In stroke rehabilitation, the assessments of the severity of stroke that are based on objective and robust measurements are the key to improve the efficacy of the rehabilitation efforts. It is essential, therefore, to complement the existing tools, where the assessments are partly relied on therapists’ subjective judgements, with a tool that can quantify important indicators of stroke recovery. One such indicator is the level of spasticity. The reliability of the current methods of measuring the severity of spasticity can be significantly improved by incorporating a feasible way to measure muscle forces and activations during stroke assessment. However, most of the present methods of estimating muscle forces require input parameters that are difficult to obtain in a clinical setting. A musculoskeletal arm model has been developed to bridge the gap between the domains of muscle forces estimation and stroke rehabilitation assessment. The project is divided into three stages. In the first stage, a biomechanical arm model that computes the joint torques with kinematic data from sensors is developed. The model has three features that eliminate the need for parameters that are difficult to obtain thus making it a feasible tool in clinical settings. The first is the use of a hybrid method that combines the data from sensors and a shoulder rhythm model to compute the orientation of the shoulder complex. The second is a method to compute the elbow joint angles without the need to compute the ambiguous carrying angle. The third is a method of estimating the inertial properties using published data, scaled by parameters that can be easily measured. The musculoskeletal properties of the human arm are added to the model in the second stage. The muscle model consists of 22 muscles that span from the thorax via the shoulder and the upper arm to the forearm. The muscle path is defined using Obstacle Set method where the anatomical structures are modelled using regular-shaped rigid bodies. Dynamics of the muscle is computed based on the Hill’s type muscle model that consists of an active contractile element, a passive parallel element and a series element. Due the difficulties in defining the moment arms, an optimization routine is designed to compute the optimal moment arms for each muscle for a subject. The muscle-sharing problem is solved using optimization which minimises the square of sum of muscle stresses. The muscle activation predicted by the model is compared to EMG signal for validation. In the final stage of this project, the model is used in the application of spasticity assessment. The tonic stretch reflex threshold (TSRT) which is an indicator for the severity of spasticity is computed using the model. Fifteen patient subjects participated in the experiments where they were assessed by two qualified therapists using Modified Ashworth Scale (MAS), and their motions and EMG signals were captured at the same time. Using the arm model, the TSRT of each patient was measured and ranked. The estimated muscle activation profiles have a high correlation (0.707) to the EMG signal profiles. The null hypothesis that the rankings of the severity using the model and the MAS assessment have no correlation has been tested, and was rejected convincingly (p ≈ 0.0003). These findings suggest that the model has the potential to complement the existing practices by providing an alternative evaluation method.

Theropoda was one of the most successful dinosaurian clades during the Mesozoic and has remained a dominant component of faunas throughout the Cenozoic, with nearly 10,000 extant representatives. The discovery of Archaeopteryx provides evidence that avian theropods evolved at least 155 million years ago and that more than half of the tenure of avian theropods on Earth was during the Mesozoic. Considering the major changes in niche occupation for theropods resulting from the evolution of arboreal and flight capabilities, we have analyzed forelimb and hindlimb proportions among nonmaniraptoriform theropods, nonavian maniraptoriforms, and basal avialans using reduced major axis regressions, principal components analysis, canonical variates analysis, and discriminant function analysis. Our study is the first analysis on theropod limb proportions to apply phylogenetic independent contrasts and size corrections to the data to ensure that all the data are statistically independent and amenable to statistical analyses. The three ordination analyses we performed did not show any significant groupings or deviations between nonavian theropods and Mesozoic avian forms when including all limb elements. However, the bivariate regression analyses did show some significant trends between individual elements that suggested evolutionary trends of increased forelimb length relative to hindlimb length from nonmaniraptoriform theropods to nonavian maniraptoriforms to basal avialans. The increase in disparity and divergence away from the nonavian theropod body plan is well documented within Cenozoic forms. The lack of significant groupings among Mesozoic forms when examining the entire theropod body plan concurrently suggests that nonavian theropods and avian theropods did not substantially diverge in limb proportions until the Cenozoic. J. Morphol. 276:152-166, 2015.

