Made available in DSpace on 2014-12-17T14:13:34Z (GMT). No. of bitstreams: 1 AnaMCS.pdf: 1887892 bytes, checksum: 05f9c6bffc3d95915a924712e4e7b5c7 (MD5) Previous issue date: 2007-12-19 / The purpose of this paper was to study patients with congenital and acquired hemiparesis, their clinical aspects, the presence or not of epileptic seizures, and electroencephalographic (EEG) and Magnetic Resonance Imaging (MRI) findings. We analyzed the interrelation between etiology, the presence and seriousness of epileptic seizures (ES) and the possible causes of refractoriness. This is a prospective study using the clinical diagnosis of a child neurologist, who attested to the presence of unilateral motor lesions. We compared the electroencephalographic findings in patients with or without epileptic seizures, and investigated if among the former, these seizures were controlled or not, their likely etiology and risks of refractoriness. EEG background activity on the lesion and contralateral side was analyzed, in addition to the presence of concomitant epileptiform activity. Encephalon MRIs of all the patients were studied to correlate etiology and the control or not of epileptic seizures. The disorganization of bilateral EEG activity correlated with the difficult-to-control epileptic seizures. Suitably organized background activity contralateral to the lesion is a good prognosis in relation to epileptic seizures. Focal epileptogenic activity does not necessarily predispose to epileptic manifestation. The MRI is more important in determining etiology than in prognosing epileptic seizures. This study used a multidisciplinary approach involving child neurologists, a physical therapist and a neuroradiologist. This meets the criteria of multidisciplinarity of the Postgraduate Program in Health Sciences / O objetivo do nosso trabalho foi estudar pacientes com hemiparesia, cong?nitas e adquiridas, seus aspectos cl?nicos e epidemiol?gicos, a presen?a ou n?o de crises epil?pticas e os achados eletrencefalogr?ficos e de neuroimagem por Resson?ncia Nuclear Magn?tica. Tentando relacionar a etiologia ? presen?a e gravidade de crises epil?pticas e as poss?veis causas de refratariedade. Trata-se de um estudo prospectivo a partir do diagn?stico cl?nico por um neurologista infantil que atestou a presen?a de les?o motora unilateral. Compararam-se os achados eletrencefalogr?ficos em pacientes sem ou com crises epil?pticas, e dentre esses ?ltimos, se h? ou n?o controle das crises, sua prov?vel etiologia e riscos de refratariedade. Analisou-se a atividade de base do EEG do lado da les?o e contra lateral a esta, al?m da presen?a de atividade epileptiforme concomitante. Estudaram-se as RNM do enc?falo realizadas em todos os pacientes, tentando relacionar a etiologia e controle ou n?o de crises epil?pticas. A desorganiza??o da atividade de base bilateral no EEG correlacionou-se com crises epil?pticas de dif?cil controle. A atividade de base adequadamente organizada contra lateral a les?o ? de bom prognostico em rela??o ?s crises epil?pticas. A atividade epileptog?nica focal n?o necessariamente predisp?e a manifesta??o epil?ptica. A RNM ? mais importante na determina??o da etiologia do que no progn?stico das crises epil?pticas. A realiza??o deste estudo foi concretizada pela abordagem multidisciplinar, envolvendo neurologistas infantis, fisioterapeuta e neurorradiologista. Este aspecto preenche os requisitos de multidisciplinaridade do programa de p?s-gradua??o em Ci?ncias da Sa?de

Les Encéphalopathies Épileptiques Précoces sont des pathologies rares et sévères caractérisées par des crises fréquentes commençant dans les trois premiers mois de vie accompagnées d’un EEG intercritique altéré et un pronostic très défavorable. Au cours de la caractérisation génétique d’une cohorte de 402 patients, nous avons mis en évidence une délétion de 19,9 kb localisée en Xp11.23 chez un garçon et 34 mutations de novo du gène KCNQ2. La première partie de mon projet a consisté en l’étude de la pathogénicité de la délétion Xp11.23, qui implique trois gènes dont WDR45. Les mutations de WRD45 ont été décrites dans une dégénérescence neuronale avec accumulation