Fipronil é um inseticida fenilpirazol de amplo espectro, desenvolvido para inibir seletivamente receptores GABA associados a canais de cloreto de insetos; tanto em Medicina Veterinária, como em Agricultura tem sido utilizado para o controle de pragas. Embora vários estudos procurem compreender os mecanismos da toxicidade neuronal dos praguicidas em mamíferos, há poucos relacionados aos efeitos neurocomportamentais. Assim, o presente estudo investigou os efeitos da exposição prolongada de ratos ao fipronil, observando-se alguns comportamentos ligados ao sistema GABAérgico, como atividade no campo aberto, no labirinto em cruz elevado (LCE), bem como na convulsão induzida por picrotoxina e pentilenotetrazol; avaliou-se ainda os níveis cerebrais de alguns neurotransmissores, como GABA, dopamina, noradrenalina, serotonina e seus respectivos metabólitos. Além disso, foram realizadas análises anátomo-histopatológicas em fígado, cérebro e rins dos animais. Ratos Wistar receberam, por via intragástrica (gavage), durante 28 dias um dos seguintes tratamentos: fipronil (0,1; 1,0 ou 10,0 mg/Kg/dia) ou água destilada 1 mL/Kg/dia. Após uma hora da última administração do fipronil ou água destilada, os ratos tiveram seu comportamento avaliado no campo aberto e no LCE com auxílio do sistema computadorizado EthoVision®. Observou-se no campo aberto apenas redução significante do nº de levantamentos nos animais tratados com 10,0 mg/Kg de fipronil, quando comparados com os ratos do grupo controle. No LCE, a exposição prolongada de ratos ao fipronil nas doses de 1,0 e 10,0 mg/Kg provocou redução na distância percorrida pelos animais e o tempo de permanência dos animais nos braços abertos, além de aumentar o tempo de permanência nos braços fechados. Para o cálculo da dose convulsivante mínima, seguiu-se o mesmo protocolo de tratamento, sendo observada diminuição significante na dose de picrotoxina e de pentilenotetrazol necessária para a indução da convulsão em animais tratados com 10,0 mg/Kg fipronil. A determinação dos níveis de neurotransmissores e seus respectivos metabólitos mostrou aumento dos níveis de dopamina no córtex frontal de ratos tratados com 10,0 mg/Kg de fipronil, redução nos níveis de GABA no striatum de ratos tratados com 1,0 mg/Kg de fipronil. Em relação à serotonina houve aumento de seus níveis no córtex frontal de ratos tratados com 1,0 mg/Kg e seu metabólito, ácido 5 (5HIAA), foi observado redução de seus níveis no córtex frontal de ratos tratados com 0,1 e 1,0 mg/kg p.c. de fipronil. No striatum também houve redução de seus níveis em ratos tratados com 0,1 e 1,0 mg/Kg de fipronil. O estudo anátomo-histopatológico revelou que a exposição prolongada ao fipronil pode causar hepatotoxicidade, caracterizada por aumento dos pesos absoluto e relativo do fígado e tumefação celular de hepatócitos. Em conclusão, os resultados mostraram que a exposição de ratos por 28 dias, via gavage, ao fipronil pode causar efeitos comportamentais relacionados a alterações em sistemas centrais de neurotransmissão e também hepatotoxicidade. / Fipronil is a phenylpyrazole insecticide with broad spectrum, developed to selectively inhibit insect GABA-gated chloride channels; both in Veterinary Medicine, and in Agriculture it has been used for the control of nuisances. Although several studies try to understand the mechanism of neuronal toxicity of pesticide in mammalian, there are few studies related to neurobehavioral effects. Thus, the present study investigated the effects of fipronil long term exposure in rats, being observed some behaviors connected to GABAergic system, as activity in open field, in elevated plus maze (EPM), as well as in the seizures induced by picrotoxinin and pentylenotetrazole. In addition, this study determinated the brain levels of some neurotransmitter as GABA, dopamine, noradrenaline, serotonin and metabolic levels and investigated liver, brain and kidney damage. Wistar rats received by intragastric (gavage) way during 28 days one of this treatment: fipronil (0,1, 1,0 or 10,0 mg/Kg) or distilled water; the rats behavior were evaluated in open field and elevated plus maze apparatus with system computer EthoVision®. There was a significant reduction of rearing in open field in rats treated with 10,0 mg/Kg of fipronil when compared with control rats. In the EPM, there was a decrease of distance moved in open arms and increase of time spent in closed arms to rats treated with 1,0 and 10,0 mg/Kg of fipronil when compared to control. It was still noticed the reduction in the time spent in open arms EPM in rats treated with 1,0 and 