No description available.

No description available.

No description available.

Although the management of Motor Neuron Disease (MND) remains devoid of a cure, persons affected by this devastating condition are nonetheless entitled to the best quality care that is available. A paucity of information exists documenting the perceptions of healthcare consumers regarding the management that is provided. In addition optimal healthcare comprises an intricate interaction of patient-centred care, patient-centred communication, and bioethical practice, and when these three dimensions are implemented according to acceptable standards, high-quality healthcare is perceived by the healthcare consumer. Given however the socio-political challenges that face healthcare systems, the management of MND needs to be considered against current trends in service delivery and the need for evidence-based medicine. An exploratory study was therefore conducted to investigate the perceptions of persons with MND and their family members regarding current medical and rehabilitative management. The sample comprised six persons with MND who presented with a communication impairment, as well as six family members. Participants’ perceptions were elicited through the use of a semi-structured interview schedule, and questions focused on healthcare professionals’ behaviours during healthcare encounters. In addition emphasis was placed on the potential of the communication impairment to influence management. A standardised dysarthria assessment was conducted to characterise the nature of the speech impairment in each person with MND. Qualitative responses obtained from the interviews were analysed in accordance with a matrix-based approach, while quantitative data from the dysarthria assessment were analysed using descriptive statistics. Despite individual variability, perceptions of both persons with MND and their family members revealed general dissatisfaction with regard to medical and rehabilitative management. The majority of persons with MND were not referred for intervention following diagnosis, and the recommended team approach for the management of MND was absent. In addition the bioethical practice of many healthcare professionals was deemed questionable, and the communication impairment was perceived to impose a significant burden on the healthcare encounter. Furthermore all participants perceived a lack of available support systems for persons with MND, and it was thus not uncommon for individuals to pursue complementary and alternative medicine. South Africa’s current healthcare climate also appeared to further limit healthcare for this clinical population. In an attempt to improve the management of MND, implications are provided in terms of health communication, intervention, bioethical practice, and support systems. A proposed new framework of ideal service delivery for healthcare consumers of MND management is also presented. Further implications are outlined with regard to the need for innovative models of service delivery in South Africa’s healthcare context, as well as the role of speech-language pathologists, other healthcare professionals, policy makers, and educators in the improvement of the medical and rehabilitative management of MND. Finally theoretical implications and implications for future research are also documented.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

No description available.

Yes / Motor neuron disease (MND) is a progressive neurodegenerative disease with no effective treatment. One of the principal pathological hallmarks is the deposition of TAR DNA binding protein 43 (TDP-43) in cytoplasmic inclusions. TDP-43 aggregation occurs in both familial and sporadic MND; however, the mechanism of endogenous TDP-43 aggregation in disease is incompletely understood. This study focused on the induction of cytoplasmic accumulation of endogenous TDP-43 in the motor neuronal cell line NSC-34. The endoplasmic reticulum (ER) stressor tunicamycin induced casein kinase 1 (CK1)-dependent cytoplasmic accumulation of endogenous TDP-43 in differentiated NSC-34 cells, as seen by immunocytochemistry. Immunoblotting showed that induction of ER stress had no effect on abundance of TDP-43 or phosphorylated TDP-43 in the NP-40/RIPA soluble fraction. However, there were significant increases in abundance of TDP-43 and phosphorylated TDP-43 in the NP-40/RIPA-insoluble, urea-soluble fraction, including high molecular weight species. In all cases, these increases were lowered by CK1 inhibition. Thus ER stress signalling, as induced by tunicamycin, causes CK1-dependent phosphorylation of TDP-43 and its consequent cytosolic accumulation. / Funded by a biomedical research grant from the Motor Neurone Disease Association (ref Rattray/Apr15/837-791). The Bioimaging Facility microscopes used in this study were purchased with grants from BBSRC, Wellcome Trust and the University of Manchester Strategic Fund.

Amyotrophic Lateral Sclerosis is the most common type of motor neuron disease, characterized by progressive degeneration of the upper and lower motor neurons. Sufferers present with symptoms of muscle weakness and this quickly develops on to paralysis and finally death due to respiratory failure within 5 years of disease onset. Although the majority of cases are sporadic, about 10% are familial and it is hoped that through the investigation of these few cases a greater understanding of the disease process, the reasons for its delayed onset and vulnerability of motor neurons will be achieved. Recently a novel mutation linked to ALS was discovered in an evolutionary conserved protein named Vesicle associated membrane protein (VAMP) associated protein B (VAPB). VAPB is an integral type II membrane protein localised at the Endoplasmic Reticulum and thought to have a role in protein transport. The orthologue in Drosophila has been shown to be involved in the homeostatic regulation of bouton formation at the Neuromuscular Junction through an association with the microtubule network. To elucidate the mechanism through which this protein causes ALS, Pennetta et al have created a Drosophila model of the disease by expressing the mutated orthologue in the fly. To complement this model, I have undertaken a number of biochemical experiments to look for potential interactors of the VAP proteins. The yeast two hybrid system utilises the yeast GAL4 transcriptional activator to indicate a protein interaction within a yeast cell and can be used to test a cDNA library for interactors. Through this technique a number of interesting binding partners have been found that may play crucial roles in the progression of the disease.

No description available.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition that affects corticospinal and spinal motor neurons and leads to death within 30 months of symptom onset in half of all cases. It remains incurable and treatment is supportive. The genetic and molecular understanding of ALS has gone through a rapid expansion in recent years, notably with the discoveries of TDP-43, a heterogeneous ribonucleoprotein as a major component of neuronal inclusions in ALS, as well as the discovery of the C9orf72 hexanucleotide expansion as the most common genetic cause of this disease. This first part of this thesis addresses the question of which of the various pathological hallmarks of the C9orf72 Hexanucleotide Repeat Expansion (HRE) in autopsy material correlates best with the clinical presentation. The main finding is that TDP-43 distribution, rather than C9orf72 RNA foci or dipeptide aggregation in the brain, corresponds best with the areas relevant to the clinical subtype of ALS-FTD. Subsequently the role of TDP-43 was investigated in induced pluripotent stem cell derived motor neurons, and no evidence of the hallmarks of TDP-43 dysfunction, were seen in this model of the disease. No mislocalisation is found on immunofluorescence, and biochemical analysis shows no differences in insoluble species between the patient and control cell lines. In the final section, RNA sequencing was used to study the transcriptome of a BAC transgenic mouse carrying a human M337V transgene expressed at low levels, to identify early presymptomatic differences in gene expression. Interestingly, no changes were found in genes known to be associated with ALS through mutations, and the constitutive nuclear functions of TDP-43 in the regulation of splicing was maintained, prior to the emergence of a clinical phenotype in the mouse. This favours a gain of function mechanism for TDP-43 mutations in ALS.