de fer et presque exclusivement chez des patients de sexe féminin. Le diagnostic initial, chez ce patient, montre une IRM normale avec un phénotype d'EEP et l'accumulation de fer a été détectée à partir de 5 ans. Ce travail m’a permis de décrire le premier patient atteint d’EEP porteur d’une délétion de WDR45. La deuxième partie de mon projet a concerné le gène KCNQ2. Nos résultats ont montré que les mutations sont impliquées dans deux mécanismes physiopathologiques, une délocalisation subcellulaire et un gain de fonction. Ces résultats ouvrent de nouvelles perspectives en terme de compréhension de la pathologie et de thérapies qui peuvent être proposées. Une dernière partie de ce projet a consisté en l’élaboration de nouveaux modèles in vitro, j’ai mis au point des lignées stables exprimant KCNQ2 qui permettront le criblage de molécules thérapeutiques à haut-débit, ainsi que des progéniteurs neuronaux différenciés à partir de cellules iPS issues de la reprogrammation de fibroblastes de patients. / Early onset epileptic encephalopathies are rare and severe disorders, characterized by frequent motor seizures occurring before three months of age associated with an altered interictal EEG pattern. The prognosis is poor. During the course of the genetic characterization of a cohort of 402 EOEE patients, we identified a de novo deletion located at Xp11.23 in a male patient and 34 KCNQ2 de novo mutations. The first part of my project consisted in the study of the pathogenicity of the Xp11.23 deletion that encompasses three genes including WDR45. Mutations in the WDR45 gene been have recently identified in patients suffering from neurodegeneration with brain iron accumulation. WDR45 mutations have been almost exclusively found in females. Our patient with the Xp11.23 deletion presented a normal MRI and the EOEE phenotype was predominant. Iron accumulation began only at 5 years. My work reveals that deletions of WDR45 are viable in males and can be diagnosed as EOEE. The second part of my project was aimed at the functional study of two KCNQ2 gene mutations. During this work, my results showed that those mutations were involved in new pathological mechanisms, namely a mislocalization or gain of function. Those results provide new perspectives in term of disease knowledge and therapy. The last part of my project consisted in the development of two new in vitro models for the study of KCNQ2 mutations: stable cell lines expressing the Kv7.2 channel for high-throughput screening of drugs and the production of neurons from induced pluripotent stem cells arising from reprogrammed patient fibroblasts.

Les récepteurs nucléaires des xénobiotiques et les enzymes métaboliques P450 (CYP) constituent les principaux éléments contrôlant la biotransformation des médicaments, ainsi que le maintien de des barrières physiologiques au niveau périphérique, plus particulièrement, dans le foie et dans l’intestin. Plusieurs études ont mis en évidence la présence des CYP ainsi que les récepteurs nucléaires contrôlant leur expression, tels que le Constitutive Androstane Receptor et le Pregnane Xenobiotic Receptor (CAR et PXR). Des résultats précédant indiquent la surexpression des CYP2E1 et CYP3A4 dans des tissus et des cellules isolées du cerveau de patients épileptiques pharmacorésistants. L’importance de ces résultats réside dans le rôle du CYP2E1 et CYP3A4 dans la biotransformation de plusieurs médicaments antiépileptiques (MAE) suggérant ainsi un mécanisme de pharmacorésistance aux médicaments. Contrairement aux autres récepteurs nucléaires, les fonctions physiologiques des récepteurs nucléaires des xénobiotiques au niveau vasculaire sont mal connues. Nos résultats montrent des changements spatio-temporaux de l’expression des CYP2E1 et CYP3A4 dans le cerveau après une crise aigüe et pendant le processus d’épileptogenèse chez la souris. Une exposition in vivo et in vitro au MAE Phénytoïne induit une augmentation du niveau du CYP2E1. Le Phénobarbital et la Carbamazépine n’ont pas eu d’effet. Les souris privées des récepteurs nucléaires des xénobiotiques (PXR KO et CAR KO) ne présentent pas de changement de niveau basal des CYP