published_or_final_version / abstract / toc / Paediatrics / Master / Master of Philosophy

The thesis presents a comparison of four techniques used for stereotactic radiosurgery, consisting of the static conformal beam, static cone-based, proton therapy, and the Gamma Knife techniques. The comparisons involved six test cases in which phantom target lesions were created in the center of the modified anthropomorphic RandoRTM head. The phantom lesions presented in the study were extreme irregular cases that ranged in shape and volume and were near a critical structure to receive minimal dose during treatment planning. The best treatment plans from each technique for all studies were selected and the extracted data was analyzed using physical and biological parameters. Correlations between integral biological effective dose (normal brain) and normal tissue complication probability were analyzed as a function of dose conformity (PITV), and correlations between tumor control probability and integral biological effective dose (tumor) as a function of dose homogeneity (MDPD) were analyzed, as well. These parameter pairings showed strong links. The static conformal beam and the proton SOBP techniques consistently provided low PITV and MDPD values for all cases, including the most irregular and complicated cases. Higher PITV and MDPD values, typically associated with static cone-based and the Gamma Knife techniques, were due to normal tissue and tumor tissue, respectively, being irradiated at higher dose levels than the prescribed dose. For these cases, as the PITV increased, the NTCP increased, as well, due to high doses created within the normal tissue found within the prescription isodose surface.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 6 uppsatser.

Thesis (M.Sc.). / Written for the Dept. of Pharmacology and Therapeutics. Title from title page of PDF (viewed 2008/07/30). Includes bibliographical references.

Made available in DSpace on 2014-08-13T14:50:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-07-11Bitstream added on 2014-08-13T18:00:40Z : No. of bitstreams: 1 000756751_20150731.pdf: 236798 bytes, checksum: 9b75b0cebfd8612cc949578b65a89f35 (MD5) Bitstreams deleted on 2015-08-03T12:20:55Z: 000756751_20150731.pdf,. Added 1 bitstream(s) on 2015-08-03T12:22:17Z : No. of bitstreams: 1 000756751.pdf: 892335 bytes, checksum: 952dae187bd640e40a8e14dec77be389 (MD5) / Desenvolveu-se a técnica de angiotomografia helicoidal como ferramenta para obter referências de normalidade do suprimento sanguíneo cerebral em cães sadios. O presente trabalho foi realizado em 17 animais, sendo 8 adultos jovens da raça pointer e 9 adultos sem raça definida; machos e fêmeas que apresentaram exames clínico- neurológicos e laboratoriais dentro da normalidade. Realizaram-se imagens simples e com meio de contraste iodado (MCI) não iônico injetado na veia cefálica esquerda, e foram feitas reconstruções multiplanares (MPR). Foi possível evidenciar a maioria das artérias que formam o circulo arterial cerebral, alem de algumas variações anatômicas como a presencia de uma artéria intercarotidea direita e esquerda em 3 cães dos 17 animais, e ausência do ramo direito da artéria cerebral rostral em outros 3 animais, demonstrando assim que a angiotomografia helicoidal é um exame seguro e rápido que pode ser aplicado na rotina tomográfica de cães para correta visualização do suprimento sanguíneo encefálico. Avaliou-se também o efeito do MCI não iônico a uma dose de 900 mg Iodo/kg, no rim utilizando-se ultrassonografia (US) e correlacionou-se com os valores de ureia e creatinina antes e após sua administração. Não foram visibilizadas alterações do parênquima renal em nenhum dos animais. Os valores de creatinina após a injeção do contraste permaneceram dentro da normalidade, porém os valores da ureia apresentaram aumento significativo, Assim, estudos ultrassonográficos correlacionados com exames de laboratório devem ser realizados em maior número de cães para determinar segurança e acurácia dos MCI não iônicos / Developed the technique of helical angitomography as a tool to get references from normal blood supply of the brain in healthy dogs. The present study was performed in 17 animals, 8 young adults breed pointer and 9 adult mixed breed; males and females with clinical, neurological and laboratory normal exams. There were simple images and nonionic iodinated contrast media (ICM) IV, injected