10,0 mg/Kg of fipronil when compared to control group. To calculate the minimum convulsant dose, was used the same treatment protocol and it was observed a significant reduction in picrotoxinin and pentylenotetrazole necessary dose to induction of seizure in animals treated with fipronil 10,0 mg/Kg. The level determination of neurotransmitters and their metabolites, it was observed the dopamine increasing in forebrain from fipronil treated rats by 10,0 mg/Kg. GABA levels decreased in fipronil treated rats striatum by 1,0 mg/Kg. Serotonin neurotransmitter was increased in fipronil treated rats forebrain by 1,0 mg/Kg to and its metabolite, 5HIAA, it was observed a levels decrease in fipronil forebrain treated rats by 0,1 e 1,0 mg/kg. There was decrease of 5HIAA levels in fipronil treated rats striatum by 0,1 e 1,0 mg/Kg. According to organ analyses, it was observed dose-response liver damage such as swelling liver cells. In conclusion, the data showed that fipronil administered in rats by 28 days caused behavioral effects related to central neurotransmitter alterations and hepatotoxicity.

As peçonhas de artrópodos são ricas fontes de neurotoxinas, verdadeiras ferramentas moleculares com ação seletiva e específica sobre o Sistema Nervoso Central (SNC) de mamíferos, e de grande relevância clínico-científica. Demonstramos recentemente que a peçonha de P. bistriata, quando injetada por via intracerebroventricular (i.c.v.), desencadeava crises convulsivas em ratos, um indício da existência de neurotoxinas pró-convulsivantes na peçonha dessa aranha. O grupo do Prof. Dr. Joaquim Coutinho-Netto isolou da peçonha dessa aranha várias neurotoxinas, dentre as quais uma denominada PbTx 2.2.1, que possui a capacidade de inibir a captação do neurotransmissor GABA em sinaptosomas corticais de ratos (in vitro), uma ação considerada como potencialmente anticonvulsivante. As frações PbTx 2.2.1 e 1.2.3 protegem retinas de ratos após isquêmia. Mas, não se testou o efeito anticonvulsivante dessa fração em experimentos in vivo. O presente trabalho teve dois objetivos: 1- Propor um método cromatográfico para isolar da peçonha de aranhas, neurotoxinas pró-convulsivantes não protéicas e de baixo peso molecular. Isolar e caracterizar parcialmente estas neurotoxinas da peçonha da aranha P.bistriata; 2- verificar se a fração PbTx 2.2.1 possui efeito anticonvulsivante in vivo. O isolamento da peçonha de P. bistriata, realizado com filtração em gel (Sephadex G-50 e G-25), cromatografia líquida de alta eficiência (CLAE) (colunas de fase reversa e troca catiônica), e CLAE-acoplado a espectrometria de massa (CLAE-MS) produziu uma fração (fração 7) e um subcomponente (fração 7.1) com atividade pró-convulsivante, após injeção i.c.v. Tal fração apresenta características típicas de ácidos nucléicos. Confirmou-se, através de ressonância magnética nuclear (RMN) que o constituinte majoritário desta fração é o nucleosídeo inosina. O método cromatográfico mostrou-se muito lento. Uma outra fração (fração 6) da mesma peçonha inibiu as crises causadas por bicuculina i.c.v., ao passo que a fração 1 apresentou atividade de fosfatase ácida e alcalina. A injeção i.c.v. da fração PbTx 2.2.1, 20 min antes do convulsivante bicuculina também i.c.v., bloqueou as crises convulsivas em 71,4% dos animais, o que caracteriza um efeito anticonvulsivante in vivo desta fração. Conclui-se que: 1- A peçonha de P. bistriata possui, dentre muitas, uma fração (fração 7) com efeito pró-convulsivante quando injetada i.c.v. em ratos. Nesta fração, aparentemente o composto majoritário é o nucleosídeo inosina. A peçonha da mesma aranha possui também uma fração com atividade anticonvulsivante (fração 6) e outra com atividade de fosfatase ácida e alcalina (fração 1). 2- o método cromatográfico proposto pode ser otimizado talvez pelo uso de ultrafiltração; 3- a fração PbTx 2.2.1 apresenta efeito anticonvulsivante in vivo no modelo de indução de crises por injeção i.c.v. de bicuculina. / Arthropod venoms are rich sources of neurotoxins, molecular tools with selective and specific actions over the mamalian central nervous system with great clinical and scientific importance. Previous work of our laboratory showed that the spider venom of Parawixia bistriata, when injected by intracerebroventricular (i.c.v.) route, induced convulsive seizures in rats, a sign of convulsant neurotoxins. The group of Professor Joaquim Coutinho-Netto isolated from this spider venom a neurotoxin called PbTx 2.2.1 which is a GABA transporter inhibitor in the rat cortical synaptosomal preparation (in vitro), a potencially