Indiana University-Purdue University Indianapolis (IUPUI) / Bone is a dynamic tissue that is constantly remodeling to repair damage and strengthen regions exposed to loads during everyday activities. However, certain conditions, including long-term unloading of the skeleton, hormonal imbalances, and aging can disrupt the normal bone remodeling cycle and lead to low bone mass and osteoporosis, increasing risk of fracture. While numerous treatments for low bone mass have been devised, dynamic mechanical loading modalities, such as axial loading of long bones and lateral loading of joints, have recently been examined as potential methods of stimulating bone formation. The effectiveness of mechanical loading in strengthening bone is dependent both on the structural and geometric characteristics of the bone and the properties of the applied load. For instance, curvature in the structure of a bone causes bending and increased strain in response to an axial load, which may contribute to increased bone formation. In addition, frequency of the applied load has been determined to impact the degree of new bone formation; however, the mechanism behind this relationship remains unknown. In this thesis, the application of mechanical loading to treat osteoporotic conditions is examined and two questions are addressed: What role does the structural geometry of bone play in the mechanical damping of forces applied during loading? Does mechanical resonance enhance geometric effects, leading to localized areas of elevated bone formation dependent on loading frequency? Curvature in the structure of bone was hypothesized to enhance its damping ability and lead to increased bone formation through bending. In addition, loading at frequencies near the resonant frequencies of bone was predicted to cause increased bone formation, specifically in areas that experienced high principal strains due to localized displacements during resonant vibration. To test the hypothesis, mechanical loading experiments and simulations using finite element (FE) analysis were conducted to characterize the dynamic properties of bone. Results demonstrate that while surrounding joints contribute to the greatest portion of the damping capacity of the lower limb, bone absorbs a significant amount of energy through curvature-driven bending. In addition, results show that enhanced mechanical responses at loading frequencies near the resonant frequencies of bone may lead to increased bone formation in areas that experience the greatest principal strain during vibration. These findings demonstrate the potential therapeutic effects of mechanical loading in preventing costly osteoporotic fractures, and explore characteristics of bone that may lead to optimization of mechanical loading techniques. Further investigation of biomechanical properties of bone may lead to the prescribing of personalized mechanical loading treatments to treat osteoporotic diseases.

Indiana University-Purdue University Indianapolis (IUPUI) / Mechanical loading associated with exercise is known to benefit bone health; however, most studies explore exercise benefits on bone mass independent of bone structure and strength. The purpose of this dissertation is to explore the response of the skeleton to exercise across the translational divide between animal- and human-based studies, with a particular emphasis on exercise-induced changes in bone structure and estimated strength. To explore the skeletal benefits of exercise, models were used wherein loading is introduced unilaterally to one extremity. Unilateral exercise enables the contralateral, non-exercised extremity to be used as an internal control site for the influences of systemic factors, such as genetics and circulating hormones. In study 1, a dose response between load magnitude and tibial midshaft cortical bone adaptation was observed in mice that had their right tibia loaded in axial compression at one of three load magnitudes for 3 d/wk over 4 weeks. In study 2, the ability of peripheral quantitative computed tomography to provide very good prediction of midshaft humerus mechanical properties with good short-term precision in human subjects was demonstrated. In study 3, collegiate-level jumping (long and/or high jump) athletes were shown to have larger side-to-side differences in tibial midshaft structure and estimated strength between their jump and lead legs than observed in non-jumping athletes. In study 4, prepubertal baseball players followed for 12 months were shown to gain more bone mass, structure and estimated strength in their throwing arm relative to their nonthrowing arm over the course of 12 months. These cumulative data using a combination of experimental models ranging from animal to cross-sectional and longitudinal human models demonstrate the ability of the skeleton to adapt its structure and estimated strength to the mechanical loading associated with exercise. Study of these models in future work may aid in optimizing skeletal responses to exercise.

