal femur. The high reproducibility and plausibility of our results validate our methodology. These shape differences have direct implications for anthropobiology and also orthopaedics. Although this method is not sufficiently accurate to be used alone, it has the advantage of being usable in the context of virtual or in vivo autopsy cases. Moreover, this study has updated the morphometric data for a modern population in the south of France and the Chongqing region of China. This reliable and accurate methodology can be used to perform diachronic and interethnic comparisons. Validation of this medical imaging modality opens new avenues in physical anthropology research. In the orthopaedics field, this variability means that the shape of implants used for knee arthroplasty should be re-assessed regularly and brings into question the need for gender-specific or ethnicity-specific implants.

Although rare, distal biceps tears are common in middle-aged men in their 4th and 5th decades of life. The evidence surrounding prognosis, complications and rehabilitation interventions for distal biceps ruptures are of poor quality and therefore, many questions remain to be answered. This thesis includes four manuscripts describing studies that aim to improve our understanding of the rehabilitation of surgical and non-surgical management of distal biceps tendon rupture, prognostic factors associated with surgical repair and the outcomes for non-surgical management. The first manuscript is a scoping review of rehabilitation procedures described in the literature for the management of distal biceps ruptures. Overall, rehabilitation descriptions for distal biceps ruptures are poor for both post-surgical and non-surgical management. The findings suggest heterogeneity, both on the reporting and the content of rehabilitation delivered as a stand-alone intervention or post-operatively. The second manuscript is a cross-sectional study evaluating potential factors associated with reduced function post double incision surgical repair. The findings suggest that having a smoking history and weaker biceps flexion strength are associated with a poor prognosis and accounted for 50.4% of the variability in functional scores. These findings support existing studies that indicate a smoking history is associated with less favourable pain, function and disability outcomes follow distal biceps repair. The third manuscript is a prospective study evaluating prognostic factors associated with reduced function for those undergoing double incision surgical repair. These findings suggest that the majority of persons undergoing a distal biceps repair using a two-incision approach have minimal complications and good functional outcomes. In addition, having surgery on the non-dominant hand and having a weaker grip strength at baseline accounted for 43.4% of the variability of functional scores. The fourth manuscript describes two cases of non-surgical management of a complete distal biceps rupture. Despite the common belief that surgical repair for biceps rupture results in superior elbow flexion and supination strength, these cases demonstrated that full recover of strength and function is possible through rehabilitation alone. This study contributes to the evidence-base by questioning the need for surgical repair for all cases of distal biceps ruptures. / Dissertation / Doctor of Philosophy (PhD) / The biceps tendon is prone to rupture where it inserts into the elbow. While not a common injury, it does occur more often in middle aged men following a forceful movement. Most of the research regarding the prognosis and management of distal biceps ruptures is of poor quality and imprecise due to small sample sizes. This thesis examined management in a set of studies. A scoping review indicated that rehabilitation descriptions for distal bicep ruptures were of very poor quality for both surgical and non-surgical management for this condition. A cross-sectional analysis of 60 patients revealed that having a smoking history and weaker flexion strength was associated with poor outcomes after distal biceps repairs. A prospective cohort study of 34 patients found that having surgery on the non-dominant arm and weaker grip strength was associated with poor outcomes 6-12 months after surgical repair. Given the excellent outcomes after surgery and presumption of the need for surgery as standard practice, there has been little attention to the role of conservative management. We evaluated two cases where patients refused surgery and were able to recover full strength and functional abilities using a comprehensive rehabilitation program. This thesis confirms that excellent outcomes occur after this injury and raises the need for future trials comparing surgery and rehabilitation as treatment options. The fact that this injury often occurs in healthy men may partially explain the excellent outcomes with surgery or rehabilitation.

Neutrophil degranulation involves a number of well-orchestrated structural and biochemical events. We have investigated the mechanism of intracellular signalling involved in neutrophil degranulation that was mediated by the high affinity leukotriene (LT)B[subscript 4] receptor, BLT1. The model systems used were consisted of Peripheral blood neutrophils as well as promyeloid PLB-985 cells, stably transfected with human BLT1 cDNA (PLB-BLT) or a substitution mutant (2L(304-305)/A) of the distal dileucine motif in helix VIII of BLT1, and differentiated into a neutrophil-like phenotype. The degranulation of these cells was measured in the presence and absence of factors that would affect the signaling pathway. The results show that Degranulation responses to LTB[subscript 4] were similar for differentiated PLB-BLT1 and neutrophils. However, the degranulation response of cells bearing the dileucine mutation in helix VIII of BLT1 was significantly reduced in response to LTB[subscript 4]. Pretreatment of differentiated PLB-BLT1 cells and neutrophils with Y-27632, a pharmacological inhibitor of p160-ROCK, the down-stream effector of the small GTPase RhoA, abrogated their degranulation in response to LTB[subscript 4]. The degranulation defect observed with the dileucine mutation was corrected by transient transfection of the cells bearing the mutation with a constitutively active form of RhoA. Taken together, our results suggest an essential role for the distal dileucine motif in helix VIII of BLT1 involving RhoA which allows normal neutrophil degranulation in response to LTB[subscript 4].