into the left cephalic vein; were made multiplanar reconstructions (MPR). It was possible to demonstrate the major arteries that make up the arterial polygon of Willis, in addition some anatomical variations as the presence of an artery intercarotid right and left in 3 of 17 animals, and absence of the right branch of the rostral cerebral artery in other 3 animals, demonstrating that the helical angitomography is a safe and fast examination that can be applied in dogs routine tomographic for correct visualization of the cerebral blood supply. We also evaluated the effect of nonionic MCI at a dose of 900 mg Iodine/kg, in the kidney through ultrasound (U.S.) and correlated with the values of urea and creatinine before and after administration. No changes were seen in any of the renal parenchyma. Creatinine values after MCI remained within the normal range, however the values of urea showed on increase significant statistically, therefore ultrasound studies should be conducted to correlated with laboratory testing on a larger number of dogs to determine safety and accuracy of MCI

Spontaneous mutations in the human LIS1 gene are responsible for Type I lissencephaly ("smooth brain"). The distribution of neurons within the cerebral cortex of lissencephalic children appears randomized, probably owing to a defect in neuronal migration during early development. LIS1 has been implicated in the dynein pathway by genetic analyses in fungi. We previously reported that the vertebrate LIS1 co-localized with dynein at prometaphase kinetochores, and interference with LIS1 function at kinetochore caused misalignment of chromosomes onto the metaphase plate. This leads to a hypothesis that LIS1 might regulate kinetochore protein targeting. In order to test this hypothesis, I created dominant inhibitory constructs of LIS1. After removal of the endogenous LIS1 from the kinetochore by overexpression of the N-terminal self-association domain of LIS1, dynein and dynactin remained at the kinetochores. This result indicated that LIS1 is not required for dynein to localize at the kinetochore. Next, CLIP-170 was displaced from the kinetochores in the LIS1 full-length and the C-terminal WD-repeat overexpressers, suggesting a role for LIS1 in targeting CLIP-170 onto kinetochores. LIS1 was co-immunoprecipitated with dynein and dynactin. Its association with kinetochores was mediated by dynein and dynactin, suggesting LIS1 might interact directly with subunits of dynein and/or dynactin complexes. I found that LIS1 interacted with the heavy and intermediate chains (HC and IC) of dynein complex, and the dynamitin subunit of dynactin complex. In addition to kinetochore targeting, the LIS1 C-terminal WD-repeat domain was responsible for interactions with dynein and dynactin. Interestingly, LIS 1 interacted with two distinct sites on HC: one in the stem region containing the subunit-binding domain, and the other in the first AAA motif of the motor domain, which is indispensable for the ATPase function of the motor protein. This LIS1-dynein motor domain interaction suggests a role for LIS1 in regulating dynein motor activity. To test this hypothesis, changes of dynein ATPase activity was measured in the presence of LIS1 protein. The ATPase activity of dynein was stimulated by the addition of a recombinant LIS1 protein. Besides kinetochores, others and we have found LIS1 also localized at microtubule plus ends. LIS1 may mediate dynein and dynactin mitotic functions at these ends by interacting with astral microtubules at cortex, and associating with the spindle microtubules at kinetochores. Overexpression of LIS1 displaced dynein and dynactin from the microtubule plus ends, and mitotic progression was severely perturbed in LIS1 overexpressers. These results suggested that the role for LIS1 at microtubule plus ends is to regulate dynein and dynactin interactions with various subcellular structures. Results from my thesis research clearly favored the conclusion that LIS1 activates dynein ATPase activity through its interaction with the motor domain, and this activation is important to establish an interaction between dynein and microtubule plus ends during mitosis. I believe that my thesis work not only has provided ample implications regarding dynein dysfunction in disease formation, but also has laid a significant groundwork for more future studies in regulations of the increasing array of dynein functions.

