Inhibitory glycine receptors (GlyRs) undergo developmental regulation with α2 subunits most abundant at prenatal and early postnatal stages, and α1 subunits predominating in adults. In comparing the relative amounts of mRNA for two known splice variants of the α2 subunit, α2A and α2b, in the rat spinal cord at different stages of development, I found evidence for the existence of an additional, novel variant. This variant, missing exon 3, I have termed "α2N." Examination of the RNA from spinal cords of different-aged rats indicated that α2N undergoes dramatic down-regulation during prenatal development. Its mRNA forms a significant portion of the α2 subunit pool at E14, but is nearly undetectable at the time of birth. I also examined the developmental changes in two factors that can regulate GlyR α2 pre-mRNA splicing, the splicing factor neurooncological ventral antigen-1 (Nova-1) and the brain isoform of the polypyrimidine tract binding protein (brPTB). Treatment of neurons in culture with antisense oligonucleotides to "knock down" one of the Nova-1 variants altered the expression of GlyR α2N. These results suggest that the relative levels of the variants of Nova-1 and brPTB may play a role in the developmental regulation of GlyR α2N. Based on these results I propose a model for the developmental regulation of GlyR α2N. These results provide evidence for a novel splice variant of the GlyR α2 subunit that undergoes dramatic developmental regulation, and reveal the developmental profiles of two possible regulators of its expression during development.

The fingerprint pattern (epidermal ridge pattern) becomes established at about the 10th to 16th week of pregnancy, when the lowest layer of the epidermis, the basal layer, becomes undulated. The pattern established by these undulations becomes visible on the skin surface in subsequent weeks of pregnancy. We argue that the undulation process is initiated by buckling of the basal layer. The necessary compressive stress is generated by differential growth. The instability is investigated using the classic von Karman equations for curved surfaces. The analysis reveals that ridges (rolls) are the most common pattern type and that the local ridge direction of the pattern is perpendicular to the direction of largest stress. For certain parameter regimes dot patterns (hexagons) are a stable solution of the equations. Such dot patterns are, in fact, observed on the palms of certain marsupials. The stress in the basal layer is induced by two mechanisms. First, the basal layer expands faster than the other skin structures. Such expansion is resisted at the major flexion creases and the nail furrow. Second, there is a change in fingertip geometry at the time of pattern generation that provides a different source of growth stress. The combination of the two processes predicts the correct sequence of pattern spread over the fingertip. It also explains the observation that fingerprint configurations are related to the fingertip geometry at the time of ridge formation. Computer simulations for the most important configurations exhibit many features of actual fingerprints and suggest directions for future work.

The composition of the body in relation to the distribution of skin, muscle, bone and other tissues is directly related to the activities the individual is capable of performing throughout its life stages. The infant squirrel monkey is born with 20.658 TBW devoted to muscle, 24.65% TBW in bone, 24.15% TBW in skin, and 24.7% TBW in other supporting tissues. The adult squirrel monkey tissue distribution changes to 41.0% TBW in muscle, 17.2% TBW in bone, 17.5% TBW in skin, and 24.6% TBW in other supporting tissues. Consistently the adult demonstrates a tissue distribution and size that is compatible to living in the trees, moving through areas to forage, and the ability to escape predators that enter their preferred habitat. The infant demonstrates a body composition and size consistent with limited mobility and dependence on its mother for nutrients. The trend in the change of tissue distribution through growth and maturation from infant to adult is demonstrated and explained in relation to activities at the various life stages of the squirrel monkey.

