京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第18912号 / 人健博第26号 / 新制||人健||2(附属図書館) / 31863 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 市橋 則明, 教授 松田 秀一, 教授 木下 彩栄 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

A thesis submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 1994. / Dislocation of the hip is a common deformity in cerebral palsied (CP) patients who are not walking. Surgery of the hip is performed to prevent or correct the deformity. This surgery is based on the assumption that a dislocated hip contributes towards patient management problems, in that it compromises nursing care, interferes with sitting, snd may be painful. Reports on the outcome of surgery vary, and there is a controversy as to whether an established hip dislocation should be reduced. This study was undertaken to investigate the above assumptions, and to assess the long term outcome of hip surgery, both in terms of stability, and patient management, In the background to the study, abnormal development of the CP hip, causation theory, rationale of treatment (both conservative and surgical) and the evolution of hip surgery are described. This comparative study involves two groups of patients. Surgically treated patients are compared to a random sample of untreated patients matched for age and nonambulatory status. The treated patients (Group A) had undergone surgery at the Johannesburg Hospital between 1980 and 1987, and the minimum follow-up period

Cerebral palsy is a condition primarily defined by damage to the developing brain primarily resulting in a physical impairment, although the affected individual may present with concomitant impairments. The number of children presenting with cerebral palsy appears to be increasing, and while the medical effects of this disability have been well documented in the literature, a paucity of knowledge exists on the parental experience of caring for a child with cerebral palsy, particularly in rural South Africa. This dissertation will report on a study conducted in Tonga, a rural area of South Africa, which assessed caregivers’ experiences of caring for a child with cerebral palsy. Qualitative methods, including participant observation and narrative interviews were used and the SiSwati narratives of 27 participants were transcribed and analysed using theoretical coding. A number of recurrent themes emerged including the impact of gender on caregiving, the influence of traditional beliefs and practices and the experience of western medicine. However, the pervasive nature of poverty served to influence all aspects of caring for a child with cerebral palsy. These themes are discussed in relation to current healthcare policies, the influence of the HIV/AIDS pandemic, the concept of ‘ubuntu’ and socio-political aspects of healthcare. The findings highlight the value of using cultural narratives and participant observation as a means of exposing aspects related to the experience of disability that cannot be portrayed using quantitative methods. It emphasizes the nature of disempowerment amongst marginalized communities and draws attention to the need for both multisectoral and community involvement to bring about transformation.

No description available.

