Thesis (Ph. D.)--Oregon State University, 2007. / Printout. Includes bibliographical references (leaves 127-134). Also available on the World Wide Web.

The Hippo pathway is a cell signaling pathway involved in organ size regulation and tumorigenesis in mammals. This pathway regulates the activity of Yes-associated protein (YAP), a transcriptional coactivator which binds to the transcription factor TEAD to promote expression of genes controlling growth and proliferation of tissues, as well as inhibition of apoptosis. The Hippo pathway has recently been implicated as a pathogenic mechanism in neurodegenerative disorders. Specifically, mammalian sterile 20 (Ste20)-like kinase 1 (MST1), a protein kinase in the Hippo pathway, has been found to promote neuronal death under conditions of oxidative stress. Moreover, homozygous deletion of MST1 in a mouse model of Amyotrophic Lateral Sclerosis (ALS) significantly delayed onset of neurodegenerative symptoms. We examined the expression levels of key Hippo pathway components in cortex, lumbar spinal cord, and gastrocnemius muscle samples of male and female G39A SOD1 mice using western blots. Our results revealed a significant increase in phosphorylated MST1 (pMST1) in lumbar spinal cord of presymptomatic transgenic animals, and found this increase to be sex and gene copy number dependent. These results suggest that the Hippo pathway is dysregulated in the SOD1 mouse model and that MST1 may play a critical role in pathogenesis and disease progression in ALS.

Background: Multiple Sclerosis (MS) is a chronic degenerative condition. It presents with highly varied physical and psychological symptoms and an unpredictable prognosis, causing difficulties for both professionals and patients. A high prevalence of comorbid psychological symptoms are reported in MS research, yet these may be underreported and underdiagnosed clinically in people with MS. Previous research has taken a dualistic approach, focussing on physical and psychological symptoms separately, resulting in a lack of knowledge on how MS is managed holistically. The aim of this research was to explore the experiences of both people with MS and professionals in the management of physical and psychological symptoms throughout the care pathway for people with MS.Methods: A qualitative approach was used. A systematic review was conducted to investigate existing qualitative literature exploring United Kingdom (UK) health care experiences of people with MS. A qualitative study using semi-structured interviews to explore the experiences of receiving or providing care for people with MS (n =24), general practitioners (n = 13), practice nurses (n = 13) and MS specialist nurses (n = 9). People with MS were purposively sampled from primary care and community settings in North West England. Primary care professionals were purposively sampled from across the North West. Specialist Nurses were purposively sampled from four NHS Foundation Trusts across the North of England. Transcripts formed the data and these were analysed using constant comparison analysis. Once themes had been derived from the data, this data was then interrogated using the concepts of candidacy and recursivity as a theoretical framework (Dixon Woods et al., 2006; Rogers, Hassell & Nicolaas, 1999).Results: Five studies meeting the review criteria were identified from the systematic review. The findings showed that previous UK research had focussed on the beginning (diagnosis) and the end (palliative care) of the care pathway for MS, resulting in a paucity of information regarding experiences of care between these points, for both people with MS and professionals. The subsequent qualitative study addressed this and identified central themes for people with MS: experiences of MS, managing self-care, access to services, interactions with health care professionals and continuity of care. For professionals the central themes identified were: the role of primary care for MS, patient-centred care for MS, access for MS care and management of people with MS. Conclusion: This study provides a unique contribution to the literature on the health care experiences of both people with MS and health care professionals responsible for their care. It has addressed the gaps in knowledge regarding the ongoing health care experiences of people with MS and the holistic management of psychological and physical symptoms. This study showed that candidacy is an appropriate theoretical framework to explain help-seeking and access to health care for MS: use of health services is based on both patient and professionals' interpretation of symptoms, perceptions of services and previous experiences. To improve identification of candidacy there is a need for greater education for patients and professionals on symptoms of MS and information on availability of local services.