anticonvulsant property. The fractions PbTx 2.2.1 and 1.2.3 protected retinal cells against isquemy. But, it has not been tested if the PbTx 2.2.1 fraction also has an in vivo anticonvulsant action. Present work has two objectives: 1- to propose a chromatographic methodology to isolate non-proteic low molecular weigh convulsant neurotoxins from spider venoms. Isolate and partially characterize these neurotoxins from P. bistriata venom; 2- test if PbTx 2.2.1 has in vivo anticonvulsant effect. Biochemical venom isolation by gel filtration (Sephadex G-50 and G-25), reverse phase and cationic exchange in high pressure liquid cromatography (HPLC) and also HPLC coupled to mass spectrometry (HPLC-MS), has pointed that the P. bistriata spider venom has a fraction (fraction 7) and a subfraction (7.1) with convulsant activity when injected i.c.v. in rats. Fraction 7 has nucleosidic characteristics. Nuclear magnetic ressonance (NMR) has showed that the principal component of this fraction is the nucleoside iosine. An other fraction (fraction 6) isolated from the same venom, inhibited seizures induced by i.c.v. bicuculine and the fraction 1 showed acid and basic phosphatase activity PbTx 2.2.1, when injected i.c.v. 20 min prior to the convulsant bicuculline (i.c.v.), has blocked seizures in 71.4 % of the animals, what was considered an anticonvulsant effect. The conclusions are: 1- the spider venom of P. bistriata has a fraction (fraction 7) with convulsant action when injected i.c.v. in rats. The major component of this fraction is the nucleoside iosine. This spider venom also has another fraction (fraction 6) with anticonvulsant activity and one with acid and alcaline phosphatase (fraction 1); 2- the chomatographic methodology can be improved, perhaps by ultrafiltration methods; 3- the PbTx 2.2.1 fraction has anticonvulsant effect in vivo.

Fundação de Amparo a Pesquisa no Estado do Rio Grande do Sul / This study presents an analysis on the effects of creatine supplementation on parameters of susceptibility to seizures induced by subconvulsant dose of pentylenetetrazol (PTZ) in an experimental rat model of traumatic brain injury (TBI). TBI is an acute neurological event that can lead to chronic neurological disease, such as epilepsy. Given the magnitude of the problem, various forms of therapy is being tested, but many have failed and yet, few take into account the susceptibility to seizures as an outcome and concentrate on a very early period of injury, getting away from the reality of patients in underdeveloped countries. Creatine is an interesting compound to be evaluated for this purpose, since it has neuromodulatory properties and may regulate synaptic plasticity in developing neurons. Thus, it became interesting to investigate whether there is any effect of creatine in this scenario. To this, creatine supplementation was held by gavage in rats subjected to fluid percussion TBI model and this supplementation began one week after TBI, once a day for four weeks. PTZ test was performed two hours after the last dose of creatine. Furthermore a similar protocol was performed to verify the persistence of the effect and secondly, to verify the acute effect of creatine, just before the PTZ test. Latency for myoclonic and tonic clonic seizures, total time of generalized seizure as the clinical severity through the scale of Racine were measured and also epileptiform discharges and spindle activity before and after the administration of PTZ were quantified. As main results, it was found a decreased susceptibility to seizures in rats supplemented by a month, and the effect remained even if there was withdrawal of creatine for a week, however, this effect was not observed in the single dose of the compound. Still, a positive correlation between epileptiform discharges and spindle activity was found, both reduced in animals supplemented continuously. Thus, creatine is presented as a candidate to be tested in studies with TBI, with the purpose of reducing the susceptibility to seizures. / Este trabalho apresenta uma análise dos efeitos da suplementação de creatina sobre parâmetros de suscetibilidade à crise epiléptica induzida por pentilenotetrazol (PTZ) em dose subconvulsivante, por modelo experimental de traumatismo cranioencefálico (TCE) em ratos. O traumatismo cranioencefálico (TCE) é um evento neurológico agudo que pode levar à doença neurológica crônica, como a epilepsia. Devido a magnitude do problema, diversas formas terapêuticas vêm sendo testadas, porém muitas falharam e ainda, poucas levam em conta o desfecho da suscetibilidade à crises