Succinic semialdehyde dehydrogenase (ALDH5A1) deficiency (SSADH-d) is an autosomal recessive, inborn error of gamma-aminobutyric acid (GABA) metabolism that results in psychomotor retardation, ataxia and seizures. A mouse model of SSADH-d (the Aldh5a1-/- mouse) was created to study the pathophysiology and treatment of SSADH-d. Aldh5a1-/- mice have psychomotor retardation and a progressive seizure phenotype results in death around P25. The present experiments tested the effects of a ketogenic diet in the treatment of Aldh5a1-/- mice. The KD was found to prolong the lives of Aldh5a1-/- mice by >300% while significantly delaying the onset the ataxia and preventing weight loss that is seen in untreated Aldh5a1-/- mice. Electrophysiological recordings revealed a corresponding decrease in seizures in KD fed mutants, as compared to control diet (CD) fed mutants. We assessed spontaneous miniature postsynaptic currents (mPSC) in CD and KD fed mutants. We found that CD fed mutants had significantly decreased inhibitory mPSC (mIPSC) activity compared to CD fed wildtype controls. mIPSC activity was restored in KD fed Aldh5a1-/- mice. A similar effect was found in [35S]TBPS binding experiments. TBPS binding was significantly reduced in CD fed Aldh5a1-/- mice, but restored in KD fed mutants. Plasma analysis revealed that an elevation of serum beta-hydroxybutyrate may play a role in the KD’s effects. The KD led to a significant elevation in the number of hippocampal mitochondria in mutant mice. Further, the KD was able to normalize the deficiencies in the hippocampal ATP levels seen in the Aldh5a1-/- mice. The present data suggest that the KD is able to significantly improve the Aldh5a1-/- phenotype. The effect of the KD on mIPSC activity is novel and furthers our understanding of how the KD may exert its effects. The mitochondrial studies confirm the findings of others, that the KD elevates the number of mitochondria. The KD also restores ATP deficiencies in Aldh5a1-/- mice, which is a novel finding. Together, these show that the KD may be an effective treatment for SSADH-d in humans. These data also further our understanding of the KD’s mechanisms of action.

Succinic semialdehyde dehydrogenase (ALDH5A1) deficiency (SSADH-d) is an autosomal recessive, inborn error of gamma-aminobutyric acid (GABA) metabolism that results in psychomotor retardation, ataxia and seizures. A mouse model of SSADH-d (the Aldh5a1-/- mouse) was created to study the pathophysiology and treatment of SSADH-d. Aldh5a1-/- mice have psychomotor retardation and a progressive seizure phenotype results in death around P25. The present experiments tested the effects of a ketogenic diet in the treatment of Aldh5a1-/- mice. The KD was found to prolong the lives of Aldh5a1-/- mice by >300% while significantly delaying the onset the ataxia and preventing weight loss that is seen in untreated Aldh5a1-/- mice. Electrophysiological recordings revealed a corresponding decrease in seizures in KD fed mutants, as compared to control diet (CD) fed mutants. We assessed spontaneous miniature postsynaptic currents (mPSC) in CD and KD fed mutants. We found that CD fed mutants had significantly decreased inhibitory mPSC (mIPSC) activity compared to CD fed wildtype controls. mIPSC activity was restored in KD fed Aldh5a1-/- mice. A similar effect was found in [35S]TBPS binding experiments. TBPS binding was significantly reduced in CD fed Aldh5a1-/- mice, but restored in KD fed mutants. Plasma analysis revealed that an elevation of serum beta-hydroxybutyrate may play a role in the KD’s effects. The KD led to a significant elevation in the number of hippocampal mitochondria in mutant mice. Further, the KD was able to normalize the deficiencies in the hippocampal ATP levels seen in the Aldh5a1-/- mice. The present data suggest that the KD is able to significantly improve the Aldh5a1-/- phenotype. The effect of the KD on mIPSC activity is novel and furthers our understanding of how the KD may exert its effects. The mitochondrial studies confirm the findings of others, that the KD elevates the number of mitochondria. The KD also restores ATP deficiencies in Aldh5a1-/- mice, which is a novel finding. Together, these show that the KD may be an effective treatment for SSADH-d in humans. These data also further our understanding of the KD’s mechanisms of action.

The objectives of this thesis is to explore different approaches of modelling clustered correlated data in the form of repeated or longitudinal counts data leading to a replicated Poisson process. The specific application is from repeated epileptic seizure time to events data. Two main classes of models will be considered in this thesis. These are the marginal and subject or cluster specific effects models. Under the marginal class of models the generalized estimating equations approach due to Liang and Zeger (1986) is first considered. These models are concerned with population averaged effects as opposed to subject-specific effects which include random subject-specific effects such that multiple or repeated outcomes within a subject or cluster are assumed to be independent conditional on the subject−specific effects. Finally we consider a distinct class of marginal models which include three common variants namely the approach due to Anderson and Gill (1982), Wei et al (1989) and Prentice et al. (1981) / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