The nematode Caenorhabditis elegans is a unique resource for the study of axon guidance and cell migration. Genetic data collected from C. elegans research is integral to advancing our knowledge of genetic pathways that control axon and cell guidance, such as the UNC-6/netrin pathway, within a developing organism. In this thesis, I describe the characterization of ev821, an allele isolated from a screen for novel guidance mechanisms or components of the UNC-6 pathway. Furthermore, I show that ev821 is a maternal-effect and temperature-sensitive mutation with defects in phase 2 of distal tip cell migration in the C. elegans hermaphrodite, as well as ray-1 displacement and a blister phenotype in the C. elegans male. My research on ev821 could broaden our understanding of the mechanisms driving UNC-6 guidance, and has the potential to identify unknown factors that act within or in parallel to the UNC-6 signaling pathway.

The nematode Caenorhabditis elegans is a unique resource for the study of axon guidance and cell migration. Genetic data collected from C. elegans research is integral to advancing our knowledge of genetic pathways that control axon and cell guidance, such as the UNC-6/netrin pathway, within a developing organism. In this thesis, I describe the characterization of ev821, an allele isolated from a screen for novel guidance mechanisms or components of the UNC-6 pathway. Furthermore, I show that ev821 is a maternal-effect and temperature-sensitive mutation with defects in phase 2 of distal tip cell migration in the C. elegans hermaphrodite, as well as ray-1 displacement and a blister phenotype in the C. elegans male. My research on ev821 could broaden our understanding of the mechanisms driving UNC-6 guidance, and has the potential to identify unknown factors that act within or in parallel to the UNC-6 signaling pathway.

The human motor system exhibits remarkable adaptability, enabling us to maintain high levels of performance despite ever-changing requirements. There are many potential sources of error duringmovement to which the motor system may need to adapt: the properties of our bodies or tools may vary over time, either at a dynamic or a kinematic level; our senses may become miscalibrated over time and mislead us as to the state of our bodies or the true location of an intended goal; the relationship between sensory stimuli and movement goals may change. Despite these many varied ways in which our movements may be disturbed, existing models of human motor adaptation have tended to assume just a single adaptive component. In this thesis, I argue that the motor system maintains multiple components of adaptation, corresponding to the multiple potential sources of error to which we are exposed. I outline some of the shortcomings of existing adaptation models in scenarious where multiple kinds of disturbances may be present - in particular examining how different distal learning problems associated with different classes of disturbance can affect adaptation within alternative cerebellar-based learning architectures - and outline the computational challenges associated with extending these existing models. Focusing on the specific problem in which the potential disturbances are miscalibrations of vision and proprioception and changes in arm dynamics during reaching, a unified model of sensory and motor adaptation is derived based on the principle of Bayesian estimation of the disturbances given noisy observations. This model is able to account parsimoniously for previously reported patterns of sensory and motor adaptation during exposure to shifted visual feedback. However the model additionally makes the novel and surprising prediction that adaptation to a force field will also result in sensory adaptation. These predictions are confirmed experimentally. The success of the model strongly supports the idea that the motor system maintains multiple components of adaptation, which it updates according to the principles of Bayesian estimation.

Lack of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) causes the syndrome of apparent mineralocorticoid excess (AME): low-renin hypertension, renal sodium (Na +) retention, hypokalaemic alkalosis and polyuria. This rare autosomal recessive disorder is observed in human kindreds carrying mutations in the HSD11B2 gene. Genetically modified mice, in which the homologue Hsd11b2 is rendered non-functional, have been used to study the pathogenesis of AME. Hitherto, data obtained from humans and mice have suggested that the physiological phenotype is a consequence of enhanced reabsorption of Na + through the epithelial sodium channel (ENaC) in the renal connecting tubule (CNT) and collecting duct. However, Hsd11b2 null mice exhibit epithelial hypertrophy in a different nephron segment, namely the distal convoluted tubule (DCT). The studies described herein aimed to characterise this structural phenotype and to examine the consequences for renal Na + reabsorption in AME. Hsd11b2 null mice exhibited hypertrophy and hyperplasia in the DCT, with an elevated rate of epithelial cell proliferation in this nephron segment at 60 days of age. Hsd11b2 null kidneys contained greater quantities of the thiazide-sensitive NaCl co-transporter (NCC), the dominant Na + transporter protein in the DCT. They also contained greater quantities of the phosphorylated forms of NCC that are associated with NaCl transport activity. Despite this, there was no increase in the proportion of filtered Na + that was reabsorbed in the DCT. This was assessed in anaesthetised mice, using clearance methodology to measure the thiazide-induced increment in the fractional excretion of Na + (FENa) during continuous ENaC blockade. Wild-type DCTs did not express 11βHSD2; therefore the structural and molecular changes were not a direct consequence of the loss of 11βHSD2 in affected cells. The discussion examines the likely mechanisms causing structural remodelling in the distal renal tubule of Hsd11b2 null kidneys and potential explanations for the dissociation between structural and functional phenotypes in the DCT. There are implications for our understanding of the cellular and molecular mechanisms underlying various renal phenomena including structural remodelling in the distal tubule, resolution of the ‘aldosterone paradox’ and escape from chronic aldosterone excess.

