Slits and their Roundabout (Robo) receptors were identified based on their role in regulating axon guidance, but are known to play multiple roles in development, including regulating heart development and myoblast migration. There are 3 vertebrate Slits (Slit1 – 3) and 4 Robos (Robo1 – 4), and previous work has demonstrated expression of Slit and Robo family members in and around developing joints where their function is unclear. Mutations in human Robo3 have been linked to degenerative joint disorders, such as scoliosis and rheumatoid arthritis. Misregulation of other members of the Slit/Robo signalling pathway is also reported in cells from arthritic joints. This suggests that Slit/Robo signalling is required for normal joint development and/or maintenance, though our understanding of their roles in these processes is rudimentary. The central question of my thesis is to determine the role/s of Slit/Robo signalling in limb and joint development. In situ hybridisation confirmed strong expression of Slits and Robos throughout mouse limb and joint development, though no expression of Slit1 or Robo3 was detected. Analysis of Slit1/2, Slit3 and Robo1 mutant (loss-of-function) mice revealed normal limb development, however misexpression of dominant-negative Robo2 during chicken limb development caused shortening of cartilage elements. To begin to identify molecular changes that may compensate for the loss of Slit/Robo signalling I demonstrated members of the Sema3/PlexinA/Nrp axon guidance family are expressed in patterns comparable to those of Robo1, Robo2 and Slit3. I discovered that PlexinA1 is downregulated in Slit3 mutant mouse limbs. My results suggest the role for Silt/Robo signalling may be more complex than previously thought and do not define a clear role for signalling during limb development. My results suggest the role for Silt/Robo signalling may be more complex than previously thought and do not define a clear role for signalling during limb development. Previous work has linked Slit/Robo signalling to development of degenerative joint disorders, and I propose some hypotheses as to how Slit/Robo signalling could cause bone and joint defects.

abstract: Humans moving in the environment must frequently change walking speed and direction to negotiate obstacles and maintain balance. Maneuverability and stability requirements account for a significant part of daily life. While constant-average-velocity (CAV) human locomotion in walking and running has been studied extensively unsteady locomotion has received far less attention. Although some studies have described the biomechanics and neurophysiology of maneuvers, the underlying mechanisms that humans employ to control unsteady running are still not clear. My dissertation research investigated some of the biomechanical and behavioral strategies used for stable unsteady locomotion. First, I studied the behavioral level control of human sagittal plane running. I tested whether humans could control running using strategies consistent with simple and independent control laws that have been successfully used to control monopod robots. I found that humans use strategies that are consistent with the distributed feedback control strategies used by bouncing robots. Humans changed leg force rather than stance duration to control center of mass (COM) height. Humans adjusted foot placement relative to a "neutral point" to change running speed increment between consecutive flight phases, i.e. a "pogo-stick" rather than a "unicycle" strategy was adopted to change running speed. Body pitch angle was correlated by hip moments if a proportional-derivative relationship with time lags corresponding to pre-programmed reaction (87 ± 19 ms) was assumed. To better understand the mechanisms of performing successful maneuvers, I studied the functions of joints in the lower extremities to control COM speed and height. I found that during stance, the hip functioned as a power generator to change speed. The ankle switched between roles as a damper and torsional spring to contributing both to speed and elevation changes. The knee facilitated both speed and elevation control by absorbing mechanical energy, although its contribution was less than hip or ankle. Finally, I studied human turning in the horizontal plane. I used a morphological perturbation (increased body rotational inertia) to elicit compensational strategies used to control sidestep cutting turns. Humans use changes to initial body angular speed and body pre-rotation to prevent changes in braking forces. / Dissertation/Thesis / Ph.D. Kinesiology 2012