This study was conducted to test the hypothesis that, during renal development, the Na-K-2Cl cotransporter type 2 (NKCC2) activates the tonicity-responsive enhancer binding protein (TonEBP) transcription factor by creating medullary hypertonicity. TonEBP, in turn, drives the expression of aldose reductase (AR) and urea transporter-A (UT-A). Kidneys from 13- to19-day-old fetuses (F13-F19), 1- to 21-day-old pups (P1-P21), and adult mice were examined by immunohistochemistry. NKCC2 was first detected on F14 in differentiating macula densa and thick ascending limb (TAL). TonEBP was first detected on F15 in the medullary collecting duct (MCD) and surrounding endothelial cells. AR was detected in the MCD cells of the renal medulla from F15. UT-A first appeared in the descending thin limb (DTL) on F16 and in the MCD on F18. After birth, NKCC2-positive TALs disappeared gradually from the tip of the renal papilla, becoming completely undetectable in the inner medulla on P21. TonEBP shifted from the cytoplasm to the nucleus in both vascular endothelial cells and MCD cells on P1, and its abundance increased gradually afterward. Immunoreactivity for AR and UT-A in the renal medulla increased markedly after birth. Treatment of neonatal animals with furosemide dramatically reduced expression of TonEBP, AR, and UT-A1. Furosemide also prevented the disappearance of NKCC2-expressing TALs in the papilla. The sequential expression of NKCC2, TonEBP, and its targets AR and UT-A and the reduced expression TonEBP and its targets in response to furosemide treatment support the hypothesis that local hypertonicity produced by the activity of NKCC2 activates TonEBP during development.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20969号 / 医博第4315号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 濵﨑 洋子, 教授 三森 経世 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Over 30 tetrapod groups have evolved a snake-like, elongate, limbless body plan. Studies of the patterns of limb reduction have revealed a close relationship between the reduction of the limbs and body elongation; however, the loss of the skeletal elements that support the limb, the pectoral girdle, has been less thoroughly examined. Here, I use computed tomography to generate three dimensional models of the pectoral girdles of an Australian skink genus, Lerista. This group contains pentadactyl species, fully limbless species and many species with intermediate morphologies. I employed a 3D geometric morphometric analysis to compare the shapes of these structures and revealed that the reduction of the pectoral girdle is correlated with the degree of loss in the limbs. The girdle in species with well developed limbs is longer and more narrow than the short, broad girdle of species with highly reduced or absent limbs, but the degree of reduction is only loosely correlated with the degree of reduction in the limbs. Certain events appear to occur concurrently such as the losses of the coracoid foramen and the humerus, but other events such as the loss of the epicoracoid are not consistently associated with any other event. The extent to which limb reduction is associated with the degree of pectoral girdle reduction and the morphology of the girdles appears to be closely associated with subclade, with individuals from closely related clades showing dramatically different degrees of girdle reduction despite similarities in the degree of limb loss. Despite these differences, the patterns in Lerista are generally more similar to each other than to those of other lizard groups, and more similar to those of other skinks than to those of other groups of lizards. Though some aspects of limb loss are common to all lizard groups that have evolved a serpentine body plan, this study shows that, even in closely related groups, this transition does not proceed in exactly the same way. / Master of Science / Over 30 tetrapod groups have evolved a snake-like, elongate, limbless body plan. Many studies of the patterns of limb reduction (evolutionarily losing fingers and toes) have revealed a close relationship between the reduction of the limbs and body elongation; however, the loss of parts of the internal skeleton that support the limb (e.g. shoulder blade, collar bone) have been less thoroughly examined. Here computed tomography was used to generate three dimensional models of the pectoral girdle, the array of limb support bones, of the Australian lizard genus Lerista. This group contains species that have five fingers, species which are fully limbless (and thus have no fingers), and some that have intermediate numbers of fingers. I quantitatively compared the pectoral girdle shapes, which revealed that the reduction of the pectoral girdle occurs gradually and in a series of steps that are loosely associated with how many fingers are present. The pectoral girdle as a whole shows a more obvious reduction in length than in width, with this length reduction being loosely associated with the number of fingers present. Certain events appear to occur concurrently such as the loss of a small hole in one of the bones through which nerves that control the arm pass and loss of the upper arm bone. However other events, such as the loss of a cartilaginous structure called the epicoracoid is not consistently associated with any other event. The extent to which limb reduction is associated with the extent of pectoral girdle reduction is group dependent, with individuals from closely related groups showing dramatically different degrees of pectoral girdle reduction despite a similarity in the degree of digit loss. Despite these differences, the patterns in Lerista are more similar to each other than to those of other lizard groups, and more similar to those of other skinks than to those of other groups of lizards. Though some aspects of limb loss are common to all lizard groups that have evolved a snake-like body plan, this study reveals that even in closely related groups, this transition does not proceed in exactly the same way.