dans le cerveau. Cependant, les souris CAR KO présentent des dysfonctionnements neuronaux (altération de la mémoire, comportement anxieux et une diminution de l’intensité des rythmes EEG entre 3.5-7 Hz) et des modifications caractérisées par une augmentation de perméabilité vasculaire et une dispersion des neurones hippocampiques. L’ensemble des résultats indique une régulation dynamique des CYP dans le cerveau avec une extension de l’impact des récepteurs des xénobiotiques à des fonctions neurovasculaires. / Xenobiotic nuclear receptors and P450 metabolic enzymes (CYP) are pivotal controllers of drug biotransformation and barrier functions in peripheral organs, including the intestine and the liver. Accumulating evidence suggested that, in human, central nervous system cells express significant levels of P450 enzymes and their upstream regulators e.g. Constitutive Androstane and Pregnane Xenobiotic Receptors (CAR, PXR). We previously showed the increased and ectopic CYP2E1 and CYP3A4 expression in brain specimens or cells obtained from drug resistant epileptic patient. These results are significant as CYP2E1 and CYP3A4 are responsible for the metabolism of several antiepileptic drugs (AED), therefore, suggesting a possible new mechanism of drug resistance. However, the exact determinants of CYP expression in the epileptic brain remain unknown. In addition, the exact role of nuclear xenobiotic receptor in the brain is understudied. The latter represents a significant knowledge gap as nuclear receptors other than the xenobiotic ones were shown to contribute to physiological neurovascular functions. Our results show spatio-temporal changes of CYP2E1 and CYP3A4 brain expression occuring after status epilepticus and during epileptogenesis in mice. Exposure to the AED phenytoin, phenobarbital, but not carbamazepine, increased brain CYP2E1 expression in vivo and in vitro. Lack of the specific xenobiotic receptors CAR and PXR did not impact basal CYP brain levels. However, we found an unexpected contribution of CAR to neuronal dysfunctions (memory impairment, anxiety like-behavior and decrease 3.5-7 Hz EEG waves) and neurovascular development, as indicated by increase vascular permeability and hippocampal neuronal dispersion. These results depict a dynamic regulation of P450 enzymes in the brain also expanding the impact of xenobiotic receptors to previously unexplored neurovascular functions.

Die Bedeutung des Immunsystems in der Pathophysiologie von bipolaren Erkrankungen und Epilepsie ist ein aktueller Gegenstand der neuropsychoimmunologischen Forschung. Eine erhöhte Produktion von Zytokinen aufgrund von oxidativem Stress wurde dabei wiederholt als für die Pathophysiologie von Epilepsie und Bipolarer Störung relevant angesehen. In Hinblick auf Veränderungen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6 und Tumornekrosefaktor-alpha (TNF-α) wurden z. T. überlappende Ergebnisse bei beiden Erkrankungen beschrieben. Inwiefern diese Zytokine durch Stimmungsstabilisierer und Antiepileptika beeinflusst werden, wurde bisher jedoch nicht systematisch untersucht. In dieser Studie wurden systematisch in-vitro die Konzentrationen von IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 und TNF-α im stimulierten Blut 14 gesunder Frauen mittels Vollblutverfahren (whole blood assay) nach Zugabe von Stimmungsstabilisierern bzw. Antiepileptika gemessen. Es wurden dabei die Stimmungsstabilisierer bzw. Antiepileptika Primidon, Carbamazepin, Levetiracetam, Lamotrigin, Valproat, Oxcarbazepin, Topiramat, Phenobarbital und Lithium untersucht. Die Ergebnisse lassen darauf schließen, dass der Mechanismus von erwünschter und unerwünschter anderer Wirkung von Stimmungsstabilisierern und Antiepileptika mit der Regulation von IL-1ß, IL-2, IL-22 und TNF-α in Zusammenhang stehen könnte. Getrennt nach den im Vollblutverfahren verwendeten Stimulanzien – Toxic-Shock-Syndrome-Toxin-1 (TSST-1) vs. monoklonaler Antikörper gegen das CD3-Oberflächenantigen (OKT3) in Kombination mit dem 5C3-Antikörper gegen CD40 (OKT3/CD40) – wurden die Ergebnisse in zwei unterschiedlichen Publikationen berichtet, die dieser Promotion zugrunde liegen.