A teoria dos valores extremos desempenha um papel fundamental na modelagem de eventos associados a probabilidades muito pequenas ou eventos raros. Os modelos probabilísticos baseados nesta teoria visam predizer, a partir de um conjunto de valores máximos de um processo ambiental registrado num período relativamente curto (30 anos, por exemplo), os valores máximos esperados num período maior de tempo (50, 100 ou mais anos), que para o caso específico dos ventos, são de grande utilidade no planejamento de estruturas civis. Este trabalho consistiu no ajuste da distribuição generalizada de valores extremos (GVE), que inclui como casos particulares, as distribuições Gumbel, Fréchet e de Weibull (definidas na teoria dos valores extremos), aos dados de velocidade máxima mensal de ventos registrados durante um período de 43 anos (1956 a 1971 e 1974 a 2000) na estação agrometeorológica da Escola Superior de Agricultura "Luiz de Queiroz" em Piracicaba, Estado de São Paulo. Para a estimação dos parâmetros dessa distribuição, foi utilizado o método da máxima verossimilhança. O ajuste aos dados foi avaliado através dos gráficos quantil-quantil e do teste de Kolmogorov-Smirnov. A partir do ajuste inicial da distribuição GVE, a distribuição de Gumbel demonstrou ser a mais adequada para modelar os dados de velocidade máxima de vento em todos os meses do ano. Observou-se também, que os meses de setembro a dezembro apresentaram as maiores velocidades máximas de vento. Ventos com velocidades acima de 60 km h-1, considerados como muito fortes, também apresentaram-se neste período do ano. Por último, foram obtidos os níveis de retorno para os períodos de retorno 5, 10, 50 e 100 anos, e construídos seus respectivos intervalos de 95% de confiança, através dos métodos delta e da estatística de razão de verossimilhança. / The extreme value theory plays a fundamental role in modeling of events associated to very small probabilities or rare events. The aim of the probabilistic models based on this theory is to predict, from a set of maximum values of an environmental process recorded on a relatively short period (e.g. 30 years), the expected maximum values in a greater period (50, 100 or more years). For the specific case of wind, these values are very useful for the planing and development of civil structures. This work is concerned with the fitting of the generalized extreme value (GEV) distribution, which includes as specific cases, the Gumbel, Fréchet and Weibull distributions (defined in the extreme value theory), to the maximum wind speeds recorded monthly during a 43 years period (1956 to 1971 and 1974 to 2000) in the agrometeorological station of the College of Agriculture "Luiz de Queiroz", in Piracicaba, SP (Brazil). For the estimation of parameters of the GVE distribution the method of the maximum likelihood was used. The fitting to the data was evaluated through the quantil-quantil graph and the Kolmogorov-Smirnov test. From the initial fitting of the GEV distribution, we concluded that the Gumbel distribution was the most suitable to model the maximum wind speed for all months. It was observed that the September to December period showed the highest values of maximum wind speed. This period also showed winds with speeds above 60 km h-1, considered as very strong. Finally, we obtained the return levels for the return periods of 5, 10, 50 and 100 years, and we constructed their respective 95% confidence intervals, through the delta and the likelihood ratio statistics methods.

Orientador: Maurício Etchebehere / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T18:46:22Z (GMT). No. of bitstreams: 1 Hanasilo_CarlosEduardoHideo_M.pdf: 2000713 bytes, checksum: 42f9c82aa1621b3b005c51b618a4f40c (MD5) Previous issue date: 2012 / Resumo: Proposta: Em razão de sarcoma de partes moles serem entidades raras e lesões benignas de partes moles serem comuns, a ocorrência de ressecções não planejadas (RNP) de sarcomas de partes moles é extremamente comum. O Objetivo deste estudo é avaliar o impacto desses procedimentos não planejados na sobrevida global, na recidiva local e no surgimento de metástases à distância em pacientes portadores de sarcomas de partes moles de extremidades. Métodos: Em um estudo retrospectivo de maio de 2001 a março de 2011 foram analisados os prontuários de 52 pacientes com diagnóstico de sarcoma de partes moles, sendo 29 (55,8%) desses sem tratamento prévio e os restantes 23 (44,2%) já submetidos à cirurgia prévia de ressecção da neoplasia sem planejamento oncológico. Todos foram submetidos à cirurgia definitiva neste centro de referência em câncer. O tempo de seguimento clínico variou de seis a 122 meses, com média de 39,9 meses. Foram comparados dados entre os grupos com