To examine factors influencing normal and disordered genesis of the B lymphocyte lineage in mouse bone marrow, precursor B cell dynamics have been analysed in conditions predisposing to B cell neoplasias and deficiencies. Double immunofluorescence labeling and stathmokinetic techniques have been used to quantitate the population size and mitotic activity of pro-B cells before $ mu$ chain expression, pre-B cells expressing cytoplasmic $ mu$ chains, and B lymphocytes expressing surface IgM. Two conditions associated with prolonged macrophage activation and B cell neoplasia, pristane oil-treatment and malaria infection, have been found to stimulate the proliferation of pro-B cells but to produce increased cell loss at later cell differentiation stages, suggesting that the stimulation of cells undergoing Ig gene rearrangement may predispose to genetic errors leading to cell death or oncogenesis. During a pretumorous period in E$ mu$-myc transgenic mice a marked stimulation of pro-B and pre-B cells is associated with much subsequent cell loss, suggesting that additional mutations are needed to promote B cell survival and the emergence of a tumorigenic clone. Many early precursor B cells express c-kit but their development is not blocked by a neutralizing anti-c-kit antibody in vivo, suggesting that the role of c-kit can be replaced by alternative signalling systems. The introduction of Ig transgenes in scid mutant mice, unable to rearrange endogenous Ig genes, shows that the survival of successive stages in precursor B cell development depends upon the successful progressive expression of the IgM molecule. The work demonstrates that processes influencing both cell proliferation and loss can be critical in regulating the genesis of both normal and potentially neoplastic B cells in the bone marrow.

This thesis describes a system to record and visualise in-vivo human lumbar spinal kinematics. As well, an extensive method to quantify the system's accuracy and reliability is detailed within. A data acquisition system measures lumbar motion associated with exercises similar to daily activities (gait, ranging, and load lifting). This involves a minimally invasive procedure to insert pins into three spinous processes of the lumbar vertebrae. Three-dimensional electromagnetic position sensors are attached to these pins and stereo radiographs provide the calibration offsets necessary for the calculation of spinal segmental motion from the sensor data. Analysis software was written to aid researchers in extracting descriptive statistics and by displaying 2-D graphs of the segmental motion. As an adjunct to the analysis software, a method was developed to visualise the subject's kinematics using 3-D computer animation. This requires the subject to undergo magnetic resonance volume scans which yields vertebral surface data. This data and the previously acquired kinematics from the same person is combined through computer animation resulting in an intuitive visualisation of their spine's motion.

The conscious sheep is an important large animal model for the study of human cardiovascular and cardiopulmonary system. In this study we develop a closed-loop mathematical model of its cardiovascular system. A distributed approach is taken in describing the systemic circulation, which is divided into cerebral, coronary, foreleg, thoracic, abdominal, and hind-limb circulations. Nonlinear aspects of the systemic venous system are described, which include nonlinear pressure-volume characteristics of small and large veins and pressure-operated valves in large veins. The complete integrated model mimics typical steady-state hemodynamic data in the supine position. It is also used to predict the blood volume shifts and hemodynamic changes that accompany standing up. These include the short-term neurally mediated cardiovascular response to the orthostatic stress. Additional studies predict the circulatory response to an increased afterload (balloon inflation) presented to the right ventricle. This model is further used to predict the response of the ovine cardiovascular system to the implantation of the PAL (Para-corporeal Artificial Lung device and to test the putative effectiveness of different PAL device designs.

This study developed a mathematical model of human cardiopulmonary system which consists of component models such as ventricular mechanics, hemodynamics of the systemic and pulmonic circulations, baroreflex control of arterial pressure, airway/lung mechanics and gas transport. Instantaneous elastance functions were used to describe the mechanics of the heart chambers. The resistive, compliant and inertial properties of the circulatory system were characterized by a lumped equivalent hydraulic circuit. Transfer functions were employed to represent the input-output relations of baroreflex pathways. On the pulmonary side, the airways were characterized using a lumped pneumatic model containing a mid-airway collapsible segment. Description of lung mechanics included the resistive, compliant properties of the lung tissue, which exhibited hysteresis. Gas transport was characterized by a distributed compartmental system containing ten contiguous segments. With suitable parameter adjustment, the nominal case simulation yielded realistic predictions of pressure, volume and flow waveforms that agreed well with published data. In addition, it predicted the temporal behavior of variables that are not routinely collected in cardiac catheterization or pulmonary laboratories, and which are difficult to measure. The model also demonstrated stability under large amplitude perturbations of the physiological variables, such as Valsalva maneuver. This model maybe employed usefully to show the detailed nature of normal human cardiopulmonary interactions and baroreflex control (e.g. ventricular interaction, Valsalva maneuver). It also provides methodologies for the development of more specific models of abnormal behavior, and as such, may serve as an aid in clinical diagnosis.