Children with focal intractable epilepsy caused by MCD, FCD and TSC are in a high risk of development of cognitive delay, as a result of both drug resistant epilepsy and genetically determined abnormal structure of the neuronal networks. Epilepsy surgery represents an established and safe treatment method of focal drug resistant epilepsy, and increases the chances for these patients to be rid of epileptic seizures, anti-epileptic medication and cognitive comorbidities. Current data on genetic background of focal MCD and FCD and their comorbidities provide space to expand the diagnostic process in epilepsy surgery candidates. However, available information on genetic causes of MCD and FCD do not allow us to infer prognostic estimates on chances of seizure freedom and optimal cognitive development. Future studies should elucidate these uncertainties.

Tidigare forskning visar att ambulanssjuksköterskor upplever bristfällig utbildningsgrund samt känslor av bristande självförtroende och osäkerhet kopplat till vårdsituationer med den vuxna patienten med pågående krampanfall. Den forskning som finns etablerad omkring ambulanssjuksköterskors upplevelser av att möta den vuxna patienten med pågående kramp är dock begränsad. Ambulanssjuksköterskan har i sin yrkesutövning en förväntan på sig att inneha en handlingsberedskap för alla typer av patientärenden, så även för den vuxna patienten med pågående krampanfall. Krampanfall med tonisk-klonisk karaktär innebär ett komplext vårdmöte där ambulanssjuksköterskan måste ta ställning till multipla faktorer, både rörande en kritisk somatik samt patientens omvårdnadsmässiga behov. Studiens syfte är att beskriva ambulanssjuksköterskors upplevelse av att möta vuxna patienter med pågående epileptiskt anfall av tonisk-klonisk karaktär i prehospital miljö. Studien har genomförts som en kvalitativ, semistrukturerad intervjustudie med induktiv ansats. Genomförda intervjuer har analyserats utifrån en kvalitativ innehållsanalys och resulterade slutligen i huvudkategorin Ett vårdande som balanserar mellan trygghet och oförutsägbarhet, med efterföljande kategorier Mångbottnad upplevelse, Vårdrelationen och Prehospitalt vårdande. Resultatet visar på attambulanssjuksköterskor bär på en bred upplevelsegrund när det kommer till vårdmötet med denkrampande patienten, där känslor av osäkerhet och stress är vanlig förekommande. Ambulanssjuksköterskorna upplever även vårdmötet som utmanande i förhållande till faktorer som vårdmiljö, patientomhändertagande samt mötet med anhöriga. Ambulanssjuksköterskorna upplever att det i första hand är yrkeserfarenhet som utgör en trygghetsskapande grund i patientmötet. För att skapa förbättrade grundförutsättningar för vårdandet samt förstärka upplevelsen av trygghet för ambulanssjuksköterskor, bör ämnet lyftas tydligare inom utbildning och arbetsplatsrelaterad fortbildning. / Previous research shows that ambulance nurses experience a deficient educational basis as well as feelings of lack of self-confidence and uncertainty linked to care situations with the adult patient with ongoing seizures. However, the research that has been established about ambulance nurses' experiences of meeting the adult patient with ongoing convulsions is limited. In her professional practice, the ambulance nurse is expected to be ready to act for all types of patient matters, including for the adult patient with an ongoing seizure. Seizures with a tonic-clonic character involve a complex care encounter where the ambulance nurse must take a position on multiple factors, both concerning a critical somatic condition and the patient's nursing needs. The purpose of the study is to describe ambulance nurses' experience of meeting adult patients with ongoing epileptic seizures of tonic-clonic character in a prehospital environment. The study has been conducted as a qualitative, semi-structured interview study with an inductive approach. Conducted interviews have been analyzed based on a qualitative content analysis and finally resulted in the main category Care that balances between safety and unpredictability, with subsequent categories Multi-rooted experience, Care relationship and Pre-hospital care. The results show that ambulance nurses have a broad base of experience when it comes to the care meeting with the convulsing patient, where feelings of uncertainty and stress are common occurrences. The ambulance nurses also experience the care meeting as challenging in relation to factors such as the care environment, patient care and the meeting with relatives. The ambulance nurses feel that it is primarily professional experience that constitutes a security-creating basis in the patient encounter. In order to create improved basic conditions for care and strengthen the experience of security for ambulance nurses, the topic should be highlighted more clearly in education and workplace related continuing education.