relação à idade, tamanho da lesão, profundidade da lesão, grau histológico, margem cirúrgica, sobrevida global, recidiva local e à distância; foi avaliada a presença de lesão residual nos pacientes submetidos a cirurgias não planejadas. Resultados: Doença residual no espécime ressecado foi encontrada em 91,3% dos reoperados após RNP; O grupo RNP diferiu do grupo de cirurgias planejadas (RP) apresentando maior numero de lesões superficiais (p=0,013), de baixo grau histológico (p=0,033) e com margem comprometida com neoplasia na ampliação de margens (p=0,034); Não se observou diferença entre os grupos com relação à recidiva local (p=0,17) e sobrevida global em cinco anos (p=0,17), mas os pacientes submetidos à RP apresentaram um risco maior para o surgimento de metástase à distância (p=0,03), após ajustes das demais variáveis. Conclusões: A re-ressecção de sarcoma de partes moles previamente submetidos à ressecção não planejada é preconizada e leva a resultados semelhantes daqueles operados com planejamento com relação à recidiva local e sobrevida global de cinco anos. Entretanto, a sobrevida livre de metástase à distância foi pior no grupo RP, provavelmente devido ao viés causado pelo reduzido número de pacientes deste estudo / Abstract: Purpose: The unplanned excision of soft tissue sarcomas is extremely common because, although soft tissue sarcomas are rare entities, benign soft tissue lesions are very frequent. This study evaluated the impact of these unplanned resections on overall survival, local recurrence and distant metastasis in patients with soft tissue sarcomas of the extremities. Methods: Fifty-two patients who were diagnosed with soft tissue sarcoma were analyzed in a retrospective study between May 2001 and March 2011. Twenty-nine (55.8%) of these patients did not undergo previous treatment, and the remaining 23 (44.2%) patients underwent prior resection of the tumor without oncological planning. All patients underwent definitive surgery in the cancer referral center. The follow-up ranged from six to 122 months, with a mean age of 39.89 months. Age, lesion size and depth, histological grade, surgical margin, overall survival, local and distant recurrence and adjuvant therapies were compared. The presence of residual lesions in unplanned excisions was evaluated. Results: Residual disease was observed in 91.3% of the re-resected specimens after definitive surgery on unplanned excision group (Unpex) which exhibited greater numbers of superficial lesions (p=0,013), low histological grade (p=0,033) and contaminated surgical margins on re-resection specimens (p=0,034) compared to the planned excision group (Pex). No differences were observed in local recurrence (p=0,17) and 5-year overall survival (p=0,17) between groups, but distant metastasis were statistically associated with Pex (p=0,03) after adjustments of variables. Conclusions: The re-resection of a soft tissue sarcoma that was previously submitted to unplanned excision is recommended and leads to similar results on local recurrence-free survival and 5-year overall survival rates than sarcomas operated with previous oncological planning, but metastasis-free survival rate was worse on Pex group probably due to bias caused by small number of patients in this study / Mestrado / Fisiopatologia Cirúrgica / Mestre em Ciências

Le sport est largement conseillé chez les enfants et les adolescents mais a pour inconvénient le développement de blessures musculosquelettiques au niveau des membres et du rachis. Les blessures de surutilisation des membres représentent une part importante des blessures musculo-squelettiques.Cette thèse avait pour but de déterminer s’il existait des différences entre les sports en ce qui concerne l’incidence, la localisation et le diagnostic de blessures de surutilisation des membres chez les enfants et si certains sports étaient des facteurs de risques pour le développement de ces blessures. De plus, elle avait pour but de comparer les résultats obtenus à ceux des adultes.Pour ce faire, deux revues systématiques ont été réalisées, la première pour les enfants et adolescents et la seconde pour les adultes. De plus, une étude prospective réalisée dans une population générale d’enfants a été analysée.Il existence peu d’évidences scientifiques sur l’incidence, les localisations et les diagnostics des blessures de surutilisation dans la littérature. Pour ces deux populations, et pour tous les sports étudiés les blessures de surutilisation affectent plus fréquemment les membres inférieurs. Chez les enfants/adolescents, les blessures affectent en particulier les genoux et la jambe, sans grande différence entre les sports. Alors