epilépticas, além de se concentrarem em um período muito precoce da patologia, ficando longe da realidade dos pacientes de países subdesenvolvidos. A creatina consiste num interessante composto a ser avaliado para esse fim, já que apresenta propriedades neuromodulatorias e de regulação da plasticidade sináptica em neurônios em desenvovlimento. Assim, tornou-se interessante investigar se existe algum efeito da creatina nesse cenário. Para isso, realizou-se suplementação de creatina por gavagem em ratos submetidos ao TCE por percussão de fluído, iniciada esta suplementação uma semana após o TCE, uma vez ao dia, por quatro semanas, sendo o teste com PTZ realizado duas horas após a última dose. Também foi realizado um protocolo semelhante para verificar se o efeito da creatina era duradouro e outro, para verificar o efeito agudo, logo antes do teste com PTZ. Foram mensurados o tempo de latência para crises mioclônica e tônico clônica generalizada, tempo total de crise generalizada, gravidade da crise através da escala de Racine, bem como quantificada as descargas epileptiformes e ondas de fuso antes e após a administração de PTZ. Como resultados principais, encontrou-se a diminuição da suscetibilidade à crises epilépticas nos ratos suplementados por um mês, e o efeito permaneceu mesmo quando houve retirada da creatina por uma semana adicional, porém, esse efeito não foi observado na administração única do composto. Também houve correlação positiva do aparecimento de descargas epileptiformes e atividades de fuso, ambas reduzidas nos animais suplementados continuamente. Assim, a creatina apresenta-se como substância candidata à testes em estudos com traumatismo cranioencefálico, com a finalidade de diminuir a suscetibilidade à crises epilépticas.

La toxicité des antidépresseurs inhibiteurs de recapture de la sérotonine (IRS) dont le citalopram est le représentant le plus sélectif, est réputée faible. Or les IRS ont été rendus responsables de syndromes sérotoninergiques, de convulsions, d’anomalies électrocardiographiques, voire de troubles respiratoires et de décès. L’implication de cette classe pharmacologique au cours des intoxications médicamenteuses volontaires (IMV) apparait peu documentée par des données récentes en France. Ainsi, la morbidité des IMV impliquant un IRS aux urgences (SAU) et les symptômes les plus fréquemment observés à la suite d’une exposition toxique aux IRS sont peu décrits. De même, les mécanismes toxiques impliqués dans les décès ne sont clairs. Objectifs : Nous avons mené ces travaux dans le but de : 1- mieux connaitre l’épidémiologie des IMV dans un SAU et y préciser l’implication des IRS ; 2- explorer une éventuelle sur-morbidité liée aux IRS dans les IMV polymédicamenteuses ; 3-comprendre les mécanismes de décès induits par de fortes doses de citalopram et les moyens de les prévenir. Méthodes: Nous avons conduit une étude observationnelle des IMV admises au SAU durant 4 ans, avec appariement des patients ayant ingéré un IRS versus des patients intoxiqués non exposés à un IRS. Nous avons également mené une étude expérimentale chez le rat Sprague-Dawley pour connaitre la dose létale médiane (MLD) du citalopram et explorer la toxicité neurologique, respiratoire et systémique impliquée dans le décès consécutif à l’administration de citalopram. Des dosages de sérotonine plasmatiques et plaquettaires ont été effectués afin de caractériser le rôle de la toxicité sérotoninergique. Résultats : Les IRS étaient impliqués dans 16% des IMV au SAU, soit en 2e position après les benzodiazépines. L’attribution des symptômes observés aux effets sérotoninergiques était rarement faite (dans environ un cas sur cinq) par les médecins urgentistes en charge des patients. La survenue d’un syndrome sérotoninergique et de convulsions était plus fréquente dans le groupe de patients intoxiqués par IRS que chez les témoins appariés. Un allongement du QT a été noté chez un patient et aucune toxicité respiratoire n’a été décelée. Le recours à la ventilation mécanique était plus important du fait de troubles de la conscience, sans augmentation pour autant du nombre d’admission en réanimation en comparaison aux témoins. L’étude expérimentale nous a permis de montrer que les décès induits par le citalopram étaient toujours précédés de convulsions, et que la prévalence des convulsions étaient dose-dépendante, significativement plus fréquente pour les fortes doses de citalopram (80 et 120% de la MLD) comparativement aux autres groupes (60% de la MLD et témoins). De même, le citalopram induisait une baisse dose-dépendante de la sérotonine