Ten people with multiple sclerosis (MS) who felt they had cognitive difficulties because of their MS were investigated. This study had multiple aims. Firstly, to explore the subjective experience of cognitive deficits. Secondly, to assess whether or not there was objective evidence of cognitive difficulties on neuropsychological testing, and whether this was commensurate with a pattern of subcortical dementia. Thirdly, to determine whether their magnetic resonance imaging (MRI) scans replicated the patterns of atrophy frequently reported in MS patients with cognitive difficulties. And finally, to investigate the psychological well-being of the subjects. In depth neuropsychiatric interviews, psychiatric and psychological inventories, a comprehensive neuropsychological battery, and MRI investigations were done. The mean Full Scale Intelligence Quotient (FSIQ) fell within the superior range, at the 89th percentile. On tests of general intelligence, mental state examinations, there was little or no indication of cognitive deterioration. However, on sophisticated neuropsychological testing, there was convincing evidence of cognitive problems. Magnetic resonance imaging lesions were atypical of the reported research on cognitively compromised MS patients.

nÃo hà / Para analisar a histÃria natural da Esclerose MÃltipla (EM) no estado do CearÃ, Brasil, o autor estuda retrospectivamente 146 pacientes diagnosticados por critÃrios de Poser e / ou McDonald-2010. CasuÃstica e mÃtodos: dados biogrÃficos, clÃnicos e para-clÃnicos obtidos em visitas ambulatoriais e nos surtos. Considera como desfechos de incapacidade os marcos EDSS 4, 6 e 7. Com software estatÃstico R ( RKWard 0.5.3 ) faz anÃlise descritiva, teste exato de Fisher (p < 0,05) e curvas de anÃlise de tempo atà o evento ( Kaplan-Meier). Mais de 75 % dos pacientes sÃo acompanhados durante atà 15 anos. Resultados: EM predomina no sexo feminino (80,82 %); tem inÃcio antes dos 30 anos de idade em 47,9 % dos casos. Pacientes com educaÃÃo de nÃvel superior (33,5 %) representam mais do dobro do esperado na populaÃÃo em geral. Nas avaliaÃÃes inicial e evolutiva predominam os sintomas sensitivos, motores e esfincterianos. Pacientes mais jovens e com evoluÃÃo recorrente â remitente atingem EDSS 4 apÃs maior intervalo de tempo. A proporÃÃo de casos de EM benigna à de 4,7 %. A taxa anualizada de surtos à 0,6. Os dois primeiros surtos da maioria dos pacientes ocorreram nos primeiros 3 anos. O tempo entre 1 e 2 surtos tem relaÃÃo positiva com o tempo para atingir EDSS 4, 6 e 7. A duraÃÃo da doenÃa atà o Ãbito (8 casos, 5,4 %) foi em mÃdia de 14,4 anos. PrevalÃncia de EM no estado do Cearà à estimada em 2,9 / 100.000 habitantes. ConclusÃo: As caracterÃsticas clÃnicas e evolutivas da EM, no estado do Cearà (latitude sul entre 2o 46â e 7o 52â), sÃo semelhantes Ãs observadas mundialmente. / In order to study the natural history of Multiple Sclerosis (MS) in the state of CearÃ, Brazil, the author retrospectively analyzes 146 patients diagnosed according to Poser and/or McDonald-2010 criteria. Cases and methods: biographical, clinical and para-clinical data collected on outpatient visits and at relapses. EDSS scores 4, 6 and 7 used as disability outcomes. Statistical software R (RKWard 0.5.3) used to perform descriptive analysis, Fisher exact test (p< 0,05) and time-to-the-event curves (Kaplan-Meier). Results: over 75 % of the patients followed for as long as 15 years; disease onset before 30 years of age in 47,9 %, with female sex preponderance (80.82 %). Patients with university education (33,5 %) are in high proportion when compared to the general population. Sensory, motor and sphincter complaints are the most common, in both initial and final examinations. Younger patients with relapsing-remitting MS took a longer time to reach EDSS 4. The proportion of benign MS cases was 4, 7 %. Annualized relapse rate was 0,6 . For most patients, the first two relapses took place in the initial three years of illness.Time between 1st. and 2nd relapses bears a positive relationship with time to reach EDSS 4, 6 and 7. Disease duration until death (8 cases , 5,4 %) was an average of 14,4 years. The prevalence of MS in the state of CearÃ, Brazil, is estimated as 2,9 / 100.000 inhabitants. Conclusion: Clinical course of MS in the state of CearÃ, Brazil (south latitudes between 2o 46â and 7o 52â ) is similar to that observed worldwide.