The present study examines events of the Sertoli cell iron delivery pathway following the secretion of diferric testicular transferrin (tTf) in to the adluminal compartment of the rat seminiferous epithelium. The unidirectional secretion of tTf by Sertoli cells was verified, in vivo, and it was shown that this protein is internalized by adluminal germ cells. It was further determined by Scatchard analysis that this internalization was mediated by high affinity transferrin binding sites on the surface of round spermatids, numbering 1453/cell and displaying a K$ sb{ rm d}$ = 0.6 $ times$ 10$ sp{-9}$ M. Northern blot analysis of RNA isolated from adluminal germ cells, namely spermatocytes, round spermatids and elongating spermatids, indicated that these cells expressed Tf receptor mRNA and ferritin mRNA in levels inversely related to their stage of maturation. Finally it was determined that following binding and internalization in round spermatids, Tf became associated with the endosomal compartment and was recycled back to the cell surface. Diferric tTf binds to Tf receptor on the surface of adluminal germ cells, is internalized by receptor-mediated endocytosis and the apotTf-Tf receptor complex is recycled back to the cell surface where apotTf is released into the adlumenal fluid.

Lymphocyte homing to the lymph nodes is a well defined process, dependent on the proper function of the homing receptors LFA-1 (one of the CD18 family of integrins) and L-selectin. However, the mechanism used by lymphocytes to accumulate in the spleen is still not understood. Both B lymphocytes and Natural Killer cells are prominent in the spleen. To investigate whether CD18 integrins or L-selectin play a role in B lymphocyte and NK cell homing to the spleen, mice genetically deficient in either of these molecules were analyzed by flow cytometry. The results of this study demonstrate that neither B lymphocytes nor NK cells require the CD18 family of integrins or L-selectin for entry into the spleen. Results of this study also showed that neither cell lineage required the CD18 integrins or L-selectin for egress from their sites of birth in the bone marrow.

The sulcal patterns of the human orbitofrontal cortex have not been adequately characterized. Classical authors, as well as more recent investigators, have attempted to identify and label the sulci of this part of the brain. Nevertheless, there is considerable confusion regarding the orbital sulcal patterns with inconsistencies in the naming of orbitofrontal sulci in many modern texts. Moreover, a correlation between specific landmarks and architectonic areas has not been demonstrated. / A clarification of the patterns of the orbitofrontal sulci and their relationship to architectonic subregions is necessary if the results of functional neuroimaging and other physiological and anatomical findings are to be properly interpreted. Although studies have reported altered activity in the orbitofrontal cortex in relation to various sensory processes and pathological states it has been difficult to relate these changes to specific orbitofrontal regions because of a limited understanding of the anatomical landmarks. The absence of reliable reference markers forces the use of vague terminology (e.g., "orbital frontal activation") in describing the location of functional changes in the orbital frontal cortex. / The aim of this doctoral thesis was to gain a better understanding of the sulcal pattern of the human orbitofrontal cortex and its relation to the underlying cytoarchitecture. The first study resolved the confusion associated with the orbitofrontal sulci by identifying, quantifying, and precisely localizing the various orbital sulci from fifty human magnetic resonance scans that were transformed into the standardized stereotaxic space of Talairach and Tournoux (1988). The second study compared the individual sulci and sulcal patterns of these fifty human brains with the brains of fifty adult rhesus monkeys. Having examined the orbitofrontal sulci in these two species, a nomenclature for the human orbitofrontal sulci was established which was based on comparable sulci in the less convoluted macaque monkey brain while trying to preserve many of the familiar labels associated with this region in the human brain. The final part of this thesis examined the orbitofrontal cytoarchitecture of 10 human adult cerebral hemispheres to determine if a correlation exists between the different orbital sulci and the borders of the architectonic subregions.