Neurodegenerative diseases are becoming increasingly prevalent due to the ageing population, and are among the major contributors to disability and disease worldwide. The identification of the gene defects responsible for many of these conditions has played a major role in our understanding of the pathogenic processes involved, and provided opportunity to develop targeted treatment strategies. Cholinergic neurotransmission supports a wide range of physiological and behavioural processes and its dysfunction of cholinergic signalling has been associated with a number of disorders, including myasthenias, cardiovascular disease(1), attention-deficit hyperactivity disorder (ADHD) (2), Alzheimer’s disease (ADi), schizophrenia, addiction(3), and depression(4). SLC5A7 encodes the Na+/Cl- dependent, high-affinity choline transporter (CHT) which represents the rate limiting step in acetylcholine (Ach) synthesis and is critical for normal cholinergic signalling. The work in this thesis details two new inherited disorders, caused by distinct pathogenic disease mechanisms, associated with novel SLC5A7 mutations. Chapter three documents the discovery of two autosomal-dominantly acting SLC5A7/CHT mutations associated with adult onset motor neurone disorders. Initially we identified a frameshift mutation that results in premature truncation of the transporter protein in a large Welsh kindred affected with distal hereditary motor neuropathy type VII (dHMN-VII), in which neurodegeneration and muscle paresis is largely restricted to the distal limb muscles and vocal cords. The mutation responsible results in the dominant-negative interference of the mutant molecule with function of the wild type choline transporter, resulting in significantly reduced (although not completely abolished) transporter activity. This finding is further evidenced by the discovery of a second dHMN family associated with a distinct frameshift SLC5A7 mutation indicative of a similar dominant-negative disease mechanism. Together these findings corroborate a dominant-negative disease mechanism arising from C-terminal truncating SLC5A7 mutations associated with dHMN, and provide further insight into the role of aberrant choline transporter function in neurological disease. Chapter four describes N-terminal missense mutations located in the transmembrane spanning region of SLC5A7/CHT, associated with a severe infantile neuromuscular disorder characterised by predominantly central hypotonia and developmental delay. The phenotypic effects of these mutations are likely to result from the near abolition of CHT-mediated choline transport in homozygous individuals, and are in keeping with those observed in CHT knock-out mouse models(5). The development of a mouse model of the human motor neurone disease arising from SLC5A7 frameshift mutations should allow for further investigation of the mechanism by which truncated CHT leads to the dHMN phenotype. Chapter 5 details treatment hypotheses for dHMN, as well as the generation of a patient-specific knock-in mouse model carrying an Slc5a7 mutation orthologous to that identified in dHMN-VII families in chapter 3, and results from preliminary neurological phenotyping of the mouse model. This model will be crucially important for the exploration of treatment options in dHMN-VII motor neurone disease as a prelude to clinical trials in humans.

Diabetic foot disease (DFD) is a serious complication of diabetes and, along with critical limb ischemia, significantly exacerbates the prognosis of patients. Peripheral arterial disease in patients with diabetes has an atypical clinical course, its diagnosis is challenging and is one of the most common causes of morbidity and mortality of patients with DFD. The aim of this dissertation focused on the diagnosis and treatment of DFD was to identify a suitable method for evaluating the effect of autologous cell therapy (ACT), to assess options for early diagnosis of Charcot osteoarthropathy (COA) and, possibly, to establish the association between the incidence of cardiovascular disease and DFD. In our studies concerning therapeutic vasculogenesis, we observed a significant increase in the antiangiogenic factor endostatin after ACT in contrast to its unchanged levels after standard percutaneous transluminal angioplasty; the transient increase in endostatin seems to be a marker of therapeutic vasculogenesis after ACT. A benefit of using calf muscle perfusion scintigraphy in the assessment of microcirculation and ACT effect was not clearly demonstrated. By contrast, a promising method for the evaluation of microcirculation and the effect of revascularization after ACT was MR spectroscopy of calf...

Spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease type 2D (CMT2D)/distal SMA type V (dSMAV) are two incurable neuromuscular disorders that predominantly manifest during childhood and adolescence. Both conditions are caused by mutations in widely and constitutively expressed genes that encode proteins with essential housekeeping functions, yet display specific lower motor neuron pathology. SMA results from recessive inactivating mutations in the survival motor neuron 1 (SMN1) gene, while CMT2D/dSMAV manifests due to dominant point mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS. Using a number of different model systems, ranging from Caenorhabditis elegans to the mouse, this thesis aimed to identify potential novel therapeutic compounds for SMA, and to increase our understanding of the mechanisms underlying both diseases. I characterised a novel C. elegans allele, which possesses a point mutation in the worm SMN1 orthologue, smn-1, and showed its potential for large-scale screening by highlighting 4-aminopyridine in a screen for compounds able to improve the mutant motility defect. Previously, the gene encoding three isoforms of chondrolectin (Chodl) was shown to be alternatively spliced in the spinal cord of SMA mice before disease onset. I performed functional analyses of the three isoforms in neuronal cells with experimentally reduced Smn levels, and determined that the dysregulation of Chodl likely reflects a combination of compensatory mechanism and contributor to pathology, rather than mis-splicing. Finally, working with two Gars mutant mice and a new Drosophila model, I have implicated semaphorin-plexin pathways and axonal guidance in the GlyRS toxic gain-of-function disease mechanism of CMT2D/dSMAV.

Aim: The aim of this thesis "Examination of vegetative system in hereditary neuropathy" is to consider the level of physical fitness, physical actvity level and quality of autonomic function in patients with hereditary neuropathy Charcot Marie Tooth and an assessment of interactions of these parameters, especially with regard to possible influence by the presence of autonomic neuropathy and with regard to neurological symptoms. Background: Although vegetative neuropathy was mentioned in the first publication about CMT, it is not widely discussed topic as part of it. Methods: Seventeen probands underwent spiroergometry, heart rate variability test, six minute walk test, rating by the CMT Neuropathy Score and Overall neuropathy disability scale and completing the IPAQ questionnaire. Results: We found symptoms of autonomic neuropathy in group of patients with CMT, especially high-frequency part of heart rate variability spectrum has a particularly significant decrease. Patients with autonomic neuropathy have shown a low fitness and functional capacity, tendency to obesity and hypertension. The observed correlation of autonomic neuropathy and neurological impairment was very weak. Conclusions: We find a neuropathy of the autonomic nervous system in patiens with hereditary motor and sensitive neuropathy...

PINHEIRO , Heráclito Aragão. O fantasma no castelo do materialismo: uma história do inconsciente Freudiano. 2009. 91 f. Dissertação (Mestrado em Psicologia) – Universidade Federal do Ceará, Departamento de Psicologia, Programa de Pós-Graduação em Psicologia, Fortaleza-CE, 2009. / Submitted by moises gomes (celtinha_malvado@hotmail.com) on 2012-01-17T12:22:11Z No. of bitstreams: 1 2009_dis_HAPinheiro.PDF: 1002277 bytes, checksum: 98f8aa06827023a320f586b7fffbfdaf (MD5) / Approved for entry into archive by Maria Josineide Góis(josineide@ufc.br) on 2012-03-08T12:15:30Z (GMT) No. of bitstreams: 1 2009_dis_HAPinheiro.PDF: 1002277 bytes, checksum: 98f8aa06827023a320f586b7fffbfdaf (MD5) / Made available in DSpace on 2012-03-08T12:15:30Z (GMT). No. of bitstreams: 1 2009_dis_HAPinheiro.PDF: 1002277 bytes, checksum: 98f8aa06827023a320f586b7fffbfdaf (MD5) Previous issue date: 2009 / This research has the goal of understanding the path of Freud in his elaboration of the notion of unconscious, to realize the ways by which he got to this crucial notion to the foundation of the psychoanalytical knowing. To reach this goal I decided to deal with the models and references of Freud. The principal results were that the models which had more weight in the development of his idea of unconscious were his clinical work with the hysterics, as well as his divergence with the conventional ideas about this affection, his contact with the hypnosis and the interlocution he established with Charcot, Breuer and Fliess. And the principal references were the agnosticism and the physicalism,in relation to what it concerns the form by which he finally distanced himself. / Esta dissertação tem por objetivo compreender o percurso de Freud em sua elaboração da noção de inconsciente, perceber de que maneira ele chega até essa noção crucial para a fundação do saber psicanalítico. Para alcançar esse objetivo decidi abordar os modelos e os referentes de Freud. Os principais achados com relação aos modelos que tiveram maior peso em sua elaboração do inconsciente foram sua clínica com as histéricas, bem como seu confronto com as idéias vigentes sobre essa afecção, seu contato com a hipnose e a interlocução que estabeleceu com Charcot, Breuer e Flies. E os principais referentes foram o agnosticismo e o fisicalismo, no que concerne à forma como ele findou se afastando deste.