Plusieurs rapports ont suggéré que les formes réactives de l'oxygène (FRO) et d'azote sont impliquées dans la pathogénèse de la ScS. Les fibroblastes ScS de la peau et des organes internes surproduisent des FRO qui déclenchent la prolifération des fibroblastes et la synthèse de collagène de type I, conduisant à l'initiation et à la progression de la ScS. Le laboratoire a mis au point un modèle de souris ScS, induite par injections itératives de HOCl. Comme dans la ScS humaine, les fibroblastes de la peau de souris ScS produisent de manière constitutive de grandes quantités de FRO. Nous avons utilisé cette propriété pour induire sélectivement l'apoptose de fibroblastes de souris ScS. Le catalyseur organotelluride-(PHTE) 2NQ et le composé naturel Dipropyltertrasulfide (DPTTS) sont capables d'augmenter specifiquement la production de FRO par les fibroblastes et d’induire un stress oxydatif létal dans les fibroblastes sclérodermiques. Ce phénomène n'a aucun impact sur les fibroblastes normaux qui présentent des taux de FRO basaux faible et un statut oxydant / antioxydant normal. De nombreuses études ont également prouvé l’importance des espèces azotées dans la l’induction de la ScS. Chez les patients atteints de SSc, le taux sérique de l'oxyde nitrique est considérablement accru. De plus, le NO peut se combiner avec d'autres radicaux libres comme l'anion superoxyde (O•-2) pour former le peroxynitrite (ONOO-) qui est hautement cytotoxique et contribue à l'inflammation, la fibrose et l'apoptose des cellules endothéliales. La production de NO par les cellules endothéliales ou les fibroblastes peut être stimulée par l'angiotensine II, principal peptide de la voie rénine-angiotensine (RAS). Comme chez les patients atteints de sclérodermie, les souris HOCl/ScS présentent des taux sériques d'angiotensine II élevés, ce qui est favorable à la prolifération des fibroblastes, à la fibrose, et à l'inflammation. Ces observations nous ont conduites à tester les effets de l'Irbésartan, un antagoniste des récepteurs de l’angiotensine II de type I (AT1 RA) dans le ScS modèle murin. Un nouveau modèle animal basé sur l'exposition chronique à des ROS et présentant de nombreuses similitudes avec la maladie humaine, m'a permis d'étudier de nouveaux traitements de la ScS. Ces nouvelles approches sont basées sur l'action cytotoxique de composés pro-oxydants - (PHTE) 2NQ et DPTTS - et sur les effets anti-nitrosatifs de molécules comme l'Irbésartan. Ces stratégies thérapeutiques originales ouvrent des perspectives intéressantes dans le traitement de la ScS, où l'arsenal thérapeutique est actuellement encore limité. / Several reports have suggested that reactive oxygen and nitrogen species are involved in SSc pathogenesis. SSc fibroblast from skin and internal organs overproduce ROS that trigger the proliferation of fibroblasts and the synthesis of type I collagen leading to the initiation and progresion of SSc. As in human SSc, skin fibroblasts from SSc mice constitutively produce large amounts of ROS. We have used this property to selectively induce apoptosis in the diseased fibroblast of SSc mice. Indeed, the organotelluride catalyst-(PHTE)2NQ and natural organosulfur compound – Dipropyltertrasulfide (DPTTS) are able of increasing ROS production by fibroblasts and inducing a lethal oxidative stress specificaly in SSc fibroblasts. This phenomenon has no impact on normal fibroblasts that present normal levels of ROS and a normal oxidant/antioxidant status. Many studies have also proved an importance of nitrogen species in the pathogenesis of SSc. In patients with SSc, the serum level of nitric oxide is significantly increased. Furthermore, NO can combine with other free radicals like superoxide anion (O•-2) to form the highly cytotoxic peroxynitrite (ONOO−) that contributes to inflammation, fibrosis and apoptosis of endothelial cells. Production of NO by endothelial cells or by fibroblasts can be stimulated by angiotensin II, the main peptide of the renin-angiotensin system (RAS). The level of angiotensin II is increased in SSc patients as well as in our HOCl mouse model and can promote proliferation of fibroblasts, fibrosis, and inflammation. These observations led us to test irbesartan, an angiotensin II type I receptor antagonist (AT1 RA) in the murine model of SSc. A new animal model based on chronic exposure to ROS and with many similarities to the human disease, allowed me to study new therapeutic approaches in SSc based on the cytotoxic action of pro-oxidative compounds - (PHTE)2NQ and DPTTS - and on the anti- nitrosative effect of irbesartan. These new therapeutic strategies open interesting perspectives in the treatment of SSc, where the therapeutic arsenal is currently still limited.