Abnormally slow processing of language may be a factor contributing to the poor verbal memory seen in many patients with lesions of the anterior temporal region in the left hemisphere. This possibility was examined by comparing the performance of 12 patients with left temporal-lobe resections (LT), 10 patients with similar lesions in the right hemisphere (RT) and 13 normal control (NC) subjects on a lexical-decision task, a sentence-plausibility-judgement task, and a story-recall task. Stimuli were presented aurally, and, in the latter two tasks, at 5 different speech rates ranging from 125 words per minute (wpm) to 325 wpm. Recall of stories by LT subjects was not abnormally sensitive to the effect of increasing rate, although it was inferior to that by NC subjects at all speeds. LT patients presented aurally but not visually (Frisk and Milner, 1991), suggesting that the left anterior temporal region plays a special role in the processing of speech sounds.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

No description available.

Lafora disease (LD) is an adolescent-onset autosomal recessive progressive myoclonus epilepsy. The main clinical symptoms of the disease are worsening seizures, neurodegeneration and usually death within ten years. No therapeutics or interventions exist for this devastating disease. Mutations in two genes, EPM2A (laforin) and EPM2B (malin) are causative of more than 90 percent of LD. The pathognomonic sign of LD is the presence of abnormal glycogen which precipitates and accumulates into starch-like masses called Lafora bodies (LB). There are two main hypotheses of LB formation. Glycogen is synthesized through the combined activities of glycogen synthase (GS) and branching enzyme (BE). One hypothesis is that LB form due to an overactivation of GS, causing a misbalance between synthesis and branching. Here, malin and laforin regulate levels of GS and other protein(s) involved in glycogen synthesis and when missing, result in their overaccumulation and thus overactivation of synthesis in relation to branching. The second hypothesis is based on evidence of increased phosphorylation of glycogen in LB. In this hypothesis, glycogen becomes abnormal because of the hyperphosphorylation, causing it to precipitate. Laforin is a glycogen phosphatase, and removes phosphate from glycogen. When missing, as in LD, glycogen becomes hyperphosphorylated and forms LB. A role for malin is less clear in this hypothesis. In this thesis, I identify and characterize a third gene, PRDM8, causing an early onset form of LD in a large consanguineous family. I show that it both interacts with laforin and malin and results in their relocation to the nucleus. I also characterize a laforin-interacting protein, Epm2aip1, finding an important role for this previously uncharacterized protein in glycogen metabolism. Epm2aip1-/- mice exhibit hepatic insulin resistance, decreased hepatic glycogen synthesis, increased liver fat, and resistance against obesity in adulthood. Epm2aip1 associates with glycogen synthase (GS), and its absence impairs the allosteric activation of GS by glucose-6-phosphate. Finally, I find that genetically removing PTG, an activator of GS, from mice with Lafora disease results in near-complete disappearance of LB, and resolution of the neurodegeneration and myoclonic epilepsy. This work has revealed a gateway to the treatment of this devastating and fatal disease.

Lafora disease (LD) is an adolescent-onset autosomal recessive progressive myoclonus epilepsy. The main clinical symptoms of the disease are worsening seizures, neurodegeneration and usually death within ten years. No therapeutics or interventions exist for this devastating disease. Mutations in two genes, EPM2A (laforin) and EPM2B (malin) are causative of more than 90 percent of LD. The pathognomonic sign of LD is the presence of abnormal glycogen which precipitates and accumulates into starch-like masses called Lafora bodies (LB). There are two main hypotheses of LB formation. Glycogen is synthesized through the combined activities of glycogen synthase (GS) and branching enzyme (BE). One hypothesis is that LB form due to an overactivation of GS, causing a misbalance between synthesis and branching. Here, malin and laforin regulate levels of GS and other protein(s) involved in glycogen synthesis and when missing, result in their overaccumulation and thus overactivation of synthesis in relation to branching. The second hypothesis is based on evidence of increased phosphorylation of glycogen in LB. In this hypothesis, glycogen becomes abnormal because of the hyperphosphorylation, causing it to precipitate. Laforin is a glycogen phosphatase, and removes phosphate from glycogen. When missing, as in LD, glycogen becomes hyperphosphorylated and forms LB. A role for malin is less clear in this hypothesis. In this thesis, I identify and characterize a third gene, PRDM8, causing an early onset form of LD in a large consanguineous family. I show that it both interacts with laforin and malin and results in their relocation to the nucleus. I also characterize a laforin-interacting protein, Epm2aip1, finding an important role for this previously uncharacterized protein in glycogen metabolism. Epm2aip1-/- mice exhibit hepatic insulin resistance, decreased hepatic glycogen synthesis, increased liver fat, and resistance against obesity in adulthood. Epm2aip1 associates with glycogen synthase (GS), and its absence impairs the allosteric activation of GS by glucose-6-phosphate. Finally, I find that genetically removing PTG, an activator of GS, from mice with Lafora disease results in near-complete disappearance of LB, and resolution of the neurodegeneration and myoclonic epilepsy. This work has revealed a gateway to the treatment of this devastating and fatal disease.