Children with cerebral palsy (CP) and severe motor and speech impairments face problems in communication. Their capacities may vary across all domains of functioning, including mobility, selfcare and communication, which means these should be assessed independently, using valid and reliable instruments. The assessment of an unobservable construct like language comprehension skills is complicated because the completion of commonly available tests requires speech and motor skills. Using such tests with children with severe motor and speech impairments does not yield a valid, reliable, or representative result. To fill the gap in language assessment instruments, the Computer-Based instrument for Low motor Language Testing (C-BiLLT) was developed in the Netherlands between 2009 and 2014, and introduced intro clinical care in 2015. This test provides an accessible alternative to traditional language tests, allowing participation of children who cannot speak, finger point, or manipulate small objects. The overarching goal of the work in this thesis was to bring the C-BiLLT to Canada and to improve our understanding of the use of the C-BiLLT from a clinician and family perspective. To achieve this goal, the research described in this dissertation addressed objectives related to: 1) the cultural and linguistic adaptation of the test; 2) the psychometric properties of the new version; 3) the implementation of the test; and 4) the concept of family-centred care in relation to the C-BiLLT assessment. Three empirical studies were completed. The adaptation processes (including a validation study) that resulted in the Canadian English version of the C-BiLLT (C-BiLLT CAN) are described in Chapters 2 and 3. To understand the unique implementation attributes of the C-BiLLT, Chapter 5 describes a survey among users about their C-BiLLT use, and Chapter 6 describes an interview study in which clinician behaviours are explored into more detail. Finally, Chapter 7 describes the protocol for a qualitative study using interpretive description to understand parents’ experiences of the C-BiLLT assessment for their child with cerebral palsy and severe motor and speech impairments. The process to develop the C-BiLLT CAN comprised many phases, to ensure the linguistic and conceptual equivalence between the original C-BiLLT and the newly developed version. The benefits of a thorough cross-cultural adaptation process were confirmed by the results of the validity and reliability assessment of the C-BiLLT CAN in typically developing Canadian children. While future research is needed to confirm the feasibility and validity of the test for Canadian children with CP, our study showed that the new version is a robust instrument to assess spoken language comprehension and is available for use in clinical practice. The C-BiLLT CAN is a scientific innovation. How scientific innovations can be best implemented into clinical practice is studied by implementation science. An implementation science lens was applied to the current use of the C-BiLLT in three countries where the test is currently available in clinical practice: The Netherlands, Belgium, and Norway. The survey study described in Chapter 5 demonstrated that clinicians use the test with children with CP (the C-BiLLT’s target population), but also with children who have other diagnoses, including Down’s syndrome and autism spectrum disorder. This study also reported on the barriers and facilitators related to use of the C-BiLLT. We categorized the reported barriers and facilitators into four groups: 1) factors inherent to the C-BiLLT (i.e., its hardware, software, and content); 2) factors related to the child; 3) factors related to the clinician; and 4) factors related to the environment. To gain a better understanding of clinicians’ implementation behaviour and what is needed to facilitate behaviour change, fifteen survey respondents were interviewed individually. The COM-B model (Capability, Opportunity, Motivation – Behaviour) of behaviour change was the theoretical foundation for this study. This model describes how capability, opportunity, and motivation play a role in people’s behaviour. This study taught us how these components of behaviour interacted for clinicians who use, or attempt to use the C-BiLLT in clinical practice. The study highlights the need for support for the clinicians who use the C-BiLLT with children with severe motor and speech impairments. Compared to clinicians who use it with children with other disabilities, this group of clinicians faces more and more complex barriers. The studies described in Chapters 5 and 6 underline the importance of appropriately addressing barriers to C-BiLLT use. The growing emphasis on family-centred care in pediatric rehabilitation services inspired the conceptualization of the concluding study of this thesis, of which the protocol is described in Chapter 7. The aim of the described study is to advance Speech-Language Pathology (SLP) disciplinary knowledge around family-centred assessment for children with CP and severe motor and speech impairments. The protocol describes how we would like to address this aim by collecting parent experiences of their child’s C-BiLLT assessment. This thesis approached the C-BiLLT from the angles of cross-cultural adaptation, psychometrics, implementation, and family-centred care. The development of the C-BiLLT CAN provides the foundation for standardized and accessible assessment of spoken language comprehension for children with CP in Canada. Theory-informed knowledge translation strategies are suggested that align with real-world practice. Finally, suggestions for incorporating parents’ perspectives into the assessment process help to increase the value of the assessment for children, their families, and clinicians alike. / Dissertation / Doctor of Philosophy (PhD) / Cerebral palsy (CP) is the most common cause of physical disability in children. CP is the result of an injury to the brain before, during, or after birth and before the age of one year. While effects of the brain injury are different for each child, for many children with CP the main effect is difficulty with voluntary movement, including fine movements of the lips and tongue to make speech. Some children with speech difficulties can communicate by pointing or making gestures, but others have such severe movement difficulties that they cannot make those gestures either. These children with severe difficulties might understand what others are saying, but tests of understanding usually require the child to respond with some type of movement, so those tests do not work for children with severe movement limitations. The C-BiLLT, which is short for Computer-Based instrument for Low Motor Language Testing was developed to assess language comprehension in Dutch-speaking children with CP. The child who is being tested does not need to speak or to use other fine movements to respond. Instead, the child can respond using gross motor movements on a touch screen, input switches operated with anybody part, partner-assisted scanning and/or their own access method(s). The C-BiLLT could be useful for many children with CP around the world, but at present it is only available in Dutch and Norwegian. The aim of this study was to make the C-BiLLT suitable for children in Canada. We translated the items from Dutch to English, and replaced some items of the Dutch version so that they were familiar to Canadian children. Our study told us that this new Canadian version of the test worked as well as the Dutch test. We also learned that clinicians liked the test, and used it for children with other disabilities as well. Some clinicians had difficulties using the test, and said they needed more practice. In the future we need to make sure there are opportunities for clinicians to get more training, so they have the skills to give the test to any child who would benefit. One question we still have is how families feel when their child is being tested with the C-BiLLT. Language testing should not be scary or stressful for families or children, and we need to make sure families feel comfortable with any test. Thus, as the last step of this thesis, we designed a future study to ask parents questions about their experiences. We will use results of that study to make the C-BiLLT even more child- and family-friendly.