Orientador: Maria Jaqueline Mamprim / Coorientador: Luiz Carlos Vulcano / Banca: Cibele Figueira Carvalho / Banca: Amalia Agut Giménez / Resumo: Desenvolveu-se a técnica de angiotomografia helicoidal como ferramenta para obter referências de normalidade do suprimento sanguíneo cerebral em cães sadios. O presente trabalho foi realizado em 17 animais, sendo 8 adultos jovens da raça pointer e 9 adultos sem raça definida; machos e fêmeas que apresentaram exames clínico- neurológicos e laboratoriais dentro da normalidade. Realizaram-se imagens simples e com meio de contraste iodado (MCI) não iônico injetado na veia cefálica esquerda, e foram feitas reconstruções multiplanares (MPR). Foi possível evidenciar a maioria das artérias que formam o circulo arterial cerebral, alem de algumas variações anatômicas como a presencia de uma artéria intercarotidea direita e esquerda em 3 cães dos 17 animais, e ausência do ramo direito da artéria cerebral rostral em outros 3 animais, demonstrando assim que a angiotomografia helicoidal é um exame seguro e rápido que pode ser aplicado na rotina tomográfica de cães para correta visualização do suprimento sanguíneo encefálico. Avaliou-se também o efeito do MCI não iônico a uma dose de 900 mg Iodo/kg, no rim utilizando-se ultrassonografia (US) e correlacionou-se com os valores de ureia e creatinina antes e após sua administração. Não foram visibilizadas alterações do parênquima renal em nenhum dos animais. Os valores de creatinina após a injeção do contraste permaneceram dentro da normalidade, porém os valores da ureia apresentaram aumento significativo, Assim, estudos ultrassonográficos correlacionados com exames de laboratório devem ser realizados em maior número de cães para determinar segurança e acurácia dos MCI não iônicos / Abstract: Developed the technique of helical angitomography as a tool to get references from normal blood supply of the brain in healthy dogs. The present study was performed in 17 animals, 8 young adults breed pointer and 9 adult mixed breed; males and females with clinical, neurological and laboratory normal exams. There were simple images and nonionic iodinated contrast media (ICM) IV, injected into the left cephalic vein; were made multiplanar reconstructions (MPR). It was possible to demonstrate the major arteries that make up the arterial polygon of Willis, in addition some anatomical variations as the presence of an artery intercarotid right and left in 3 of 17 animals, and absence of the right branch of the rostral cerebral artery in other 3 animals, demonstrating that the helical angitomography is a safe and fast examination that can be applied in dogs routine tomographic for correct visualization of the cerebral blood supply. We also evaluated the effect of nonionic MCI at a dose of 900 mg Iodine/kg, in the kidney through ultrasound (U.S.) and correlated with the values of urea and creatinine before and after administration. No changes were seen in any of the renal parenchyma. Creatinine values after MCI remained within the normal range, however the values of urea showed on increase significant statistically, therefore ultrasound studies should be conducted to correlated with laboratory testing on a larger number of dogs to determine safety and accuracy of MCI / Mestre

Although the mu rhythm is traditionally defined as a normal EEG variant, recent evidence suggests that mu may have functional significance in a variety of disorders such as autism, Parkinson's disease, and multiple sclerosis. While an increasing number of articles have focused on the blocking mechanism of mu in relation to various cognitive processes and disorders, few have examined the significance of a prominent mu rhythm in the background EEG. A few studies have examined the relationship between the mu rhythm and psychological disturbance, such as attentional and affective disorders. Increasing evidence suggests that EEG and qEEG variables may be useful in classifying psychiatric disorders, presenting a neurophysiological alternative to traditional symptom-based diagnosis and classification. Thus, the intention of the present study was to examine the relationship between neuropsychological variables, gathered from multiple assessment sources, and the presence of a prominent mu rhythm in the EEG. Results did not show a statistically significant difference between individuals with and without a prominent mu rhythm on the Test of Variables of Attention (TOVA); although individuals in the mu group showed a pattern of increased impulsivity and performance decrement over time. For adults, no significant differences were observed between groups on psychological variables measured by the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). However, for children, the mu and control groups differed on several behavioral and emotional variables on the Child Behavior Checklist (CBCL). Results are examined in the context of other research and clinical implications are discussed.