Les encéphalopathies épileptogènes sont des maladies graves de l’enfance associant une épilepsie, souvent réfractaire, et un retard de développement. Les mécanismes sous-tendant ces maladies sont peu connus. Cependant, nous postulons que ces épilepsies puissent être causées par une dysfonction du réseau inhibiteur. En effet, des défauts de migration ou de maturation des interneurones GABAergiques (INs) corticaux induisent l’épilepsie, tant chez l’humain que chez la souris. Dans le but d’étudier les causes génétiques des encéphalopathies épileptogènes sporadiques inexpliquées, le laboratoire de la Dre Rossignol a procédé au séquençage d’exome entier d’une cohorte d’enfants atteints. Cela a permis d’identifier, chez un patient, une nouvelle mutation de novo, possiblement pathogène, dans le gène MYO9b. MYO9b est impliqué dans la migration de cellules immunitaires et cancéreuses et est exprimée durant le développement cérébral. Nous émettons l’hypothèse voulant que MYO9b puisse être importante pour la migration des INs corticaux. Les résultats présentés dans ce mémoire démontrent que Myo9b est exprimé dès le stade embryonnaire par les progéniteurs des INs corticaux et que son expression se restreint aux INs dans le cortex mature. De plus, nous démontrons que la répression ex vivo de Myo9b sélectivement dans les INs au sein de tranches corticales organotypiques embryonnaires mène à des défauts morphologiques majeurs de ces cellules en migration. En effet, ces cellules présentent une morphologie multipolaire et des neurites rostraux plus longs et plus complexes. Ces changements morphologiques pourraient avoir un impact majeur sur la migration des INs et ainsi perturber le développement des réseaux inhibiteurs. / Epileptic encephalopathies are early-onset diseases characterized by refractory epilepsy with developmental delay. To identify the underlying genetic cause of these disorders, Dr Rossignol’s laboratory has performed whole-exome sequencing in children with sporadic epileptic encephalopathies. They have identified a novel de novo mutation in the MYO9B gene in one patient. Myo9b is known to regulate cell migration in the immune system and in cancer cells. It is expressed in the developing rodent brain, but its roles during brain development are largely unknown. Recent evidence suggests that epilepsy can be caused by an imbalance between inhibition and excitation in cortical circuits. Indeed, defects in the development or the functions of cortical GABAergic interneurons (INs) have been associated with epilepsy in human and in mouse models. Therefore, we postulated that Myo9b might play a role in the development of INs. In this thesis, I show that Myo9b is expressed in INs from early embryonic ages to post-natal ages. Furthermore, I demonstrate that the ex vivo downregulation of Myo9b in INs in cortical embryonic organotypic cultures causes morphological defects in migrating INs, including aberrant polarization of these cells. These morphological changes might result in aberrant IN migration, which would be expected to perturb the cortical inhibitory-excitatory ratio.

