In the present investigation, a comprehensive set of reliable data for the human spine has been established, and a useful aggregation and analysis of the data has also been carried out. Data obtained has been presented in tabulated and graphical forms to allow easy comparison with other researchers' data. The new accurate data obtained has been used in the construction of a kidney-shaped model of a functional spinal unit which has been subjected to finite element testing that resulted in very good agreement with the results of other published models. A computer-based formulation for the dynamic analysis of an' inertia-variant spatial human body system has also been developed. The human body system is modelled as a multi-body system consisting of interconnected rigid, elastic and visco-elastic components. Each of these components is allowed to undergo large angular rotations. A linear visco-elastic Kelvin-Viogt model is employed whereby stress is assumed to be proportional to the time rate of strain. The focus in this work is placed on the analysis and diagnosis of lumbar and lumbo-sacral back problems associated with lifting activities. All human links are treated as rigid, while the entire lumbar spine is considered to be elastic. Flexibility of the lumbar spine is introduced into the mathematical model using a set of short and stubby finite elements which describe the behavior of the vertebrae and discs at the lumbar region and which accounts for both geometric and inertia nonlinearities. The implementation of the model and analysis of results has been limited to the two-dimensional case in the sagittal plane in recognition of the well known difficulties encountered in solving human body systems. Health and safety issues in material handling are currently receiving the concern of many researchers as well as manufacturing companies. Therefore, two case studies were carried to establish the importance, accuracy and validity of the model developed in this thesis. A two dimensional lifting task with a flexible lumbar spine formed the first case study whilst the second was a pushing task.

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The precise mechanisms by which human intervertebral discs (IVD) respond to load remains unknown and are a challenge to investigate in vitro. In this study, a novel mechanical loading system was devised, built, tested and successfully used to apply hydrostatic pressure to nucleus pulposus (NP) and annulus fibrosis (AF) cells and explants obtained from human nondegenerate and degenerate IVD. Cells were removed from the IVD, cultured in monolayer to generate sufficient numbers and subsequently embedded in alginate constructs prior to application of dynamic cyclic hydrostatic pressure at physiological levels.

Injury to the human neck is a frequent consequence of automobile accidents and has been a significant public health problem for many years. The term `whiplash' has been used to describe these injuries in which the sudden differential movement between the head and torso leads to abnormal motions within the neck causing damage to its soft tissue components. Although many different theories have been proposed, no definitive answer on the cause of `whiplash' injury has yet been established and the exact mechanisms of injury remain unclear. Biomechanical research is ongoing in the field of impact analysis with many different experimental and computational methods being used to try and determine the mechanisms of injury. Experimental research and mathematically based computer modelling are continually used to study the behaviour of the head and neck, particularly its response to trauma during automobile impacts. The rationale behind the research described in this thesis is that a computational model of the human head and neck, capable of simulating the dynamic response to automobile impacts, could help explain neck injury mechanisms. The objective of the research has been to develop a model that_,, can accurately predict the resulting head-neck motion in response to acceleration impacts of various directions and severities. This thesis presents the development and validation of a three-dimensional computational model of the human head and cervical spine. The novelty of the work is in the detailed representation of the various components of the neck. The model comprises nine rigid bodies with detailed geometry representing the head, seven vertebrae of the neck and the first thoracic vertebra. The rigid bodies are interconnected by spring and damper constraints representing the soft-tissues of the neck. 19 muscle groups are included in the model with the ability to curve around the cervical vertebrae during neck bending. Muscle mechanics are handled by an external application providing both passive and active muscle behaviour. The major findings of the research are: From the analysis of frontal and lateral impacts it is shown that the inclusion of active muscle behaviour is essential in predicting the head-neck response to impact. With passive properties the response of the head-neck model is analogous to the response of cadaveric specimens where the influence of active musculature is absent. Analysis of the local loads in the soft-tissue components of the model during the frontal impact with active musculature revealed a clear peak in force in the majority of ligaments and in the intervertebral discs very early in the impact before any forward rotation of the head had occurred. For the case of rear-end impact simulations it has been shown for the first time that the inclusion of active musculature has little effect on the rotation of the head and neck but significantly alters the internal loading of the soft-tissue components of the neck.

Le rein joue un rôle crucial dans de multiples processus biologiques, tels que le maintien de l’homéostasie acide-base et de la balance sodée. Le transport de chlore dans le néphron distal est un élément majeur de ces deux fonctions physiologiques. Au cours de ma thèse, j’ai travaillé sur deux projets relatifs à la physiologie et la physiopathologie du transport de chlore dans le néphron distal. Le premier travail concerne la caractérisation fonctionnelle et moléculaire d’un modèle murin dont le gène Slc4a1 codant pour l’échangeur d’anion de type 1 (AE1) a été modifié, pour introduire une mutation ponctuelle (R589H) dans la séquence protéique. Cette mutation est la plus fréquente des mutations de cette protéine responsable d’acidose tubulaire rénale distale chez l’Homme. Comme les patients, ces souris présentent une acidose tubulaire distale. Nos résultats ont montré que la diminution de l’activité d’échange Cl-/HCO3-, due à la baisse drastique de l’expression d’AE1 dans les cellules -intercalaires du canal collecteur, affecte l’expression et la distribution apicale de la pompe à protons, ce qui altère de ce fait la fonction d’acidification de l’urine. Le second travail porte sur l’étude de la régulation du transport de chlore par le complexe protéique ClC-Kb/Barttin, par phosphorylation de la Barttin. Ce travail démontre que la phosphorylation de la Barttin stimule le transport de chlore du canal ClC-Kb, en augmentant la distribution et la stabilité du complexe ClC-Kb/Barttin à la membrane. Ainsi, la phosphorylation de la Barttin pourrait représenter un mécanisme d’adaptation du transport de chlore en réponse à des variations des apports alimentaires en NaCl. / Kidney plays a major role in several biological fonctions as sodium balance or acid-base homeostasis. Chloride transport in the distal nephron is a key element of these two processes. During my thesis, i have worked on two projects related to physiology and pathophysiology of chloride transport in distal nephron. The first study is the functionnal and molecular characterization of a mouse model bearing the most common dominant dRTA mutation in human AE1, R589H, which corresponds to R607H in the mouse. R607H knock-in mice display incomplete dRTA. Our results showed that reduced basolateral anion exchange activity in type A intercalated cells inhibits trafficking and regulation of V-type ATPase, compromising luminal H+ secretion. In the second study, we investigated the role of a phosphorylation site in the regulation of chloride transport by the ClC-Kb/Barttin channels complex. Our results indicates that Barttin phosphorylation stimulates chloride transport by ClC-Kb channels by increasing the number of active channels in the membrane and hence are involved in the mechanisms of adaptation of renal chloride absorption in response to changes in dietary NaCl intake.