Indiana University-Purdue University Indianapolis (IUPUI) / PTH increases osteoclasts by upregulating RANKL in cells of the osteoblastic lineage, but the precise differentiation stage of the PTH target cell remains undefined. Recent findings demonstrate that PTH regulates gene expression in osteocytes and that these cells are an important source of RANKL. We therefore investigated whether direct regulation of the RANKL gene by PTH in osteocytes is required to stimulate osteoclastic bone resorption. To address this question, we examined bone resorption and RANKL expression in transgenic mice in which PTH receptor signaling is activated only in osteocytes (DMP1-caPTHR1) crossed with mice lacking the distal control region regulated by PTH in the RANKL gene (DCR -/-). Longitudinal analysis of circulating C-terminal telopeptide (CTX) in male mice showed elevated resorption in growing mice that progressively decreased to plateau at 3-5 month of age. Resorption was significantly higher (~100%) in DMP1-caPTHR1 mice and non-significantly lower (15-30%) in DCR -/-mice, versus wild type littermates (WT) across all ages. CTX in compound DMP1-caPTHR1; DCR -/-mice was similar to DMP1-caPTHR1 mice at 1 and 2 months of age, but by 3 months of age, was significantly lower compared to DMP1-caPTHR1 mice (50% higher than WT), and by 5 months, it was undistinguishable from WT mice. Micro-CT analysis revealed lower tissue material density in the distal femur of DMP1-caPTHR1 mice, indicative of high remodeling, and this effect was partially corrected in compound vi mice. The increased resorption exhibited by DMP1-caPTHR1 mice was accompanied by elevated RANKL mRNA in bone at 1 and 5 months of age. RANKL expression levels displayed similar patterns to CTX levels in DMP1-caPTHR1; DCR -/-compound mice at 1 and 5 month of age. The same pattern of expression was observed for M-CSF. We conclude that resorption induced by PTH receptor signaling requires direct regulation of the RANKL gene in osteocytes, but this dependence is age specific. Whereas DCR-independent mechanisms involving gp130 cytokines or vitamin D 3 might operate in the growing skeleton, DCR-dependent, cAMP/PKA/CREB-activated mechanisms mediate resorption induced by PTH receptor signaling in the adult skeleton.

The evolution of jaws in cichlid fishes of the East African Great Lakes is a textbook example of adaptive radiation in vertebrates. Karl Liem postulated that this adaptive radiation has been possible due to the functional decoupling of two cichlid functional units – the pharyngeal jaw (PJ) and the oral jaw (OJ). This functional decoupling of the jaws has enabled the OJ to be relieved of its dual role of prey capturing and processing and has allowed the PJ to take on the role of prey processing. As a result, African cichlids have adapted the morphology of their functional units (i.e., oral jaws) to specialize in a feeding mechanism best suited for their habitat. However, global morphological changes (across the OJ and PJ) are understudied, especially, at the genetic level. In this study, two rock dwelling species of African Cichlids from Lake Malawi were used - Labeotropheus fuelleborni (LF) and Tropheops “red cheek” (TRC). Both species have distinct craniofacial morphologies for specialized benthic feeding (LF) and for generalized feeding (TRC). This morphological variation allowed us to investigate the functional decoupling of the jaws by studying differences in bone shape and muscle volumes in an F5 hybrid population. Strong phenotypic correlations were observed between and within the tissues of the OJ and PJ. Further, to identify phenotype to genotype associations, a Quantitative Locus (QTL) analysis and a fine mapping analysis was conducted. The results show some evidence of overlapping genetic control (i.e., pleiotropy) suggesting some genetic coupling between the two jaws.

В диссертационном исследовании проанализированы нарушения опорно-двигательного аппарата у женщин старше 40 лет, а также механизмы лечебного воздействия средств оздоровительной гимнастики ушу на опорно-двигательный аппарат. Разработана, обоснована и определена эффективность программы физической реабилитации женщин старше 40 лет с нарушениями опорно-двигательного аппарата средствами оздоровительной гимнастики ушу. / The dissertation analyses the musculoskeletal system disorders in women over 40 years old, as well as the mechanisms of therapeutic effects of Wushu recreational gymnastics on the musculoskeletal system. The effectiveness of physical rehabilitation program for women over 40 years old with disorders of musculoskeletal system by means of wushu health gymnastics has been identified, explained and developed.