Anterior cruciate ligament (ACL) injuries are common orthopaedic injuries among athletes who participate in sports that involve cutting and changing directions. Many of these adolescent athletes intend to return to sports (RTS), and therefore undergo ACL reconstruction (ACLR). These athletes exhibit unfavorable landing biomechanics from muscle atrophy and asymmetrical neuromuscular control post-ACLR, putting them at a higher risk of re-injury. Thus, rehabilitation following ACLR is important to improve kinetic and kinematic outcomes and reduce re-injury risk. Biofeedback during rehabilitation is thought to be one way to potentially restore neuromuscular control deficits of athletes recovering from ACLR. Therefore, understanding the effectiveness of a biofeedback intervention on factors associated with re-injury among post-ACLR patients is essential in successful RTS. The purpose of this study is to analyze the effect of a 6-week biofeedback intervention on eccentric knee joint power (ECCKP), limb stiffness, and limb stiffness symmetry (using normalized symmetry index, NSI), in addition to secondary lower extremity outcomes that are associated with these metrics, during landing among patients following ACLR. This study used data collected from an ACL-Biofeedback Trial (ClinicalTrials.gov: AR069865) where participants were randomized into a biofeedback (BF) or control group (C). The BF group received visual and tactile feedback during a series of controlled squats while the C group participated in several online and in-person educational sessions. Participants completed 10 stop-jump tasks before (pre), after (post), and 6 weeks after (ret) the intervention. Kinetic, kinematic, and ground reaction forces (GRF) were collected from embedded force plates and 3D motion capture. Partaking in a biofeedback intervention did not improve ECCKP, limb stiffness, or limb stiffness NSI compared to controls. A group-by-time interaction was found for hip excursion (p=0.035), and a main effect of time was found for ECCKP, with this variable increasing by 18.5% from pre to ret (p=0.001). In addition, when considering surgical versus non-surgical limbs, this cohort exhibited interlimb asymmetries in stiffness, peak resultant GRF (rGRF), and time to reach peak rGRF (p<0.009). Further, a group-by-limb interaction (p=0.005) and a 7.1% reduction in peak rGRF were found from post to ret (p=0.02). Participants in this study also exhibited limb stiffness asymmetry greater than 10%, which supports existing literature that observed interlimb asymmetries in athletes following ACLR around the typical RTS time (9-12 months post-ACLR). The results from this analysis demonstrated that the current biofeedback intervention was inadequate in improving ECCKP, limb stiffness, and limb stiffness NSI, but additional biofeedback studies with larger sample sizes that investigate task dependencies are needed to better understand the effectiveness of biofeedback interventions. / Master of Science / Anterior cruciate ligament (ACL) injuries are common orthopaedic injuries among athletes who participate in sports that involve cutting and changing directions. Many of these adolescent athletes intend to return to their pre-injury level, therefore undergo a surgical procedure called ACL reconstruction (ACLR). However, following this procedure, athletes display unsafe and stiff landing patterns due to muscle weakness and asymmetrical neuromuscular, or mind-body, control post-ACLR, which increases their risk of re-injury once they return to sport (RTS) following recovery. Rehabilitation for patients following ACLR is of the utmost importance in improving unsafe movement patterns to reduce the risk of re-injury. Biofeedback training refers to receiving external signals that can be processed and transferred to the muscles in the body. This technique aims to restore the neuromuscular deficits of athletes following ACLR and could potentially be helpful during ACLR rehabilitation. Therefore, understanding the effectiveness of a biofeedback intervention on outcomes associated with an increased risk of re-injury in patients following ACLR is important to safely RTS. The purpose of this study is to determine the effect of a 6-week biofeedback intervention on the ability of the knee to absorb impact forces (quantified as eccentric knee joint power, ECCKP), limb stiffness, and limb stiffness symmetry (measured with normalized symmetry index, NSI), along with secondary outcomes related to these variables, among patients following ACLR. This study used data collected from an ACL-Biofeedback Trial (ClinicalTrials.gov: AR069865) where participants were randomized into a biofeedback (BF) or control group (C). The BF group received visual and resisted feedback during a series of controlled squats while the C group participated in several online and in-person educational sessions. Participants completed 10 stop-jump tasks before and after the intervention, and biomechanical data was obtained. The biofeedback intervention did not result in an improved ability for the knee to absorb impact from landing, and it was not able to decrease limb stiffness or limb stiffness asymmetry. It was able to improve hip excursion, which allows for a favorable, less upright posture when landing. ECCKP improved for both groups, indicating that the biofeedback did not add extra benefit to the participant's rehabilitation outside of the study. Asymmetries were observed between the surgical and non-surgical limbs in limb stiffness, peak GRF, and the time it takes to reach this peak GRF. This sample exhibited limb stiffness asymmetry greater than the recommended 10% threshold, raising concern for when these athletes RTS. The results from this analysis demonstrated that the current biofeedback intervention was inadequate in improving ECCKP, limb stiffness, and limb stiffness NSI, but biofeedback in ACLR rehabilitation can still be efficacious in improving hip biomechanics and overall neuromuscular control but may be task-dependent and call for a larger sample size.