Orientador: Marilisa Mantovani Guerreiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-08T00:49:32Z (GMT). No. of bitstreams: 1 Teixeira_KarineCoutoSarmento_M.pdf: 1612063 bytes, checksum: b67ceb8ce8a89e338f504be9b41ab015 (MD5) Previous issue date: 2006 / Resumo: Polimicrogiria é uma malformação da organização cortical que se caracteriza por múltiplos pequenos giros separados por espessos e rasos sulcos. O objetivo do presente estudo foi descrever as manifestações clínicas e eletroencefalográficas de pacientes com polimicrogiria, que têm epilepsia e/ou distúrbio específico de linguagem e dos familares dos pacientes com distúrbio específico de linguagem, correlacionando-os com a neuroimagem. Os pacientes foram submetidos a exame clínico e neurológico, com particular atenção aos sinais pseudobulbares, e realizaram eletroencefalograma de rotina com até 4 horas de duração. Quando possível, foram submetidos a vídeo-monitorização. Os dados de neuroimagem foram classificados em: polimicrogiria perisylviana (subdividida em holosylviana, parietal posterior bilateral, generalizada), polimicrogiria hemisférica e polimicrogiria frontal. Os achados eletroencefalográficos foram categorizados em: normal; anormal com atividade epileptiforme; anormal com atividade não epileptiforme; anormal com atividade epileptiforme e não epileptiforme; anormal com estado de mal elétrico (EME); anormal com atividade epileptiforme contínua e quanto à presença ou não de ativação da atividade epileptiforme pelo sono. Foram estudados 40 pacientes: 16 pacientes com polimicrogiria holosylviana, 14 com polimicrogiria parietal posterior, quatro com polimicrogiria generalizada, três com polimicrogiria hemisférica e três com polimicrogiria frontal. Observou-se nos pacientes com polimicrogiria holosylviana: sinais pseudobulbares em 11, hemiparesia em seis sendo um paciente com dupla hemiparesia. Três possuíam deficiência mental e cinco tinham epilepsia. O eletroencefalograma estava alterado em oito pacientes e atividade epileptiforme foi registrada em seis, sendo que em dois foi registrada atividade epileptiforme contínua focal. Entre os pacientes com polimicrogiria parietal posterior bilateral, cinco apresentavam sinais pseudobulbares e um possuía hemiparesia. Nenhum tinha alteração cognitiva ou epilepsia. Apenas um paciente apresentou ao eletroencefalograma atividade epileptiforme focal. Todos os pacientes com polimicrogiria generalizada tinham sinal pseudobulbar, deficiência mental e epilepsia. O quadro motor estava presente em três pacientes e apenas um deles não apresentava atividade epileptiforme no eletroencefalograma. Entre os pacientes com polimicrogiria hemisférica, todos apresentavam sinal pseudobulbar e hemiparesia, dois pacientes tinham deficiência mental e epilepsia, e um paciente atraso do desenvolvimento neuropsicomotor. Nos registros eletroencefalográficos, dois pacientes apresentaram EME focal. Os pacientes com polimicrogiria frontal não possuíam sinal pseudobulbar e em um único paciente foi detectada hemiparesia. Epilepsia estava presente em dois pacientes. No registro eletroencefalográfico, dois exames apresentaram anormalidades não-epileptiformes. Com os dados acima descritos foi possível observar que: os sinais pseudobulbares foram mais freqüentes em pacientes com idade menor ou igual a 15 anos; atividade epileptiforme e lentificação da atividade de base teve associação com epilepsia e alteração cognitiva e o distúrbio específico de linguagem apresentou uma relação inversa com estes achados eletroencefalográficos; a maioria dos nossos pacientes apresentou exame eletroencefalográfico normal; na polimicrogiria holosylviana, as atividades epileptiformes predominaram na região fronto-temporal e as atividades não epileptiformes predominaram na região fronto-centro-temporal; EME ocorreu em polimicrogiria hemisférica e atividade epileptiforme contínua focal ocorreu em polimicrogiria holosylviana bilateral assimétrica com provável displasia cortical associada; a ativação da atividade epileptiforme pelo sono foi um achado freqüente em nossa casuística; existe correlação direta entre as manifestações clínicas e anormalidades eletroencefalográficas e extensão do córtex polimicrogírico / Abstract: Polymicrogyria is a malformation of cortical organization that is characterized by multiple and small gyri. The aim of this study was do describe clinical and eletrographic features of patients with polymicrogyria, whom have epilepsia and/or developmental language disorder, and to correlate