<p>Dedicated to the memory of Dr. Colin E. Webber</p> / <p>This comparative study of peripheral (p) QCT, high-resolution pQCT (hr-pQCT) and 1.0 Tesla pMRI technologies quantified short-term test-retest reproducibility, validity, one-year detection limit and clinical sensitivity of each modality’s derived bone measures. Select bone outcomes were evaluated from scans performed on Hamiltonian women above 50 years old and externally validated in a population-based cohort. In the local cohort (age: 74 ± 9 years and BMI 27.65 ± 5.74 kg/m²), Tb.Sp measured on pMRI, Ct.Th and vBMD from pQCT showed significant correlations (r²=0.52-0.85) with hr-pQCT, yielding slopes near unity. Bland-Altman analyses revealed significant relationships between pQCT and pMRI bone outcome values (Tb.Th(-), Tb.N(+), BV/TV(-)) and agreement with hr-pQCT. Short-term reproducibility was < 5% for pQCT but only BV/TV was < 5% for pMRI. Co-registration and excluding individuals with fractures mildly reduced precision error and one-year change. In the local cohort, only Ct.Th and cortical vBMD associated with fractures (OR: 1.09-3.28) using hr-pQCT, which was externally validated in the national cohort. Certain trabecular measures on pMRI and pQCT erred towards increased odds for fractures locally. For pQCT, these became significant in the national cohort (OR:1.04-3.81). This Canadian reference dataset for hr-pQCT showed larger Tb.Sp and smaller Tb.N compared to Americans but age-related decline in Ct.Th and BV/TV was faster in Europeans. This study demonstrated validity of pMRI and pQCT-derived volumetric bone outcomes and reasonable short- and long-term precision error for pQCT but not 1.0T pMRI. A single CT slice from pQCT was comparable to 110 slices from hr-pQCT in associations with fractures.</p> / Doctor of Philosophy (Medical Science)

Necessary for effective ambulation, head stability affords optimal conditions for the perception of visual information during dynamic tasks. This maintenance of head-in-space equilibrium is achieved, in part, by the attenuation of the high frequency impact shock resulting from ground contact. While a great deal of experimentation has been done on the matter during steady state locomotion, little is known about how head stability or dynamic visual acuity is maintained during asymmetric walking. In this study, fifteen participants were instructed to walk on a split-belt treadmill for ten minutes while verbally reporting the orientation of a randomized Landolt-C optotype that was projected at heel strike. Participants were exposed to the baseline, adaptation, and washout conditions, as characterized by belt speed ratios of 1:1, 1:3, and 1:1, respectively. Step length asymmetry, shock attenuation, high (impact) and low (active) frequency head signal power, and dynamic visual acuity scores were averaged across the first and last fifty strides of each condition. Over the course of the first fifty strides, step length asymmetry was significantly greater during adaptation than during baseline (p d =2.442). Additionally, high frequency head signal power was significantly greater during adaptation than during baseline (p d =1.227), indicating a reduction in head stability. Shock attenuation was significantly lower during adaptation than during baseline (p d =-0.679), and a medium effect size suggests that dynamic visual acuity was lower during adaptation than during baseline as well (p =0.052; d =0.653). When comparing the baseline and adaptation conditions across the last fifty strides, however, many of these decrements were greatly reduced. The results of this study indicate that the locomotor asymmetry imposed by the split-belt treadmill during the early adaptation condition is responsible for moderate decrements to shock attenuation, head stability, and dynamic visual acuity. Moreover, the relative reduction in magnitude of these decrements across the last fifty strides underscores the adaptive nature of the locomotor and visuomotor systems.

Thesis (MScPhysio)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Aims: To assess the effect of a vertical height adjustment of the chair and visual display unit (VDU) on work related upper quadrant musculoskeletal pain (WRUQMP) and sitting comfort in computer users. The upper quadrant refers to the occiput, cervical and upper thoracic spine including the clavicles and scapulae. Methods: An N=1 study was conducted using the ABC design whereby an ergonomic workstation adjustment, of VDU and chair height, was compared to the subject’s usual workstation settings. Pain and sitting comfort were measured using visual analogue scales (VAS). The subject was assessed over the four week phases as she performed her typical VDU work. The results were compiled and tabulated. Results: Both the mean and variance in pain intensity decreased after the workstation intervention. A deterioration was noted in sitting comfort. Conclusion: The vertical height adjustment of the chair and VDU may have contributed to a decrease in WRUQMP in this subject. This safe, economical workstation intervention may be a practical management option for the computer user suffering from WRUQMP. Further research into the measurement of comfort whilst sitting at a computer workstation, is recommended. / AFRIKAANSE OPSOMMING: Doelwitte: Om die effek te bepaal van n vertikale aanpassing van die stoel en beeldskerm van rekenaargebruikers op werksverwandte boonste kwadrant muskuloskeletale pyn en sitgemak. Die boonste kwadrant verwys na die oksiput, servikale en boonste torakale werwelkolom en sluit ook die klavikel en skapula in. Methode: Die N=1 studie is onderneem met gebruik van die ABC ontwerp in terme waarvan n ergonomiese aanpassing van stoel en beeldskerm vergelyk is met die normale gebruik van die deelnemer. Pyn en sitgemak is gemeet deur die gebruik van die Visueel analoogskaal. Die interwensies is ge-evalueer oor vierweekfases tydens normale rekenaar gebruik van die deelnemer. Die resultate is saamgestel en getabuleer. Uitkoms: Beide die gemiddelde en veranderlike pynintensiteit het verminder nadat die werkstasie aangepas is. Geen verbetering in sitgemak is opgemerk nie. Gevolgtrekking: Die vertikale hoogte-aanpassing van die stoel en beeldskerm het moontlik bygedra tot die verminderde pynvlakke in hierdie deelnemer. Hierdie veilige, ekonomiese verstelling is moontlik n praktiese beheeropsie vir rekenaargebruikers wat werksverwandte boonste kwadrant muskuloskeletale pyn verduur. Verder studie in die meet en waarneming van sitgemak tydens rekenaarwerk is nodig.