que chez les adultes des différences apparaissent entre les sports et les zones les plus souvent touchées sont différentes des enfants. Concernant les diagnostics, il n’y a pas de différence entre les sports chez les enfants ; et il n’est pas possible de se prononcer chez les adultes. On note des différences entre les diagnostics retrouvés chez les enfants/adolescents et les adultes.L’étude prospective permet d’obtenir l’incidence des blessures pour neuf sports, et identifie parmi ceux-ci deux sports à risque : le football et le handball. / In youngsters, physical activity has many direct health benefits but can also cause musculoskeletal injuries. Overuse injuries of the extremities represent an important part of all the musculoskeletal injuries that can occur in childhood.The aim of this thesis is to determine if some sports are more likely to expose children and adolescents to a greater risk of developing overuse injuries of the extremities and to investigate if there is difference regarding the diagnosis and the localisation of these injuries between different types of sports. Another aim was to compare these findings with those relating to adults.To achieve this, two systematic reviews have been done, one for youngsters and one for adults, and data from a large prospective study of schoolchildren were analysed.Paucity of relevant information in the literature made it difficult to obtain clear answers to our questions. However, we noticed that, for both population and all sports, overuse injuries more often affected the lower limb. In youngsters, the sites most often affected are the knee, the lower limb and the foot, and this is almost the same for all sports that were studied. In adults the localisation varies for the different sports and is not the same between youngsters and adults. Also the diagnoses do not vary between sports in youngsters ; whereas it was not possible to study this in adults. The diagnoses were different between the two populations studied. The prospective study of the schoolchildren permitted to determine the incidence of overuse injuries reported in children participating in nine different sports and to relate these results to their exposure to these sports (dose-response). Two sports were identified as risk factors: football and handball.

This thesis presents the design, simulation, and evaluation of a passive, wearable, and human-scale actuator that includes pulleys and uses polymers for energy storage. Repetitive tasks such as packing boxes on an assembly line may require high strength movements of the shoulder, arm, and hand and may result in musculoskeletal disorders. With the objective to offset the weight of the arm and thereby lower the forces on the muscles in the shoulder and arm, this actuator is able to provide gravity compensation for the upper extremities of workers, if used in conjunction with an arm exoskeleton. The actuator is passive, meaning that it does not use motors or sensors, but instead creates a force on a cable that is a function of the displacement of the cable. This thesis details the design of the actuator and the selection of an appropriate polymer for use with the actuator. To determine the best polymer for this application, tests were conducted on nine polymers to ind their average Young's modulus and their hysteresis. A 90A abrasion-resistant polyurethane rubber belt was used in the final design due to its high modulus and low hysteresis. The final actuator design was tested in an Instron machine to validate its performance. During testing, the actuator provided 720N in extension and 530N in retraction, which are roughly 112% and 83% of the torque required to lift a human arm, respectively. / Master of Science

Thesis (M.Tech.: Chiropractic)-Dept. of Chiropractic, Durban University of Technology, 2007 xiii, 77, Annexures 1-19, 19 leaves / The increasing contribution of chiropractors in health care has generated greater interest in understanding the characteristics of chiropractic practice patterns and treatments (Mootz et al., 2005). However, despite the rapid growth and extensive use of chiropractic, good descriptive data on chiropractors and their patients remains limited (Coulter and Shekelle, 2005). Even fewer studies have been reported which deal specifically with patients attending chiropractic-teaching clinics (Nyiendo and Olsen, 1988). According to Nyiendo and Haldeman (1986), there remains a paucity of empirical data regarding the type of patients seeking care at a chiropractic-teaching clinic and the types of treatments provided at these clinics. According to Till and Till (2000), South Africa is largely a developing country with