these data with neuroimaging findings. Our patients underwent clinical and neurological examination, and a routine electroencephalogram. Whenever possible, video-electroencephalographic monitoring was performed. Neuroimaging data were classified as: perisylvian polymicrogyria (subdivided as holosylvian, posterior parietal and generalized), hemispheric polymicrogyria and frontal polymicrogyria. Electrographic findings were classified as: normal; abnormal with epileptiform activity; abnormal with non-epileptiform activity; abnormal with epileptiform and non-epileptiform activities; abnormal with electrographic status (ES); abnormal with continuous epileptiform activity; sleep activation. We studied 40 patients: 16 with holosylvian polymicrogyria; 14 with posterior parietal polymicrogyria; four with generalized polymicrogyria; three with hemispheric polymicrogyria; and three with frontal polymicrogyria. Patients with holosylvian polymicrogyria showed: pseudobulbar signs in 11; hemiparesis in six one of them with double hemiparesis. Three had mental retardation and five had epilepsy. The elecgroencephalogram was abnormal in eight patients and epileptiform activity was registered in six, two of them with focal. Patients with posterior parietal polymicrogyria showed: five with pseudobulbar sign and one with hemiparesis. Cognitive delay and epilepsy was not found in this group. Only one patient had electroencephalogram with focal epileptiform discharges. Patients with generalized polymicrogyria had pseudobulbar sign, epilepsy and mental retardation. Motor deficit was found in three patients. Electroencephalogram findings showed epileptiform activity in three. Patients with hemispheric polymicrogyria had pseudobulbar sign and hemiparesis. Two of them had mental retardation and epilepsy. One had neurodevelopmental delay. Electrographic examinations showed focal ES in two patients. Patients with frontal polymicrogyria had no pseudobulbar sign and one of them had hemiparesis. Two patients had epilepsy. Electroencephalogram findings showed non-epileptiform activities in two patients. Our data demonstrated that: pseudobulbar sign are more frequent among patients under 15 years old; epilepsy and cognitive delay are both correlated with epileptiform activity and slowness of the background activity and developmental language disorder had a inverse correlation with this finds; in holosylvian polymicrogyria, epileptiform activities predominated in fronto-temporal regions and non-epileptiform activities predominated in centro-temporal regions; ES occurred in hemispheric polymicrogyria and focal continuous epileptiform activities in asymmetric bilateral holosylvian polymicrogyria with associated cortical dysplasia; sleep activation was a frequent finding; the severity of clinical and electrographic features correlated with the extent of cortical lesion / Mestrado / Neurologia / Mestre em Ciências Médicas

Healthy brain development requires coordinated synapse growth and synapse elimination, with disruptions to these processes often resulting in neurodevelopmental disorder. While glia, the non-neuronal cells of the brain, are increasingly recognized as important regulators of both of these processes, the extent of this regulation and, in the case of disorder, dysregulation is still unknown. In this dissertation, I made classic use of the mouse visual system to outline the contours of glial regulation of synapse development in both synapse growth and synapse elimination. First, I examined astrocytes and microglia in the context of normal brain development, characterizing their spatiotemporal expression patterns in and around the mouse optic tract throughout late embryonic and early postnatal development, as RGC axons are growing into their synaptic target, the dLGN (Chapter 2). Next, I examined astrocyte and microglia in the context of disorder. Here, I found that synapses are reduced in size and eye-specific RGC synapse segregation is enhanced in a mouse model of Fragile X Syndrome, the most common single-gene cause of autism and intellectual disability, (Fmr1 KO mouse) during brain development. I identified glial phagocytic genes as disrupted within the developing Fmr1 KO dLGN and demonstrated that both microglial and astrocytic engulfment of synapses were aberrantly increased during this period of enhanced segregation, providing evidence that over-active glial engulfment may drive aberrant synapse refinement during development in a model of Fragile X Syndrome (Chapter 3).