plaquettaire et une élévation dose-dépendante de la sérotonine plasmatique. L’incidence du syndrome sérotoninergique était, par contre, comparable. Le citalopram n’induisait ni hypoxémie, ni hypercapnie, ni hyperlactatémie ; mais il était responsable d’un allongement du temps inspiratoire et d’un « braking expiratoire » mimant un phénomène adaptatif à l’hypoxémie. Par ailleurs, le prétraitement par diazépam ou cyproheptadine des rats intoxiqués avec une dose létale de citalopram prévenait les convulsions et le décès. Conclusions : La toxicité des IRS et du citalopram en particulier, semble essentiellement neurologique, tant chez l’homme que chez l’animal. Le syndrome sérotoninergique et les convulsions devraient être rassemblés en marqueurs de la toxicité sérotoninergique. Il est nécessaire de sensibiliser les médecins urgentistes à cette toxicité, en utilisant les critères de Hunter, plus simples et probablement plus spécifique. La place des antidotes restent à définir, mais, selon notre modèle expérimental, ils pourraient être efficaces pour réduire cette toxicité spécifique. / Toxicity of the serotonin-reuptake inhibitors (SRI) including citalopram, the most selective one, is considered as relatively low. However SRI may be responsible for serotonin syndrome, seizures, electrocardiographic abnormalities, respiratory failure, and even death. Implication of SRI in deliberate drug poisonings has not been assessed by recent data in France. Morbidity of SRI-related poisonings as well as the most common resulting presentations in the emergency department (ED) remains poorly described. Moreover, mechanisms of SRI-attributed death remain unclear. Objectives: We conducted these clinical and experimental studies: 1-to better understand the epidemiology of drug poisonings in one ED in Paris area and analyze SRI involvement; 2- to investigate a possible over-morbidity related to SRI in multidrug poisonings and describe the most common SRI-related complications; 3- to understand mechanisms of death induced by elevated doses of citalopram and its possible prevention. Methods: We conducted an observational study during 4 years in an ED matching patients who ingested at least one IRS with patients who did not. We also conducted an experimental study in the Sprague-Dawley rat to determine the median lethal dose (MLD) of citalopram and investigate citalopram-related neurological, respiratory, and systemic toxicity as well as mechanisms of citalopram-induced death. Platelet and plasma serotonin were measured to ensure the serotoninergic mechanism. Results: SRI were involved in 16% of the drug poisonings admitted to the ED, ranking at the second place after the benzodiazepines. Attribution of the observed signs and symptoms to the serotonin toxicity was rarely performed by the emergency physicians in charge, in only one out of five cases. Onset of serotonin syndrome and seizures were more frequent in SRI-exposed patients than in their matched controls. QT prolongation was observed in one patient while no direct respiratory toxicity was reported. Mechanical ventilation was more frequently used in SRI-exposed patients due to impaired consciousness, despite no resulting increased admission rate to the intensive care unit in comparison to the controls. Based on our rat study, citalopram-induced death always occurred after seizures which were dose-dependent, with a greater prevalence at the two highest doses of citalopram (80 and 120% of the MLD) than in the other groups (60% of control and the MLD). Citalopram-induced decrease in platelet serotonin and increase in plasma serotonin were dose-dependent. However, incidence of serotonin syndrome appears similar in all the groups. Citalopram did not induce hypoxemia, hypercapnia or hyperlactacidemia, but resulted in a slight prolongation in the inspiratory time and an "expiratory braking" that could be attributed to an adaptive phenomenon to hypoxemia. Pretreatment with diazepam and cyproheptadine prevented rats treated with lethal-doses of citalopram from seizures and death. Conclusions: SRI and citalopram in particular are mainly responsible for neurological toxicity, both in humans and rats. Serotonin syndrome and seizures should be grouped as markers of serotonin toxicity. Emergency physicians should become more aware of this specific toxicity. Using the simpler and probably more specific Hunter criteria may be useful in the ED. The exact indications of antidotes remain to be defined, but our experimental model seems to support their effectiveness to prevent IRS-related specific serotonin toxicity.