scattered developed communities. Its requirements and opportunities as they relate to chiropractic may differ significantly from those in other developed countries. It was also estimated that in South Africa only a fraction of the country’s population have any notion of what chiropractic is, thus the largest challenge lies with educating the public about chiropractic (http://www.chiroweb.com, 2005). The lack of attention given to the chiropractic management of extremity conditions has contributed to a perception that chiropractic is unable to manage extremity conditions proficiently (Hoskins et al., 2006). There is a noted lack of research on the management of extremity conditions within chiropractic (Hoskins et al., 2006); therefore the current study focused on all components of the extremity system. Objectives: The purpose of this research is to conduct a descriptive study of extremity cases on record at the Durban University of Technology Chiropractic Day Clinic from 1995 to 2005 and the objectives are as follows: •To determine the prevalence of extremity complaints over the past decade at the Durban University of Technology Chiropractic Day Clinic. •To identify the demographics of patients that visited the Durban University of Technology Chiropractic Day Clinic. •To identify the most common presenting region and complaints of the extremity system as well as the aetiology and associated signs and symptoms of these complaints at the Durban University of Technology Chiropractic Day Clinic. •To identify the nature of the interventions and methods most commonly used in the management of patients at the initial consult and where possible contra-indications to any treatment modality

A dissertation submitted in partial compliance with the requirements for a Master's Degree in Technology: Chiropractic, Durban University of Technology, 2007. / The increasing contribution of chiropractors in health care has generated greater interest in understanding the characteristics of chiropractic practice patterns and treatments (Mootz et al., 2005). However, despite the rapid growth and extensive use of chiropractic, good descriptive data on chiropractors and their patients remains limited (Coulter and Shekelle, 2005). Even fewer studies have been reported which deal specifically with patients attending chiropractic-teaching clinics (Nyiendo and Olsen, 1988). According to Nyiendo and Haldeman (1986), there remains a paucity of empirical data regarding the type of patients seeking care at a chiropractic-teaching clinic and the types of treatments provided at these clinics. According to Till and Till (2000), South Africa is largely a developing country with scattered developed communities. Its requirements and opportunities as they relate to chiropractic may differ significantly from those in other developed countries. It was also estimated that in South Africa only a fraction of the country’s population have any notion of what chiropractic is, thus the largest challenge lies with educating the public about chiropractic (http://www.chiroweb.com, 2005). The lack of attention given to the chiropractic management of extremity conditions has contributed to a perception that chiropractic is unable to manage extremity conditions proficiently (Hoskins et al., 2006). There is a noted lack of research on the management of extremity conditions within chiropractic (Hoskins et al., 2006); therefore the current study focused on all components of the extremity system. Objectives: The purpose of this research is to conduct a descriptive study of extremity cases on record at the Durban University of Technology Chiropractic Day Clinic from 1995 to 2005 and the objectives are as follows: •To determine the prevalence of extremity complaints over the past decade at the Durban University of Technology Chiropractic Day Clinic. •To identify the demographics of patients that visited the Durban University of Technology Chiropractic Day Clinic. •To identify the most common presenting region and complaints of the extremity system as well as the aetiology and associated signs and symptoms of these complaints at the Durban University of Technology Chiropractic Day Clinic. •To identify the nature of the interventions and methods most commonly used in the management of patients at the initial consult and where possible contra-indications to any treatment modality / M