The sphincter of Oddi (SO) is a neuromuscular structure located at the junction of the bile and pancreatic ducts with the duodenum. The primary functions of the SO are to regulate the delivery of bile and pancreatic juice into the duodenum, and to prevent reflux of duodenal contents into the biliary and pancreatic systems. Neural, hormonal or functional disturbances of biliary motility can lead to painful and sometimes life threatening clinical conditions, such as SO dysfunction and acute pancreatitis. Clearly understanding the regulation of biliary and duodenal motility patterns is necessary and may provide useful pharmacological sites for drug development to aid in the treatment of these diseases. Spontaneous activity of the SO is regulated by complex interactions between the enteric nervous system, hormones, possibly interstitial cells of Cajal and other bioactive agents, together with modulation via neural reflexes between the duodenum, common bile duct/gallbladder, and stomach. Purines are one group of neurotransmitters/regulatory agents that have been shown to effect gastrointestinal motility, however their functions in the regulation of SO motility have not been elucidated. The studies described in this thesis used in vitro organ bath techniques and in vivo preparations to determine the effects of exogenous purines on possum SO and duodenal motility. The possum SO has been extensively characterized and is an excellent model for motility studies. In vitro, exogenous adenosine was found to decrease spontaneous activity in both the SO and duodenum. In contrast exogenous ATP induced both excitatory and inhibitory responses in the SO and duodenum. Interestingly, the adenosine and ATP-induced effects were predominantly exhibited by the proximal portion of the SO (proximal-SO), with no or little effect observed in the distal portion of the SO (distal-SO). These data support the hypothesis that the SO is comprised of different functional components that can act differently in response to certain stimuli, and highlights the importance of studying each of the SO components. Agonists and antagonists, together with immunohistochemical studies, were used in an attempt to identify the P1 and P2 receptor sub-types responsible for mediating the adenosine- and ATP-induced responses. In the duodenum the adenosine-induced decrease in spontaneous activity was likely to be mediated by A2A and A3 receptors, but the receptors mediating the proximal-SO response could not be identified. In the duodenum ATP induced a complex non-neural response consisting of a P2X1, and P2Y2 and/or P2Y4 mediated immediate inhibition. This was followed by a return to baseline activity or small excitation. The response concluded with a late inhibitory response, likely to be mediated by P2Y1 receptors, but the effects of other P2Y receptors could not be excluded. In contrast, ATP application to the proximal-SO evoked a partially neurally mediated early excitation, likely via P2X receptors, followed by an inhibition of activity, likely via activation of non-neural P2Y2 and/or P2Y4 receptors. In vivo studies with exogenous application of adenosine and ATP to the SO activated neural pathways to produce increased motor activity. Characterisation of these neural pathways found ATP and/or adenosine to activate excitatory cholinergic motor neurons. ATP also activated an inhibitory nicotinic/nitrergic pathway. This is the first comprehensive investigation of the possible involvement of purines in the regulation of SO motility. These studies demonstrate that exogenous purines influence SO and duodenal motility, inducing complex neural and non-neural responses, acting via multiple P1 and P2 receptors. It now remains to be determined if endogenously released purines induce similar responses, together with elucidation and location of the receptor sub-types involved.

The Strain Index (SI) has repeatedly shown high levels of validity for differentiating between safe and hazardous tasks for the distal upper extremity (DUE). One limitation of the SI is the lack of reliability data. This study was designed to evaluate the test-retest repeatability of the SI. Fifteen raters, divided into five teams of three, were asked to use the SI to analyze 73 video AVI files of different job tasks; initially as individuals and then as teams. Several months later, raters were asked to repeat individual and team job task assessments. Raters were instructed to analyze tasks using five of six SI task variables, while the sixth was held constant. For three of these task variables, additional data was collected such as peak force and duration of job cycle. Test-retest repeatability was measured using Pearson's R, Spearman's rho, and tetrachoric correlation according to the nature of the variable. Spearman's rho values for individual and team task variable ratings ranged from 0.68 to 0.96 (0.88 average). Pearson's R for task variable data ranged from 0.76 to 0.99 for both teams and individuals with an average of 0.91. The Strain Index's rho values for individuals and teams were 0.70 and 0.84, respectively. For hazard classification, the tetrachoric correlation for individuals was 0.81 and 0.88 for teams. Results of this study support the conclusion that the Strain Index is repeatable when used by teams as well as individuals.