Les épilepsies bénignes partielles idiopathiques de l'enfant sont associées à un pronostic favorable, car les crises sont rares et disparaissent à l'adolescence. La nature bénigne de ces syndromes est remise en question en raison de difficultés d'apprentissage et de déficits cognitifs subtils, fréquemment rapportés dans cette population. Nous étudions l’incidence des décharges épileptiques inter-critiques sur la cognition, et observons leurs influences sur l’organisation cérébrale et les fonctions cognitives. Nous proposons des épreuves informatisées, à des patients avec des pointes centro-temporales (EPCT) principalement localisées à l'un des deux hémisphères et occipitales de type Panayiotopoulos (SP), afin d'évaluer des compétences verbales, visuo-spatiales, visuo-attentionnelles, ainsi que trois processus d’imagerie mentale visuelle jamais étudiés dans ces syndromes. Les données comportementales renforcent l’idée d’une spécificité des perturbations selon la latéralisation hémisphérique des pointes inter-critiques et confirment leur incidence sur l’organisation de l’asymétrie hémisphérique fonctionnelle associée aux fonctions étudiées. Par ailleurs, nous montrons que le SP a une incidence particulièrement négative sur les processus d'imagerie mentale visuelle, compétences centrales pour la réussite scolaire de l’enfant et l’enrichissement de son imaginaire. Nos résultats sont en adéquation avec la remise en question actuelle de la nature bénigne de ces épilepsies sur le plan cognitif. Comparer les déficits et l’asymétrie hémisphérique fonctionnelle selon la localisation principale des pointes procure de nouveaux arguments pour un impact spécifique des manifestations inter-critiques, car seuls les mécanismes cognitifs sous-tendus par les régions concernées sont perturbés. Cela apporte des éléments d’explications sur les difficultés d'apprentissages signalés chez ces enfants, et incite à proposer des aménagements pédagogiques. / Benign idiopathic partial epilepsies of children are associated with a favorable prognosis because of rare seizure and usually recovery during adolescence. The benign nature of these syndromes is questioned because of learning difficulties and subtle cognitive deficits, frequently reported in this population. We study the incidence of the epileptic discharges on the cognition, and observe their influences on brain organization and cognitive functions. We propose computerized tests to patients with centrotemporal spikes (BECT) mainly localized in one of both hemispheres and occipital discharges, Panayiotopoulos syndrome (PS), to estimate verbal, visuo-spatial and visuo-attentional skills, as well as three visual imagery processes still never studied in these syndromes. Behavioural data strengthen the idea of a specific disturbances according to the hemispheric lateralization of the discharges and confirm their incidence on the organization of the functional hemispheric asymmetry associated with the studied functions. Furthermore, we show that PS has a particularly negative impact on the visual imagery process, important skills in the child's academic success and enrichment of his imagination. Our results are consistent with the current questioning of the benign nature of epilepsy on the cognitive level. Compare the deficits and the functional hemispheric asymmetry according to the main localization of discharges gets new arguments for a specific impact of the epileptiform activity, because only the cognitive mechanisms underlain by the concerned regions are disrupted. This provides evidence to explain the learning difficulties identified in these children, and encourages them to provide educational facilities.

Apresentamos dados e argumentos que indicam que: a) as crises epilépticas apresentadas por Trinomys yonenagae em campo e em cativeiro são espontâneas e idiopáticas; e b) elas podem ser decorrentes de processos evolutivos. A epilepsia nesta espécie foi caracterizada em cativeiro a partir de um cadastro iniciado há 16 anos, formado por progenitores e descendentes de seis colônias de T. yonenagae, coletados na Caatinga de Ibiraba (BA), e adultos (129,90 ± 5,92g) e filhotes nascidos em cativeiro num total de 295 indivíduos. A prevalência e a incidência em indivíduos epilépticos (EE) foram estimadas e as crises epilépticas foram analisadas por meio das manifestações comportamentais, baseando-se na escala de Racine. Aspectos da procriação (n=11), a locomoção, a ansiedade (testes de arena, n= 35) e índices fisiológicos (balanço hídrico-alimentar, n=6), importantes ao fitness, foram mensurados. Somente duas colônias apresentaram EE representando 9% e 28% dos nascimentos. Do total de indivíduos (165 e 130) 9,8% são EE (n=29; 14 e 15), sendo que as representam 52% e os 