Abstract Febrile seizures (FS) occur in 2-5% of children. Their pathogenesis is unknown. Elevated levels of prostaglandins (PG) have been found in cerebrospinal fluid after such seizures, and a third of all patients have recurrences. No safe ways of reducing the risk of recurrences have been found. The outcome has been shown in prospective studies to be good, by they have been linked to mesial temporal sclerosis (MTS) in patients with severe temporal lobe epilepsy (TLE). The aim was to analyze the records on the role of PGs in the pathogenesis of FS, to find risk factors for recurrences that are amenable to intervention and to evaluate the prevention of recurrences and the connection of FSs with MTS. We performed a systematic review of the effect of PGs and their synthetase inhibitors on seizures and a meta-analysis of the prevention of recurrences. The prophylactic effect of diazepam and acetaminophen on recurrences was evaluated in a placebo-controlled trial with 180 FS patients, and risk factors for recurrences were analysed from these data. To find MTS, MRI volumetry was performed after 12 years of follow-up on 64 cases chosen out of 329 unselected FS patients: twenty-four with a prolonged initial seizure, eight with a later unprovoked seizure and 32 age, sex and handedness-matched controls. PGD2, PGE1 and PGE2 had mainly anticonvulsive effects and PGF2alfa proconvulsive ones. NSAIDs had seizure-modulating effects in adult animals ranging from attenuation to provocation. Each degree of increase in fever doubled the recurrence risk, and each febrile episode increased it by 18%. The meta-analysis showed phenobarbital and valproate to prevent recurrences, but they cannot be recommended for FS as they have severe side-effects. The meta-analysis nullified the alleged effect of diazepam, and neither this nor acetaminophen prevented recurrences in a clinical trial. No MTS was found in any patient group. PGs may be involved in the pathogenesis of FS. No safe prophylaxis for recurrences is available, although the effect of antipyretics needs further evaluation. Measures to reduce feverish infections in order to prevent FS recurrences seem logical. MTS is uncommon even after prolonged FS.

As demand for food and farmland is increasing in Hanoi, the transition from an agricultural-based economy to an industrial one puts the livelihoods of urban farmers at risk. The urbanization displaces people and alter livelihoods of many urban poor in the peri-urban areas of Hanoi. This study uses the Sustainable Livelihood Approach in discussing the variety of chocks stakeholders associated with production, trading and consuming of vegetables, are exposed to. The findings provide a holistic perspective to the opportunities and constraints which urban agriculture is facing in modern day Hanoi. An outlining of urban agricultural production patterns according to the Von Thünen Model recognizing a slight alteration in which urban expansion hinders the production. Urban dwellers in peri-urban areas between a 5-15-kilometer radius from the city center are most vulnerable for land seizures and compensation rates are incused by corruption. Although there is potential for urban agriculture as demand for vegetables are high, the modernization of the country will continue to limit cultivation in the urban districts of Hanoi. Additionally, supermarkets with certified safe produced vegetables are currently in conflict with culturally embedded shopping practices. As public officials turn to the supermarketization to provide food safety, the rural-urban migration has shaped vegetable shopping differently.

No description available.