T2 relaxation imaging can be used to measure signal from water trapped between myelin bilayers; the ratio of myelin water signal to total water is termed the myelin water fraction (MWF). First, results from multi-component T2 relaxation and diffusion tensor imaging (DTI) were compared for 19 multiple sclerosis (MS) subjects at 1.5 T to better understand how each measure is affected by pathology. In particular, it was determined that the detection of a long-T2 signal within an MS lesion may be indicative of a different underlying pathology than is present in lesions without long-T2 signal. Next, the single-slice T2 relaxation measurement was implemented, refined, and validated at 3.0 T. Scan parameters were varied for phantoms and in-vivo brain, and changes in multi-exponential fit residuals and T2 distribution-derived parameters such as MWF were monitored to determine which scan parameters minimized artifacts. Measurements were compared between 1.5 T and 3.0 T for 10 healthy volunteers. MWF maps were qualitatively similar between field strengths. MWFs were significantly higher at 3.0 T than at 1.5 T, but with a strong correlation between measurements at the different field strengths. Due to long acquisition times, multi-component T2 relaxation has thus far been clinically infeasible. The next study aimed to validate a new 3D multi-component T2 relaxation imaging technique against the 2D single-slice technique most commonly used. Ten healthy volunteers were scanned with both the 2D single-slice and 3D techniques. MWF maps were qualitatively similar between scans. MWF values were highly correlated between the acquisition methods. Although MWF values were generally lower using the 3D technique, they were only significantly so for peripheral brain structures, likely due to increased sensitivity of slab-selective refocusing pulses used for the 3D approach. The 3D T2 relaxation sequence was then applied to the study of MS to take advantage of the increased brain coverage. Thirteen MS subjects and 11 controls underwent T2 relaxation and DTI examinations to produce histograms of MWF and several DTI-derived metrics. MS MWF histograms differed considerably from those of controls, and differences in MS MWF histograms did not mirror differences in DTI histograms relative to matched controls. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), occurring in isolated attacks or progressive forms. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS. With the relentless accumulation of evidence for a significant pathogenic role of EBV in MS, I believe it may be possible to prevent and cure MS by effectively controlling EBV infection. Currently, monoclonal antibodies (MAb) are used as therapeutics for a molecular targeted approach to slowing disease progression in MS. However, to my knowledge, there have been no antibodies targeted against EBV infection in any model of MS. The objective of this study is to determine whether or not a MAb against EBV could be a therapeutic target for EAE. In this study, I will propose an experiment that will examine the effects of intraperitoneal injection of MAb F-2-1 in 2-month-old new humanized BALB/c Rag2-/- ll2rg-/- (BRG) adult EBV/EAE male mice. My expected results suggest that mice with EBV/EAE + MAb F-2-1 may have an attenuated clinical disease course. Through immunohistochemical studies, I will also propose that MAb F-2-1 may decrease inflammation, demyelination and axonal loss in the CNS of mice with EAE. I believe that this novel treatments success would depend on MAb F-2-1’s ability to inhibit clonal expansion of EBV-infected autoreactive B cell in the CNS. Ultimately, my proposed experiment suggests that inhibition of virus-cell fusion of EBV to the B cell membrane might attenuate neuropathology in EAE. I hope that my prospective study highlights the importance of controlling EBV in patients with MS and provides grounds for optimism on how to successfully treat MS by controlling EBV infection. In conclusion, by proposing an alternative therapeutic approach, I hope that this hypothetical experiment will aid in future investigations that could further our knowledge on treatment and prevention of multiple sclerosis