Pain management options for the equine orthopedic patient are limited and can have harmful systemic effects. Methods of local drug delivery such as intravenous regional limb perfusion (IVRLP) are able to provide more focal therapy with a decreased risk of systemic side effects. The primary goal of the present study was to develop a novel, targeted pain management approach able to mitigate the complications encountered with systemic opioid administration. There were two main objectives with respect to elucidating the usefulness of a butorphanol IVRLP. The first of these was to evaluate the feasibility of IVRLP to deliver butorphanol to the treated limb, and the second was to develop a method for evaluating the analgesic efficacy of the procedure. The findings suggest butorphanol IVRLP is well tolerated, results in measurable levels of butorphanol in the treated limb and may be of analgesic benefit.

Due to mechanical loading, cartilage experiences distortional change, volumetric change, and fluid flow. Research has shown cells to be responsive to unconfined compression, a load that produces all three conditions. To isolate the factor(s) responsible for chondrogenesis, the first goal of this research was to design and implement a device for the application of shear deformation to cells. Secondly, using this device, Stage 23/24 chick limb bud cells were suspended in 2% alginate and subjected to 20% shear deformation at 1 Hz. for two hours daily for three days. Gene expression, DNA content, sGAG content, and cartilage nodule formation were determined after eight days in culture and compared to results obtained for non-loaded cells. Results indicated that shear deformation at the applied level did not have a significant effect on chondrogenesis in Stage 23/24 chick limb bud cells, suggesting that this cell type is not extremely sensitive to distortional change.

The global objective of this research was to identify the proteins secreted by stem cells in response to mechanical stress. Since it has been shown in previous studies that conditioned medium from compressed chick limb bud cells cultured in alginate can initiate chondrogenesis in non-compressed cells, it was hypothesized that the conditioned medium contains valuable growth/differentiation factors. Due to cartilage?s limited capacity for repair, factors that stimulate stem-cell mediated regeneration are highly sought. To discern these proteins, conditioned medium was collected from cyclically compressed stage 23/24 chick limb buds suspended in alginate. The proteins were extracted, separated by 2-D gel electrophoresis, and evaluated by mass spectroscopy. While a few regulators of chondrogenesis were observed, such as FGF receptor, actin, and IP3 receptor, many potential peptides were not found in the database. However, this study showed that ascertaining proteins produced by chondrocytes in response to mechanical stimulation should be pursued.

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