Epileptic seizures are characterised by an onset of abnormal brain activity that evolves in space and time, which ultimately returns to normal background activity. For different types of seizures, the abnormal activity can be vastly different both in duration, electrographic morphology and spatial extent. Mechanistic understanding of the different seizure dynamics (spatially, as well as temporally) is crucial for the advancement and improvement of clinical treatment. To gain a deeper mechanistic insight into different seizure dynamics, mathematical models of brain processes were developed in this thesis. These models are used to explain electrographic seizure dynamics in their temporal, as well as their spatio-temporal evolution. Our studies show that the temporal evolution of seizure dynamics can be understood in terms of prototypic waveforms, which in turn can be represented in terms of three neural population processes. Such a minimal framework lends itself to a detailed phase space analysis, which elucidates seizure waveforms and seizure transitions as topological properties of the phase space. Based on the phase space considerations we show how during spike-wave seizures, single-pulse stimuli can have more complex effects than previously thought. In terms of the spatio-temporal dynamics of seizures, mechanisms for focal seizure onset and propagation are investigated in a model cortical sheet of coupled, discretised columns. The coupling followed nearest-neighbour, as well as realistic mesoscopic cortical connectivities. Different possible causes (e.g. spatial heterogeneities) of seizure generation, as well as different seizure spreading patterns (via different networks) have been investigated. We conclude that focal seizure onset can be due to global (e.g. whole-brain level) causes, global conditions & local triggers, and local (e.g. cortical column level) causes. Clinically relevant predictions from this work include the suggestion of a specific stimulation protocol in spike-wave seizures that incorporates phase space information; and the suggestion of using microscopic cortical incisions to disrupt the integrity of abnormal cortical tissue in order to prevent focal seizure onset. In conclusion, multi-scale computational modelling of seizure dynamics is proposed as an important tool to link theoretical understanding, experimental results, and patient-specific clinical data.

A epilepsia compreende um grupo de alterações neurológicas frequentes em humanos e animais, caracterizada pela ocorrência periódica de crises convulsivas. A causa do processo pode ter várias origens sendo necessária a realização de exames complementares para o diagnóstico definitivo. A análise de biomarcadores, em especial as proteínas de fase aguda, como a proteína C-reativa (PCR), auxilia na identificação de doenças neurológicas inflamatórias e infecciosas, já que após serem produzidas pelo fígado conseguem atingir o tecido danificado e ter suas concentrações elevadas rapidamente na circulação. A concentração de PCR está diretamente relacionada à resposta de fase aguda, independentemente da origem ou natureza do estímulo, podendo ser um processo inflamatório, infeccioso ou até mesmo de origem neoplásica. Embora a PCR tenha sido estudada e monitorada em pacientes com as mais variadas doenças, até o momento não foi determinada a presença de PCR no soro e líquor de cães com epilepsia idiopática. O objetivo deste estudo foi avaliar as concentrações de PCR no líquor e soro de cães apresentando epilepsia idiopática e verificar se essa protéina pode ser utilizada como biomarcador para auxiliar no diagnóstico da doença. Para tanto foram compostos três grupos. O primeiro, denominado A, com 23 animais clinicamente normais; o segundo denomindo B, composto por 17 cães manifestando convulsão em até 24 horas anteriores ao momento da coleta de mateiral; e o terceiro denominado C, com 16 cães apresentando convulsões de 24 horas até 120 horas antecedendo o momento da coleta do líquor e do soro. Foram mensuradas as proteínas totais séricas e realizadas as eletroforeses, além da análise do líquor e tomografia computadorizada. Animais com alterações estruturais detectadas na tomografia foram excluidos do estudo. As concentrações de PCR séricas foram avaliadas por meio da técnica ELISA utilizando-se kit comercial Tridelta Development Ltd, espécie específico. Além desta avaliação, os grupos B e C foram alivados quanto à concentração de PCR no liquor. Os resultados foram analisados pelo teste de Kruskal Wallis, seguido pelo teste de Dunn, enquanto para eletroforese e análise de PCR no líquor utilizou-se teste T não pareado. Não houve diferença significante em relação à eletroforese de proteínas séricas nos três grupos, assim como não se observaram alterações na análise do líquor nos grupos B e C. As concentrações séricas de PCR em cães normais variaram níveis não detectáveis a 6,36 µg/mL, com média de 0,98 µg/mL. As concentrações séricas nos animais do grupo B variaram de 1,04 µg/mL a 5,03 µg/mL, com média 2,14 µg/mL, enquanto no grupo C as concentrações foram de níveis não detectáveis a 1,9 µg/mL com média 0,51 µg/mL. A análise estatística demonstrou diferença significante entre os grupos sendo a média do grupo B superior aos demais (p= 0,0002). As concentrações liquóricas de PCR foram muito baixas quando comparadas