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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Cardiovascular pathology is seen in both animals and humans after domoic acid intoxication. Whether this damage is direct (i.e., cardiotoxic) or indirect (i.e., CNS/autonomic seizures) is not known. We have previously shown that acute in vitro domoic acid (0.05-0.25[mu]M; 10 min) treatment of isolated cardiac mitochondria compromises mitochondrial FADH and NAD⁺-linked respiratory control and mitochondrial energetics. Domoic acid was shown to traverse and bind the cellular membrane of H9c2 cardiac myoblasts. However it did not compromise cellular viability as assessed using cell quantification or lactate dehydrogenase leakage assays. Exposure of intact H9c2 cells to domoic acid only resulted in complex II-III activity impairment and assessment of reactive oxygen species (superoxide and hydrogen peroxide) production in both isolated cardiac mitochondria and H9c2 cardiomyocytes failed to show any significant differences following exposure to domoic acid. Acute ex vivo domoic acid treatment of an isolated myocardium in Langendorff perfusion mode failed to result in cardiac haemodynamic dysfunction, however there appeared to be small but significant decrease in mitochondrial oxygen utilization. The absence of any substantial damage to intact cardiomyocytes and isolated myocardium suggested that domoic acid does not have a direct toxicological effect on cardiac energetics. We therefore investigated the possibility that cardiovascular pathology is an indirect consequence of autonomic seizure activity. Domoic acid was administered intraperitoneally or intrahippocampally and the development of cardiac pathologies was assessed and compared. Sprague-Dawley rats receiving either i.p. or i.h. domoic acid were assessed behaviourally and shown to reach similar levels in their cumulative seizure scores. Assessment of the cardiac haemodynamics (LVDP, dP/dt, heart rate and coronary flow) revealed a significant time-dependent decrease in function at 1, 3, 7 & 14-days post-i.p. and 7 & 14-days post-i.h. domoic acid administration. Measurement of ventricular mitochondrial oxygen utilization revealed a similar time-dependent decrease in respiratory control, which appeared to be associated with increased proton leakage, shown by an increase in state-4 respiration rate (P<0.01). Assessment of the mitochondrial electron transport chain (complexes I-V) and the mitochondrial marker of integrity, citrate synthase, showed marked time-dependent impairment in both models of domoic acid -induced seizures. Oxidative stress did play a small role in the myocardial damage as indicated by the small decrease in aconitase activity (P<0.05). Plasma IL-1α, IL-1β and TNF-α levels were significantly increased from 3-days post seizures. Haematoxylin & Eosin staining of ventricular sections revealed the formation of contraction bands, inflammation and oedema, confirming a structural pathology. Cardiac damage did not differ between i.p. and i.h. animals, suggesting cardiac damage following domoic acid results from CNS autonomic seizures and resultant sympathetic storm. This thesis has demonstrated, for the first time, that the cardiac pathology seen following domoic acid exposure is most likely to be a result of CNS activation and resultant seizure episodes, and is not a consequence of the direct interaction between domoic acid and the myocardium. We have also demonstrated for the first time, that seizure episodes result in chronic cardiac dysfunction and a structural pathology which is similar, but not identical to that seen following isoprotenerol administration in vivo.

No description available.

Seizure activity is the primary symptom in a common but very serious neurological disorder known as epilepsy. Brain glycogen is utilized for neuronal function, prompting us to investigate the role of brain glycogen during seizure activity in mouse models. Seizures were induced with Pentylenetetrazole (PTZ) in both wild-type mice and mice lacking brain glycogen (MGSKO/GSL30 mice). A time course of brain glycogen utilization after onset of seizure activity revealed a reduction of brain glycogen in wild-type mice. The glycogen synthase activity ratio increased after onset of seizure activity, while the glycogen phosphorylase activity ratio remained constant. Brain and blood glucose levels increased after seizure onset in wild-type mice. Despite lacking brain glycogen, MGSKO/GSL30 mice exhibited acute seizure activity. No differences were observed in seizure intensity, onset time, and duration between genotypes. These findings suggest that brain glycogen is important, but not required for PTZ-induced acute seizure activity in mice. / Access to thesis permanently restricted to Ball State community only / Department of Biology

