This study investigated memory in children with temporal lobe epilepsy and the ability to discern hippocampal dysfunction with conventional memory tests that are typically used to detect more global memory impairment. All data was obtained retrospectively from the epilepsy surgery program at a local children’s hospital. The research population consisted of 54 children with intractable epilepsy of temporal onset, balanced across pathology types (with and without hippocampal disease) and other demographics. Each was given a clinical battery prior to surgical intervention, which included the WRAML/WRAML2 Verbal Learning subtest from which the dependent variables for this study were extracted. The research hypothesis had predicted that memory retention between verbal learning and recall would be worse for participants with pathology that included hippocampal sclerosis than for those with non-hippocampal temporal lobe pathology. A two-way mixed-design ANOVA was used to test the hypothesis, which allowed incorporation of variables of interest related to memory factors, pathology type, and hemispheric laterality, as well as their various interactions. There was a significant main effect for change in the number of words retained from the final learning trial to the delayed recall. Although the interaction between memory retention and pathology type was not statistically significant, the average of the memory scores as it related to pathology by side did show significance. Thus, results did not support the hypothetical relationship between retention and hippocampal function. However, additional exploratory analyses revealed that the final learning trial by itself was associated with hippocampal pathology, which applied only to those participants with left-hemisphere lesions. Logistic regression with the final learning trial correctly classified 74 percent of participants into the appropriate pathology category, with 81 percent sensitivity to hippocampal dysfunction. Mean participant memory scores were nearly one standard deviation below the normative mean for both delayed recall and total learning scaled scores, regardless of pathology type or lesion hemisphericity. Thus, while the conventionally used indices of the WRAML Verbal Learning test are useful for determining overall memory status, they are not specific to pathological substrate. The within-subject main effect showed an expected loss of information across the time of the delay, but overall the recall score showed no association with hippocampal functioning. This study revealed the possibility of measuring hippocampal function at statistically significant group levels using learning scores from a widely used measure of verbal memory, even in participants with intact contralateral mesial temporal structures. It also indicated that hippocampal structures do not play a role during recall measures given after a standard time delay. Data further demonstrated a role of the hippocampus for encoding and transferring information beyond short term/working memory into long term. During the learning process, the hippocampus appears to work in concert with short-term memory systems, but does not take over the encoding process until enough repetitions have occurred to saturate the working memory buffer. This research represents a small, yet important step forward in our understanding of the hippocampus, with potentially important implications for the future study of memory constructs and mensuration.

<div><b>Rationale:</b> Focal cortical dysplasia (FCD) is a neurodevelopmental disorder that is associated with abnormal cortical development and is one of the most common drug-resistant epilepsies. The mechanistic target of rapamycin (mTOR) pathway is a highly complex pathway </div><div>associated with cell proliferation, synaptic plasticity, neuroinflammation, and cortical development. Hyperactivation of this pathway has also been implicated in hyperexcitability, seizures, and accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) through hyperphosphorylation of tau. Interestingly, Aβ and hyperphosphorylated tau have been reported in both rodent models and human patients of temporal lobe epilepsy (TLE) and FCD however, the mechanisms through which this occurs are still yet to be defined. Therefore, to identify the possible link between Aβ and tau pathology in FCD, we determined the spatial distribution and protein levels of Aβ and phosphorylated tau (p-tau) along with mTOR signaling </div><div>molecules. We hypothesized that there would be presence of Aβ and tau pathology as well as an increase in Aβ and p-tau protein levels that would be correlated with hyperactivation of the mTOR and GSK3 signaling pathways in tissue biopsies from human FCD patients compared to brain tissues from non-epileptic (NE) individuals.</div><div><br></div><div><b>Methods:</b> Cortical brain samples surgically resected from patients with FCD were used and compared to NE samples surgically resected from glioblastoma patients with no history of seizures or epilepsy. Immunostaining was used to determine the distribution of phosphorylation of S6 (p-S6), a marker for mTOR activation, and NeuN, a marker for neurons, along with Aβ and p-tau. Additionally, western blotting (WB) was used to determine the levels of mTOR signaling through p-S6 and GSK3 (p-GSK) along with Aβ and p-tau.</div><div><br></div><div><b>Results:</b> We found cortical dyslamination, mTOR activation, p-tau, and Aβ accumulation in cortices of patients with FCD with drug-resistant epilepsy. However, we did not find a </div><div>significant difference in the protein levels of p-S6 (p = 0.422), p-GSK3 (p = 0.947), p-tau (p = 0.649), and Aβ (p = 0.852) in cortical tissue homogenates derived from FCD patients when compared to those of NE samples. Additionally, we did not find sex differences in the protein </div><div>levels of p-S6 (p = 0.401), p-GSK3 (p = 0.331), p-tau (p = 0.935), and Aβ (p = 0.526). There was no significant correlation between age and p-S6 (p = 0.920), age and p-GSK3 (p = 0.089), age and p-tau (p = 0.956), and age and Aβ (p = 0.889). Moreover, there was no significant correlation between mTOR activation (p-S6), Aβ (p = 0.586) and p-tau (p = 0.059) nor GSK3 activation (p-GSK3), Aβ (p = 0.326), and p-tau (p = 0.715). Lastly, there was no significant correlation within the mTOR and GSK3 pathway activation within the same patients (p = 0.602).</div><div><br></div><div><b>Conclusion:</b> These data suggest that mTOR hyperactivation occurs alongside the presence of Aβ and tau pathology. However, several unknown factors such as medical and medication history may be altering the expression or suppression of these proteins. Additionally, there may be alternative pathways that crosstalk with mTOR signaling therefore influencing Aβ and tau pathology in FCD patients with drug-resistant epilepsy. Further investigation will need to be conducted to understand the detailed mechanisms through which Aβ and tau pathology occur in </div><div>FCD.</div>