àquelas observadas em cães com afecções inflamatórias e infecciosas e não foram em sua maioria detectáveis no líquor quando o período entre a convulsão e a coleta foi superior ao período de 24 horas. Concluiu-se que as convulsões associadas à epilepsia idiopática promovem uma resposta de fase aguda caracterizada pelo aumento de PCR sérica e liquórica nas primeiras 24 horas e que essas concentrações decaem após esse período, podendo estar associadas à liberação de mediadores inflamatórios no SNC e às contrações musculares. Assim sendo, a PCR sérica pode ser utilizada como um biomarcador para diferenciar a epilepsia idiopática de outras causas de convulsão. A técnica ELISA para análise de PCR no líquor, pode se somar às outras análises liquóricas, necessitando ainda de validação. / Epilepsy is a group of neurological disorders of humans and animals characterized by recurrent seizures. Epilepsy can have a number of causes and some complementary tests can help with a precise diagnosis. Biomarkers analysis, in special acute protein phase such as C reactive protein (PCR) can help identify inflammatory and infection neurological disease. Acute phase proteins are produced by liver and reach damaged tissue increasing blood concentration. Today studies show that increases in the PCR blood concentration is related to acute inflammatory response independent of mint, whether it is inflammatory, neoplastic or infection. Although PCR has been studied in many diseases, in special neurological disorder followed or not by seizures, until now PCR has not been founded in blood or liquor of dogs with idiopathic epilepsy. The purpose of this study is to evaluate PCR concentration in blood and liquor of patients with idiopathic epilepsy and verify if the protein can be considered a biomarker to help its diagnose. The study has 3 groups. The first named control group A, with 23 healthy animals, the second named B with 17 dogs that have had seizures within 24h, and the third named C with 16 dog that have had seizures after 24 to 120 hours from blood or liquor collection. The investigation is based on analyzing total protein and electrophoretic protein profile, liquor analysis and tomography. Patients with structural brain damages detected by tomography were excluded from the study. In the control group PCR concentration were analyzed by ELISA method and kit Tridelta Development Ltd, species specific. In groups B and C were also procedure PCR analyses in liquor sample. The results were analyzed by the Kruskal Wallis test and the Dun test, while electrophorese and PCR of liquor where analyzed by the T test not parried. There was no significant difference in electrophorese in the three groups and there were not found alterations in the liquor analyzes of the groups B and C. PCR blood concentration in healthy dogs vary between not detectable values to 6,36mcg/ml, with an average of 0,98mcg/ml. Blood concentrations from animal of group B vary from 1,04 mcg/ml to 5,03, with and average of 2,14mcg/ml. Meanwhile in group C blood concentration values were from not detectable to 1,9 mcg/dl, with an average 0,50 mcg/ml. Statistic analyses show significant difference between groups. Group B average was higher (p=0,0002). PCR liquor concentration was lower to those found on dogs with inflammatory infection diseases and the majority were not detectable in the liquor when the sample has been collected after 24 hours from the seizures. It is able to conclude that seizures associated with idiopathic epilepsy promote an acute phase response characterized by an increase of blood and liquor PCR concentrations within 24 hours, and after this period PCR concentrations declined due to the liberation of inflammatory mediators by the CNS and muscle contractions. Therefore blood can be used as a biomarker to differentiate idiopathic epilepsy from other seizures causes. The ELISA technique for PCR liquor analysis still needs to be validated.

Epileptic seizure presents a formidable threat to the life of its sufferers, leaving them unconscious within seconds of its onset. Having a mortality rate that is at least twice that of the general population, it is a true cause for concern which has gained ample attention from various research communities. About 800 million people in the world will have at least one seizure experience in their lifespan. Injuries sustained during a seizure crisis are one of the leading causes of death in epilepsy. These can be prevented by an early detection of seizure accompanied by a timely intervention mechanism. The research presented in this dissertation explores Kriging methods to exploit spatial correlations of electroencephalogram (EEG) Signals from the brain, for fast and accurate seizure detection in the Internet of Medical Things (IoMT) using edge computing paradigms, by modeling the brain as a three-dimensional spatial object, similar to a geographical panorama. This dissertation proposes basic, hierarchical and distributed Kriging models, with a deep neural network (DNN) wrapper in some instances. Experimental results from the models are highly promising for real-time seizure detection, with excellent performance in seizure detection latency and training time, as well as accuracy, sensitivity and specificity which compare well with other notable seizure detection research projects.