Las hemorragias retinianas en los lactantes han sido durante mucho tiempo uno de los signos de maltrato, en concreto, del síndrome del niño zarandeado, considerado prácticamente patognomónico de esta enfermedad. Sin embargo, en los últimos años existe una fuerte controversia acerca de otras posibles causas. Teóricamente las convulsiones, apneas, accesos de tos o cualquier otro desencadenante de una maniobra de Valsalva tienen como consecuencia un aumento de la presión venosa central, que se acompaña de un aumento repentino de la presión venosa de la retina y podrían producir hemorragias retinianas.HIPÓTESIS DE TRABAJO: Ni las convulsiones, ni las crisis de tos, ni los episodios aparentemente letales ocasionan hemorragias retinianas. Por tanto, su hallazgo debe relacionarse con maltrato, y obliga a proseguir el estudio para realizar el diagnóstico diferencial.OBJETIVOS: Conocer la prevalencia y las circunstancias que rodean al episodio de hemorragias retinianas en niños ingresados por convulsiones, episodio aparentemente letal y tos ferina.Valorar si la presencia de hemorragias retinianas puede considerarse un marcador clínico de maltrato físico en niños menores de dos años que consultan por convulsión, episodio aparentemente letal o crisis de tos pertusoide.Determinar si es necesario realizar un fondo de ojo para descartar maltrato en menores de dos años que consultan por convulsión, episodio aparentemente letal o crisis de tos pertusoide.PACIENTES Y MÉTODO: Estudio de transversal exploratiorio para valorar la presencia de hemorragias retinianas en niños menores de 2 años, previamente sanos, ingresados por primera convulsión, episodio aparentemente letal o accesos de tos pertusoide. Posteriormente se compara su prevalencia con la de un grupo histórico de niños maltratados. RESULTADOS: Se diagnosticaron dos casos de hemorragias retinianas en niños que habían consultado por convulsión, ambos correspondieron a niños víctimas de maltrato. En ningún otro de los 352 niños restantes se objetivaron hemorragias retinianas en el fondo de ojo.CONCLUSIONES: En la muestra de 352 niños ingresados por convulsiones, episodios aparentemente letales y accesos de tos pertusoide no se encontraron hemorragias retinianas causadas por estos motivos de consulta. La aplicación del .protocolo de maltrato llevó al diagnóstico final del Síndrome del Niño Zarandeado en 2 casos que presentaban hemorragia retiniana. La presencia de hemorragias retinianas en un niño menor de dos años que ha presentado una convulsión, un episodio aparentemente letal o accesos de tos pertusoide obliga a la investigación para descartar maltrato físico ya que estos motivos de consulta no pueden catalogarse a priori como causa de las hemorragias retinianas. Las convulsiones sin causa clara y los episodios aparentemente letales idiopáticos deben ser susceptibles de realización de fondo de ojo para descartar hemorragias retinianas. Su hallazgo, debe desencadenar otros estudios con el fin de descartar maltrato infantil. En nuestro estudio no hemos encontrado ningún niño con tos pertusoide y hemorragia retiniana por lo que no consideramos necesaria la realización de un fondo de ojo en estos niños. / DOCTORAL THESIS TITLE:"Prevalence of retinal haemorrhages in convulsions, apparent life-threatening events and whooping cough. Their importance in the differential diagnosis of child maltreatment"AUTHOR:Ana Isabel Curcoy BarcenillaSUMMARY:INTRODUCTION: Retinal haemorrhages (RH) are among the most common findings of shaken baby syndrome but may be associated with accidental head trauma as well as a variety of systemic illnesses. Theoretically, convulsions, apparent life-threatening events and whooping cough may cause retinal haemorrhages due to sudden rise in retinal venous pressure, following an increase in central venous pressure secondary to a rise intrathoracic pressure. OBJECTIVES: In children under two:a. To determine the prevalence of retinal haemorrhages in infants admitted to hospital with convulsions, apparent life-threatening events and whooping cough.b. To assess whether the presence of retinal haemorrhages can be considered a clinical marker of physical abuse in children with convulsions, apparent life-threatening events and whooping cough.c. To ascertain whether infants admitted to hospital with convulsions, apparent life-threatening events and whooping cough have to be subjected to a funduscopic examination in order to rule out maltreatment. MATERIALS AND METHODS: Transversal study to assess the presence of retinal haemorrhages in children under 2 years previously healthy infants admitted with first convulsions, apparent life-threatening events and whooping cough. Then compare their prevalence with a historical group of abused children. RESULTS: We diagnosed two cases of retinal haemorrhages in children who had admitted for convulsion, both children were diagnosed as being abused. No retinal haemorrhages were found in any other 352 children studied. CONCLUSIONS:a. In the 352 children admitted with convulsions, apparent life-threatening events and whooping cough were not retinal haemorrhages caused by these complaints. The application of Maltreatment protocol led to the final diagnosis of shaken baby syndrome in 2 cases with retinal haemorrhage. b. The presence of retinal haemorrhages in a child under two years who has presented convulsions, apparent life-threatening events and whooping cough an in-depth investigation was carried out in order to rule out maltreatment, because these pathologies can not be categorized a priori as a cause of retinal haemorrhages.c. An apparently unprovoked seizure and idiopathic apparent life-threatening events need to undertake a funduscopic examination to rule out retinal haemorrhages. The finding of retinal haemorrhages should trigger further studies in order to rule out child abuse. In our study we did not find any child with cough and retinal haemorrhages, therefore not considered necessary to realize a funduscopic examination on these children.

Thesis (M.Sc.). / Written for the School of Computer Science. Title from title page of PDF (viewed 2008/05/30). Includes bibliographical references.