Bakgrund: Att leva med epilepsi leder till ökad psykisk belastning. Personer med epilepsi har ofta bristande kunskap om sjukdomen och behovet av utbildning är stort. Personen behöver lära sig symtom och sätt att undvika situationer som kan trigga anfall. Vårdpersonal har en viktig roll när det gäller utbildning, rådgivning och stöd till personer med epilepsi och deras familjer. Syftet med denna litteraturöversikt var att beskriva och utvärdera effekter av utbildning till personer med epilepsi och/eller dennes närstående. För att besvara detta valdes litteraturöversikt som metod bestående av vetenskapliga artiklar med kvantitativ ansats. Resultatet visade att det framgångsrikt går att utbilda personer och/eller dess närstående i kunskap om epilepsi och egenvårdsförmåga. Livskvalitén för personer med epilepsi tycks dock inte påverkas av utbildning. Slutsatsen var att utbildning tycks ha en god effekt för personer med epilepsi avseende kunskap och egenvårdsförmåga. Vidare forskning med randomiserad, kontrollerade studier med större urval skulle vara av stort värde för att öka kunskapen om effekter av utbildning vid epilepsi ytterligare. / Background: Living with epilepsy leads to increased psychological stress. People with epilepsy often have insufficient knowledge about the disease and the need for education is essential. The person needs to learn the symptoms and ways to avoid exposing themselves to situations that may trigger seizures. Health professionals have an important role in education, counseling and support to people with epilepsy and their families. The aim of this literature overview was to describe and evaluate the effects of education to people with epilepsy and / or its family. To answer this, a literature overview was selected as a method consisting of scientific articles with a quantitative approach. The result showed that to educate individuals and / or its family in the knowledge of epilepsy and self-care ability could be successfully be carried out. Quality of life in people with epilepsy does not seem to get effect of patient education.   The conclusion was that education seems to have positive effect for people with epilepsy on knowledge and self-care ability. Continued research with randomized, controlled trials with larger sample would be of great value to further increase the knowledge about the effects of education in people living with epilepsy.

<p>Understanding the mechanisms of limbic epileptogenesis in cellular and molecular terms may provide novel therapeutic targets for its prevention. The neurotrophin receptor tropomyosin-related kinase B (TrkB) is thought to be critical for limbic epileptogenesis. Enhanced activation of TrkB, revealed by immunodetection of enhanced phosphorylated TrkB (pTrkB), a surrogate measure of its activation, has been identified within the hippocampus in multiple animal models. Knowledge of the cellular locale of activated TrkB is necessary to elucidate its functional consequences. Using an antibody selective to pTrkB in conjunction with confocal microscopy and cellular markers, we determined the cellular and subcellular locale of enhanced pTrkB induced by status epilepticus (SE) evoked by infusion of kainic acid into the amygdala of adult mice. SE induced enhanced pTrkB immunoreactivity in two distinct populations of principal neurons within the hippocampus--the dentate granule cells and CA1 pyramidal cells. Enhanced immunoreactivity within granule cells was found within mossy fiber axons and giant synaptic boutons. By contrast, enhanced immunoreactivity was found within apical dendritic shafts and spines of CA1 pyramidal cells. A common feature of this enhanced pTrkB at these cellular locales is its localization to excitatory synapses between excitatory neurons, presynaptically in the granule cells and postsynaptically in CA1 pyramidal cells. Long-term potentiation (LTP) is one cellular consequence of TrkB activation at these excitatory synapses that may promote epileptogenesis.</p><p>The importance of TrkB in diverse neuronal processes, as well as its involvement in various disorders of the nervous system, underscores the importance of understanding how it is activated. The canonical neurotrophin ligand which activates TrkB is brain derived neurotrophic factor (BDNF). Zinc, however, has also been demonstrated to activate this receptor through a mechanism whereby it does not directly interact with it, known as transactivation. Presynaptic vesicles of mossy fiber boutons of stratum lucidum are particularly enriched in zinc, where it is co-released with glutamate in an activity dependent fashion, and incorporated into these vesicles by the zinc transporter, ZnT3. Given the presence of large quantities of zinc within stratum lucidum, we hypothesized that this metal may contribute to TrkB transactivation at this locale. To this end, we examined the contributions of both BDNF and synaptic vesicular zinc to TrkB activation in stratum lucidum of mouse hippocampus under physiological conditions. Utilization of mice which are genetic knockouts for BDNF and/or ZnT3 allowed us to examine TrkB activation in the absence of one or both of these ligands. This was done using an antibody for pTrkB in conjunction with confocal microscopy, assaying immunoreactivity at the cellular and synaptic locales within stratum lucidum where pTrkB was previously found to be enriched. Our results suggest that BDNF contributes to TrkB activation within stratum lucidum. Interestingly, ZnT3 mice displayed an increase in BDNF protein and TrkB activation, demonstrating that synaptic zinc regulates BDNF and TrkB signaling at this locale.</p> / Dissertation