Cerebral palsy (CP), depending on disease severity, can result in diminished quality of life not only from decreased function but from societal stigmatization. Coordinating various care provider appointments, expense of short-term treatments, difficulty navigating transportation, and relying on caregivers can complicate patient and family lives. The costs of CP are substantial on the healthcare system, with one managed Medicaid database averaged across 15 U.S states finding the average annual Medicaid costs for children with CP to be 15 times higher than children without CP and averaged to $22, 383 United States dollar (USD) compared to $1,358 USD respectively (Pulgar et al., 2019). Cost effective treatment and effective prevention strategies are increasingly warranted for the CP population. Due to the varying manifestations associated with CP, a standardized treatment for this condition is challenging. Current treatments may enhance quality of life and temporarily reduce pain or discomfort, but they do not cure CP. While perinatal prevention strategies potentially provide the greatest chance to prevent CP from occurring and should be the focus of health care policy, financial barriers remain especially with strained health care budgets. While cure remains elusive, focus on treatments and prevention strategies to limit disease impact is paramount. In the last decade some attention has turned to the use of stem cell treatments in children and adolescents with CP to provide more impactful outcomes with earlier intervention potentially limiting the devastating musculoskeletal effects seen with severe disease. While primarily results from clinical trials both nationally and internationally suggest stem cell treatment increases gross motor function in children and adolescents, questions remain whether these treatments provide clinically meaningful improvement compared to traditional therapies. The goal of this thesis is to discuss the current pharmaceuticals and non- pharmaceutical treatments with rehabilitative therapies that are historically used to reduce severity of secondary manifestations associated with CP in children. Human stem cell clinical trials for CP will be reviewed to assess efficacy and risks as this treatment is translated into clinical practice for children. In addition to stem cell treatment, public health practices of prevention during prenatal visits will be reviewed as it is an encouraging method to reduce preterm births which are a risk factor for CP development.

No description available.

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23830号 / 人健博第101号 / 新制||人健||7(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 青山 朋樹, 教授 市橋 則明, 教授 宮本 享 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Background and Purpose –The mammalian target of rapamycin (mTOR) pathway has been implicated in cellular responses to hypoxia and inflammation. Cerebral palsy (CP) is a neurodevelopmental disorder often linked to hypoxic and inflammatory injury to the brain, however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR inhibition would prevent neuronal death and diminish inflammation in a mouse model of CP. Methods – Post-natal day 6 mouse pups were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing injury to several brain areas. Mice received rapamycin (5mg/kg) following HIL, and then daily for 3 subsequent days. The phospho-activation of the mTOR effector mTOR effector proteins S6, S6K and 4EBP as well as upstream negative regulators, TSC1 and Redd1, were assessed as an in vivo measure of the mTOR signaling cascade. Expression of hypoxia inducible factor 1 (HIF-1 alpha) was assayed as an indicator of hypoxia-mediated cellular injury. Neuronal cell death was defined with Fluoro-Jade C (FJC) and cleaved-caspase 3 (CC3), a marker of apoptosis. Autophagy was measured using Beclin-1 and LC3II expression. Lastly, neuroninflammation following HIL was evaluated by examining Iba-1 labeled microglia number and morphology, as well as P-STAT3 expression. Results – Neuronal death, HIF-1alpha expression, and numerous Iba-1 labeled microglia were evident at 24 and 48 hours following HIL. Basal mTOR signaling was unchanged by HIL. Coincident with persistent mTOR signaling, a decreased in Redd1 expression but not TSC1 was observed in HIL. Increased P-STAT3 expression was observed at 24 and 48 hours post-HIL. Rapamycin treatment following HIL significantly reduced neuronal death, decreased HIF-1 alpha and P-STAT3 expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. Increase in neuronal death was observed with concomitant administration of rapamycin and chloroquine, an autophagy inhibitor. Administration of a S6K inhibitor, PF-4708671, following HIL also decreased FJC staining further supporting an mTOR-dependent effect of HIL. Conclusions – mTOR inhibition prevented neuronal cell death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in CP. / Biomedical Neuroscience