Wong, Wan Man. / Thesis submitted in: December 2006. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 85-98). / Abstracts in English and Chinese. / Abstract --- p.i / Abstract in Chinese --- p.iii / Acknowledgements --- p.v / Lists of Figures and Tables --- p.vi / Table of Abbreviations --- p.xi / Table of Contents --- p.xv / Chapter Chapter I --- Introduction / Chapter 1.1 --- Brain and Reproductive Organ Expressed Gene --- p.1 / Chapter 1.2 --- Programmed cell death --- p.4 / Chapter 1.3 --- Limb development in mouse --- p.8 / Chapter 1.4 --- Role of BRE in apoptosis --- p.12 / Chapter 1.5 --- Role of programmed cell death in interdigital tissue regression --- p.14 / Chapter 1.6 --- Aim of study --- p.17 / Chapter Chpater II --- Materials and methods / Chapter 2.1 --- Mice --- p.18 / Chapter 2.2 --- In-situ hybridization / Chapter 2.2.1 --- Histology --- p.18 / Chapter 2.2.2 --- Preparation of riboprobe for in-situ hybridization --- p.19 / Chapter 2.2.3 --- In-situ hybridization --- p.20 / Chapter 2.3 --- Interdigital tissue culture --- p.21 / Chapter 2.4 --- Gene interference / Chapter 2.4.1 --- Construction of Bre-siRNA --- p.22 / Chapter 2.4.2 --- siRNA transfection of cultured interdigital cells --- p.23 / Chapter 2.5 --- Semi-quantitative RT-PCR / Chapter 2.5.1 --- Sample collection of interdigital cells and explants --- p.23 / Chapter 2.5.2 --- RNA isolation and extraction --- p.24 / Chapter 2.5.3 --- Reverse-transcription and cDNA synthesis --- p.25 / Chapter 2.5.4 --- Polymerase chain reaction --- p.26 / Chapter 2.6 --- Assay of cell viability by MTT --- p.28 / Chapter 2.7 --- Comparative proteomics --- p.30 / Chapter 2.7.1 --- Collection of interdigital cells --- p.30 / Chapter 2.7.2 --- Preparation of cell lysate --- p.31 / Chapter 2.7.3 --- Assay of protein concentration in cell lysate --- p.31 / Chapter 2.7.4 --- Two-dimensional gel electrophoresis --- p.33 / Chapter 2.7.5 --- Protein identification by mass fingerprinting --- p.36 / Chapter 2.8 --- Statistical Method --- p.38 / Chapter Chapter III --- Results / Chapter 3.1 --- Spatial and temporal expression of Bre in murine embryonic hindlimbs --- p.39 / Chapter 3.2 --- Expression of Bre isoforms in interdigital tissues --- p.45 / Chapter 3.3 --- Silencing of Bre expression by siRNA in interdigital cells --- p.49 / Chapter 3.4 --- Effect on viability of Bre-silenced interdigital cells by siRNA --- p.51 / Chapter 3.5 --- Comparative proteomic profile of Bre-silenced interdigital cultured cells --- p.53 / Chapter 3.6 --- Identification of proteins that were differentially expressed by MALDI- TOF --- p.71 / Chapter 3.7 --- The mRNA levels of proteins identified that were differentially expressed --- p.74 / Chapter Chapter IV --- Discussion --- p.77 / References --- p.85 / Appendices --- p.99 / Publication --- p.108

Indiana University-Purdue University Indianapolis (IUPUI) / Biological systems behave differently under different conditions. Advances in sequencing technology over the last decade have led to the generation of enormous amounts of condition-specific data. However, these measurements often fail to identify low abundance genes/proteins that can be biologically crucial. In this work, a novel text-mining system was first developed to extract condition-specific proteins from the biomedical literature. The literature-derived data was then combined with proteomics data to construct condition-specific protein interaction networks. Further, an innovative condition-specific differential analysis approach was designed to identify key differences, in the form of subnetworks, between any two given biological systems. The framework developed here was implemented to understand the differences between limb regeneration-competent Ambystoma mexicanum and –deficient Xenopus laevis. This study provides an exhaustive systems level analysis to compare regeneration competent and deficient subnetworks to show how different molecular entities inter-connect with each other and are rewired during the formation of an accumulation blastema in regenerating axolotl limbs. This study also demonstrates the importance of literature-derived knowledge, specific to limb regeneration, to augment the systems biology analysis. Our findings show that although the proteins might be common between the two given biological conditions, they can have a high dissimilarity based on their biological and topological properties in the subnetwork. The knowledge gained from the distinguishing features of limb regeneration in amphibians can be used in future to chemically induce regeneration in mammalian systems. The approach developed in this dissertation is scalable and adaptable to understand differential subnetworks between any two biological systems. This methodology will not only facilitate the understanding of biological processes and molecular functions which govern a given system but also provide novel intuitions about the pathophysiology of diseases/conditions.