Oligodendrocytes in the central nervous system (CNS) are responsible for wrapping axons with myelin in order to insulate them and allow for a faster conduction of the nervous impulse. The axonal signals that determine whether an axon is myelinated, and what regulates the number of wraps is still not fully understood. The importance of signals that initiate myelination is significant because they may point to novel therapies for Multiple Sclerosis, where remyelination prevents the axon degeneration that is thought to underlie chronic disease. Neuregulin 1 (Nrg1) has been identified as a key axonal signaling molecule that regulates myelin thickness and glial fate in the peripheral nervous system (PNS). In the PNS, neuregulin I type III is a necessary and sufficient signal that regulates axoglial interaction. The role of neuregulin in the CNS remains unclear and controversial. Integrins, the major family of extracellular matrix (ECM) receptors are involved in the regulation of many fundamental cellular functions. Interaction with a wide range of receptors including growth factor receptors is well described. Our lab showed that α6β1 integrin regulates oligodendrocyte survival signaling by amplification of neuregulin activity. We have found that mice expressing a dominant-negative β1 integrin (that reduces β1 integrin signaling independently of ligand binding) in myelinating oligodendrocytes require a larger axon diameter to initiate myelination. These results suggest that there are other signals in the axon that also contribute to initiation of myelination. We therefore hypothesized that β1 integrin and neuregulin act in concert and play a role in axoglial interactions that sense the axon size and initiate myelination. By crossing the dominant negative β1 integrin mice with heterozygous mice for neuregulin 1 and analyzing myelination, we have found that neuregulin does not enhance the phenotype previously described. This result together with previous reports that mice lacking NRG1, ErbB3 or ErbB4 (the neuregulin receptors expressed on oligodendrocytes) have normal CNS myelin sheaths demonstrates that neuregulin 1 is not required for CNS myelination. Interestingly, neuregulin 1 has been associated as a susceptibility gene in schizophrenia, a disease independently associated with myelin abnormalities (Davis et al., 2003; Hakak et al., 2001). Post-mortem brains of schizophrenic patients showed an increased level of neuregulin 1 type IV. We have analysed mice overexpressing neuregulin 1 type IV (Nrg1 type IV) and show that increased levels of neuregulin 1 type IV does not alter the brain morphology or myelin pattern and integrity. A possible explanation is that since neuregulin 1 type IV is human specific, the mice lack species-specific receptors or other neuregulins have compensatory equilibrium mechanism that are not destabilized by overexpression of neuregulin 1 type IV.

Background: People with Multiple Sclerosis experience difficulties with balance and mobility. Pilates exercises are often used to address these difficulties. Design: This was a multi-centre, double blind, block randomised, controlled trial. Eligible participants were recruited from seven UK centres. Participants were randomly allocated to either: Pilates based core stability training (Pilates), Standardised Exercise (SE) or Relaxation (placebo). All received face-to-face training sessions over a 12 week period; together with a home exercise programme. Blinded assessments were taken before training, at the end of the 12 week programme and at 16 weeks (follow-up). The primary outcome measure was the 10metre timed walk (10mtw). Secondary outcome measures were the MS walking Scale (MSWS-12), Functional Reach Test (FRT ) (forwards and lateral), a 10 point Visual Analogue Scale (VAS) to determine “Difficulty in carrying a drink when walking”, and the Activities-specific Balance Confidence (ABC) Scale. Effects on deep abdominal muscles were measured with ultrasound imaging (USI) in a subgroup of patients. Independent t-tests were performed to compare groups. Sensitivity analyses were undertaken to confirm the results. A mixed factorial ANOVA analysed the effect of intervention over time upon TrAb and IO upon USI. Results: Of the 100 participants recruited, 13 relapsed leaving 94 for intention to treat analysis. At 12 weeks there were significant differences between: (1) Pilates and Relaxation for walking velocity (p=0.04), forward (p=0.04) and lateral (p=0.04) FRT. (2) SE and Relaxation for all measures (p < 0.05) apart from the VAS. These remained at 16 weeks for 10mtw (p=0.04), LFR (p < 0.01) MSWS-12 (p=0.03) and ABC (p = 0.03). There were no significant interactions (p > 0.05) between groups or over time for TrAb and IO. Conclusions: Participants improved with both Pilates and SE in the short term; with broader and longer-lasting effects in the SE group. USI did not detect any effect of group over time.