Aim: To determine the criterion validity of the Activ8a and VitaMoveb activity monitors (AM) in measuring body postures and movements (P&M) in adults with spastic cerebral palsy (CP) with different gross motor functional abilities in a simulated free-living environment. Methods: In this observational validation study participants were included between March and June 2016. Participants were divided into two groups: ambulatory and non-ambulatory adults (wheelchair users). For ambulatory adults, three Activ8 monitors (attached to the frontal thigh, lateral thigh, and in the pant pocket) and three synchronized VitaMove monitors (attached to the chest and each leg) were worn while participants were video recorded when performing a standardized activity protocol. For non-ambulatory adults, two synchronized Activ8 monitors (attached to the dominant wrist and wheelchair wheel) and three VitaMove monitors (attached to the chest and each wrist) were worn while participants were video recorded when performing a standardized wheelchair protocol. A native Dutch student provided standardized instructions while the author video recorded participants. Activities were performed in a movement laboratory and simulated free-living environment. Output data of the Activ8 and the VitaMove monitors were compared with video observation as a criterion measure. Absolute and relative time differences were calculated for each detected body P&M and for total measurement time for each participant. The following body P&M categories were detected: sitting, standing, walking, running, cycling, wheelchair driving, active upper body (stable wheelchair), and assisted driving. Agreement between the Activ8 and VitaMove during activity measurement was determined for each activity using Spearman Rho correlation coefficients, which were then compared with Meng’s test. Adapted Bland-Altman plots were completed to determine agreement at an individual level and Wilcoxon Signed-Rank tests were calculated to evaluate differences between detected P&M time across measures. Relative time differences of <10% between measures were indicative of acceptable validity. Results: Fifteen adults with spastic CP [10 men; mean(SD) age, 35.7(13) years; Gross Motor Function Classification System distribution: level I (n=6), level II (n=5), level III (n=3), level IV (n=1)] were included. For ambulatory adults (n=14), criterion validity of the Activ8 at the lateral thigh location during basic and complex daily life activities was moderate to good (average relative time differences: 0.25% for sitting, 4.69% for standing, 2.46% for walking, 3.19% for cycling, and 1.96% for light-to-moderate upright activity), except for running (34.6% average difference) The criterion validity of the VitaMove was acceptable, with the exception of standing and running (average relative time differences: 1.69% for sitting, 12.3% for standing, 4.84% for walking, 9.70% for cycling, 23.8% for running, and 0.91% for light-to-moderate upright activity). Spearman Rho correlation coefficients were significantly greater between video/lateral thigh Activ8 than video/frontal thigh Activ8 and video/pant pocket Activ8 for P&M categories sitting, basic standing, basic walking, and light-to-moderate upright activity (p<0.01 for all). Moreover, Spearman Rho correlation coefficients were significantly greater between video/Activ8 than video/VitaMove for basic walking and light-to-moderate upright activity P&M categories (p<0.01). In non-ambulatory, wheelchair users (n=3), the Wheelchair Activ8 demonstrated greater validity than the VitaMove monitor, when compared to video observation, for the detection of sedentary upper body and active upper body behaviours. Conclusion: The Activ8, positioned on the lateral thigh, demonstrates adequate validity as a tool for monitoring of body P&M during free-living activities in ambulatory adults with spastic CP. The Activ8 demonstrated superior validity as a direct measure of body P&M compared to the VitaMove AM. The sample size of non-ambulatory adults was small (n=3) and allowed for descriptive and exploratory analysis only; therefore, validity of the Wheelchair Activ8 for has to be further examined in a larger number of participants. Clinical relevance: The Activ8 and Wheelchair Activ8 shows promise as a clinical measurement tool of physical behaviour for adults with CP across GMFCS levels I-IV. The Activ8 could be used in the future development of health promotion initiatives, due to the features of goal setting and user feedback, while providing researchers greater insight in activity data than consumer-grade AMs. Suppliers: a. Activ8, trademark of Remedy Distribution Ltd. (original equipment manufacturer is 2M Engineering Ltd.), John F Kennedylaan 3, 5555XC, Valkenswaard, The Netherlands b. VitaMove, 2M Engineering Ltd., John F Kennedylaan 3, 5555XC, Valkenswaard, The Netherlands / Thesis / Master of Science (MSc)