Preterm birth (<37 weeks) is the world’s principal cause of death of children <5 years of age. Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. BPD is characterized by an arrest in alveolar and vascular development within the lung. It is a multifactorial disease, caused by a combination of supplemental oxygen, mechanical ventilation, and inflammation. BPD is also an independent risk factor for abnormal neurodevelopment. The link between BPD and abnormal neurodevelopment is poorly understood and there are currently no effective cures for these complications. We hypothesized that a crucial cell population for brain development, i.e., the neural progenitor cell (NPC) is functionally impaired in BPD and that this impairment is associated with abnormal neurodevelopment. Based on our previous findings, we also predicted that human umbilical cord-mesenchymal stromal cell (UC-MSC) extracellular vesicles (EVs), could mitigate both the lung and brain injuries in experimental BPD. We utilized several animal models of BPD, across multiple species, to determine the effects of hyperoxia, mechanical ventilation, and inflammation on the developing lungs and brain. We also utilized UC- MSC therapy to mitigate these injuries. We discovered that hyperoxia exposure damages the developing lungs as well as the brain, leading to cerebrovascular and NPC impairments, as well as reduced neurogenesis. These impairments were associated with neurobehavioural deficits in adulthood. Furthermore, we found that inflammation in combination with mechanical ventilation and hyperoxia also impairs NPC function. Importantly, we demonstrated that UC-MSC EVs can reduce inflammation, improve vascular growth, restore lung growth, and mitigate impairments in NPC self-renewal. This work highlights novel mechanisms of BPD-associated abnormal neurodevelopment and offers potential regenerative medicine therapies to alleviate these outcomes for this vulnerable population.

Developmental dysplasia of the hip (DDH) is a common newborn condition where the femoral head is not located in its natural position in the acetabulum (hip socket). Several treatment methods are being implemented worldwide to treat this abnormal condition. One of the most effective methods of treatment is the use of Pavlik Harness, which directs the femoral head toward the natural position inside the acetabulum. This dissertation presents a developed method for identifying the least energy path that the femoral head would follow during reduction. This is achieved by utilizing a validated computational biomechanical model that allows the determination of the potential energy, and then implementing the principle of stationary potential energy. The potential energy stems from strain energy stored in the muscles and gravitational potential energy of four rigid-body components of lower limb bones. Five muscles are identified and modeled because of their effect on DDH reduction. Clinical observations indicate that reduction with the Pavlik Harness occurs passively in deep sleep under the combined effects of gravity and the constraints of the Pavlik Harness. A non-linear constitutive equation, describing the passive muscle response, is used in the potential energy computation. Different DDH abnormalities with various flexion, abduction, and hip rotation angles are considered, and least energy paths are identified. Several constraints, such as geometry and harness configuration, are considered to closely simulate real cases of DDH. Results confirm the clinical observations of two different pathways for closed reduction. The path of least energy closely approximated the modified Hoffman-Daimler method. Release of the pectineus muscle favored a more direct pathway over the posterior rim of the acetabulum. The direct path over the posterior rim of the acetabulum requires more energy. This model supports the observation that Grade IV dislocations may require manual reduction by the direct path. However, the indirect path requires less energy and may be an alternative to direct manual reduction of Grade IV infantile hip dislocations. Of great importance, as a result of this work, identifying the minimum energy path that the femoral head would travel would provide a non-surgical tool that effectively aids the surgeon in treating DDH.

The primary goal of human locomotion is to translate the body from point A to point B, but humans must have the variability and stability to adapt and recover from constraints they may encounter. The overarching aim of this dissertation was to investigate how constraints arising from external factors (i.e., military load carriage and speed) and internal factors (i.e., hip pain) affect kinematic variability and local dynamic stability of gait. In study 1, I focus on using traditional biomechanical measures to investigate if females and males use different gait mechanics when carrying military-relevant loads, as females and males are known to use different mechanics when walking with no load. In this study, I found that females and males do use different gait mechanics when walking with military-relevant loads. Females make kinematic adaptations at the ankle and knee while males make kinematic adaptations at the hip. The differences in adaptations between females and males may be related to females’ greater risk of injury when carrying load. In study 2, I used the same cohort to investigate how military-relevant loads affect the kinematic variability and local dynamic stability of gait. I found that kinematic variability and local dynamic stability were similarly affected by load. Participants had greater kinematic variability and decreased local dynamic stability when carrying loads, which may indicate an increased risk of falling while carrying load. I also found that local dynamic stability increased with increased walking speed at all loads in the mediolateral and anteroposterior directions. However, decreased stability was detected in the vertical direction, which may require increased energy expenditure. The results of this study indicate that walking faster with increased loads may be more stable, but less energy efficient. In study 3, I investigated the how kinematic variability and local dynamic stability were affected in individuals with hip pain and a history of developmental dysplasia. I found that kinematic variability and local dynamic stability were not similarly affected in these individuals. I found that kinematic variability was greater in individuals with hip pain compared to healthy controls, but there was no difference in local dynamic stability between groups. The overall finding of this dissertation is that the relationship between kinematic variability and local dynamic stability may be dependent on the factor investigated. / 2020-07-06T00:00:00Z

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13580号 / 論医博第2302号 / 新制||医||1069(附属図書館) / (主査)教授 平井 豊博, 教授 江木 盛時, 教授 齋藤 潤 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

No description available.

No description available.

No description available.