Thesis (MScPhysio)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Aims: To assess the effect of a chair and computer screen height adjustment on the neck and upper back musculoskeletal symptoms in an office worker. Methods: An N=1 study was conducted using the ABC design. Ethics approval was obtained for the study and the participant provided informed written consent. The participant was assessed over three four week phases as she performed her habitual computer work. The outcome measures assessed during the three phases were the pain intensity and perceived sitting comfort. The three phases were named the baseline, intervention and wash-out phases. During the baseline phase, the outcome measures were obtained at the participant‟s habitual work station. The intervention phase involved a vertical adjustment of the chair and computer screen height. The wash-out phase allowed the participant to adjust the chair and computer screen height to their choice. A follow-up interview was conducted with the participant three months after completion of the study. The mean values and the ranges of the pain intensity and perceived comfort were obtained and compared. The data collected was captured on a Microsoft Excel 2010 spread sheet, where after the data was tabulated and presented graphically. Results: The mean pain intensity of the participant increased slightly during the intervention phase in comparison to the baseline phase, but remained stable during the wash-out phase. The mean perceived sitting comfort deteriorated initially during the intervention phase, but improved later during the intervention phase and showed greater improvement during the wash out phase. The perceived sitting comfort showed more improvement than the pain intensity during the washout phase. Both the pain intensity and perceived sitting comfort showed improvement at the three months follow up assessment, post completion of the study. Conclusion: The vertical height adjustment of the chair and the VDT did not improve the participant‟s pain intensity and perceived sitting comfort when compared to the participant‟s habitual workstation parameters. The findings do not favour the horizontal viewing angle. The findings of this study however support the use of „slightly below horizontal‟ viewing angle as being conducive to reduce the pain intensity and improve the sitting comfort of an office worker. / AFRIKAANSE OPSOMMING: Doelstelling: Om die effek te bepaal van die hoogte aanpassing van die stoel en rekenaarskerm op die nek en bo-rug muskuloskeletale simptome van 'n kantoorwerker. Metodes: „n N=1 studie was uitgevoer deur gebruik te maak van die ABC ontwerp. Etiese goedkeuring was verkry vir die studie en die deelnemer het ingeligte skriftelike toestemming verleen. Die deelnemer was ge-evalueer oor drie vier week-lange fases terwyl sy haar gewone rekenaarwerk verrig het. Die uitkomsmetings ge-evalueer tydens die drie fases was pyn intensiteit en waargenome sitgemak. Die drie fases was genoem die basislyn, intervensie en uitwas fases. Gedurende die basislyn fase was die uitkomsmetings by die deelnemer se gewone werkstasie ingevorder. Die intervensie fase het 'n vertikale aanpassing van die stoel en rekenaarskerm behels. Die uitwas fase het die deelnemer toegelaat om haar stoel en rekenaarskerm se hoogte aan te pas volgens haar keuse. 'n Opvolg onderhoud was gevoer met die deelnemer drie maande na die voltooiing van die studie. Die resultate was vasgelê op 'n Microsoft Excel 2010 data bladsy, waarna die data getabuleer en grafies uitgebeeld is. Resultate: Die gemiddelde pyn intensiteit van die deelnermer het effens toegeneem tydens die intervensie fase in vergelyking met die basislyn fase, maar het stabiel gebly tydens die uitwas fase. Die gemiddelde waargenome sitgemak het aanvanklik verswak tydens die intervensie fase, maar het later verbeter tydens die intervensie fase en het aangehou verbeter tydens die uitwas fase. Die waargenome sitgemak het groter verbetering getoon as die pyn intensiteit tydens die uitwas fase. Beide pyn intensiteit en waargenome sitgemak het verbetering getoon by die drie maande opvolg evaluasie, na voltooiing van die studie. Gevolgtrekking. Die vertikale hoogte aanpassing van die stoel en rekenaarskerm het nie die deelnemer se pyn intensiteit en waargenome sitgemak in vergelyking met die deelnemer se gewone werkstasie parameters verbeter nie. Hierdie bevindinge is nie ten voordeel van die horisontale kykhoek nie. Nietemin, ondersteun die bevindinge van hierdie studie die gebruik van die "effens onder die horisontale" kykhoek as bevorderend om die pyn intensiteit te verminder en die sitgemak van 'n kantoorwerker te verbeter.

Thesis (PhD (Physiology (Human and animal))-- University of Stellenbosch, 2007. / Definition: Stem cells are unspecialised cells with the capacity for long-term self-renewal and the ability to differentiate into multiple cell-lineages. The potential for the application of stem cells in clinical settings has had a profound effect on the future of regenerative medicine. However, to be of greater therapeutic use, selection of the most appropriate cell type, as well as optimisation of stem cell incorporation into the damaged tissue is required. In adult skeletal muscle, satellite cells are the primary stem cell population which mediate postnatal muscle growth. Following injury or in diseased conditions, these cells are activated and recruited for new muscle formation. In contrast, the potential of resident adult stem cell incorporation into the myocardium has been challenged and the response of cardiac tissue, especially to ischaemic injury, is scar formation. Following muscle damage, various growth factors and cytokines are released in the afflicted area which influences the recruitment and incorporation of stem cells into the injured tissue. Transforming Growth Factor-β (TGF-β) is a member of the TGF-β-superfamily of cytokines and has at least three isoforms, TGF-β1, -β2, and -β3, which play essential roles in the regulation of cell growth and regeneration following activation and stimulation of receptor-signalling pathways. By improving the understanding of how TGF-β affects these processes, it is possible to gain insight into how the intercellular environment can be manipulated to improve stem cell-mediated repair following muscle injury. Therefore, the main aims of this thesis were to determine the effect of the three TGF-β isoforms on proliferation, differentiation, migration and fusion of muscle progenitor cells (skeletal and cardiac) and relate this to possible improved mechanisms for muscle repair. The effect of short- and long-term treatment with all three TGF-β isoforms were investigated on muscle progenitor cell proliferation and differentiation using the C2C12 skeletal muscle satellite and P19 multipotent embryonal carcinoma cell-lineages as in vitro model systems. Cells were treated with 5 ng/mℓ TGF-β isoforms unless where stated otherwise. In C2C12 cells, proliferating cell nuclear antigen (PCNA) expression and localisation were analysed, and together with total nuclear counts, used to assess the effect of TGF-β on myoblast proliferation (Chapter 5). The myogenic regulatory factors MyoD and myogenin, and structural protein myosin heavy chain (MHC) were used as protein markers to assess early and terminal differentiation, respectively. To establish possible mechanisms by which TGF-β isoforms regulate differentiation, further analysis included determination of MyoD localisation and the rate of MyoD degradation in C2C12 cells. To assess the effect of TGF-β isoforms on P19 cell differentiation, protein expression levels of connexin-43 and MHC were analysed, together with the determination of embryoid body numbers in differentiating P19 cells (Chapter 6). Furthermore, assays were developed to analyse the effect of TGF-β isoforms on both C2C12 and P19 cell migration (Chapter 7), as well as fusion of C2C12 cells (Chapter 8). Whereas all three isoforms of TGF-β significantly increased proliferation of C2C12 cells, differentiation results, however, indicated that especially following long-term incubation, TGF-β isoforms delayed both early and terminal differentiation of C2C12 cells into myotubes. Similarly, myocyte migration and fusion were also negatively regulated following TGF-β treatment. In the P19 cell-lineage, results demonstrated that isoform-specific treatment with TGF-β1 could potentially enhance differentiation. Further research is however required in this area, especially since migration was greatly reduced in these cells. Taken together, results demonstrated variable effects following TGF-β treatment depending on the cell type and the duration of TGF-β application. Circulating and/or treatment concentrations of this growth factor could therefore be manipulated depending on the area of injury to improve regenerative processes. Alternatively, when selecting appropriate stem or progenitor cells for therapeutic application, the effect of the immediate environment and subsequent interaction between the two should be taken into consideration for optimal beneficial results.