48%. A prevalência é de 20 a 30% e a incidência variou de 2 a 10 casos/ano, nos últimos cinco anos. As crises são observadas somente em adultos (n=24) a menor latência é de 13m e a frequência é variável (1 a 24 em seis anos). A maioria iniciou-se por congelamento e 50% atingiram o estágio 5 da escala de Racine. Em todos os casais, de 5 a 50% dos filhotes são EE e ocorreu estro pós-parto, como esperado para a espécie. Os filhotes são saudáveis e tanto a média de filhotes por ninhada (1,9±0,3), como a média do número de ninhadas por casal (6,5±5,0) é igual à de casais não epilépticos (NE). O teste de arena indica que descendentes de EE (DE) e as EE são menos ansiosas que as NE. Não há diferença entre os grupos dos índices fisiológicos estimados. A diferença no número de EE nas colônias, a alta prevalência e % de filhotes EE, e a diferença de comportamento das fêmeas DE indicam a base genética desta epilepsia. Neste contexto, consideramos que em Trinomys yonenagae, a epilepsia límbica não compromete o fitness, o que abre possibilidades de ser decorrente de processos evolutivos envolvendo o escalonamento de respostas de anti-predação / We present data and discuss the possibility that: a) the seizures presented by Trinomys yonenagae in the wild and in captivity are spontaneous and idiopathic, and b) they may be due to evolutionary processes. Epilepsy was characterized in this species in captivity from a survey started 16 years ago, made up of parents and descendants from six colonies of T. yonenagae collected in the Caatinga of Ibiraba (BA), and adults (129.90 ± 5.92 g) and pups born in captivity in a total of 295 individuals. The prevalence and incidence in individuals with epilepsy (EE) were estimated and seizures were analyzed by behavioral manifestations, based on Racine´s scale. Locomotion and anxiety indexes (open-field test, n = 35), as well as aspects of breeding (n = 11) and physiological indicators (balance food and water, n = 6), important to fitness were measured. Only two colonies showed EE, representing 9% and 28% of births. Approximately 10% of total individuals (165 and 130 ) are EE (n = 29, 14 and 15 ), and the represent 52 and 48%. In the last five years prevalence is 20-30%, and incidence ranged from 2 to 10 cases/ year. Seizures are only observed in adults (n = 24), the lowest latency is 13 months and the frequency is variable (1 to 24 in six years). The first stage is freezing and 50% reached stage 5 of Racine´s scale. In all couples, 5-50% of puppies are EE and occurred postpartum estrus, as expected for the species. The puppies are healthy and both the average offspring per litter (1.9 ± 0.3), as well as the average number of litters per couple (6.5 ± 5.0) is equal to values presented by non-epileptic couples (NE). The open-field test indicates that descendants of EE (DE) and EE are less anxious than NE. There is no difference between EE and NE regarding food and water intake. The difference in the number of EE in the colonies, the high percentage of EE pups, and the difference in the behavior of DE indicate the genetic basis of this epilepsy. In this context, we consider that in Trinomys yonenagae the limbic epilepsy seems to not compromise the fitness, which opens possibilities to be the result of evolutionary processes involving the escalation of antipredator responses

Disease- and drug-related bone disorders are rapidly increasing in the population. The drugs which are used for the treatment of neurodegenerative diseases and metabolic derangements, may have negative or positive effects on bone tissues. In the first study, the possible side-effects of Carbamazepine and epileptic seizures on bone structure and composition were investigated by FTIR and synchrotron-FTIR microspectroscopy, AFM and micro- and nano-hardness analysis. The effects on the blood parameters, bone turnover and vitamin D metabolism were also investigated by ELISA and western blot analysis. The current study provides the first report on differentiation of the effects of both epileptic seizures and AED therapy on bones. Besides Carbamazepine treatment, seizures also caused a decrease in the strength of bone. The biochemical data showed that both the epileptic and drug-treated groups decreased vitamin D levels by increasing the vitamin D catabolism enzyme / 25-hydroxyvitamin D-24-hydroxylase. In the second study, the possible pleiotropic (positive) effects of cholesterol lowering drug / Simvastatin on bones were investigated by ATR-FTIR spectroscopy. The current study provides the first report on dose-dependent effects of simvastatin on protein structure and lipid conformation of bones. ATR-FTIR studies showed that although both high and low dose simvastatin strengthen bones, low dose simvastatin treatment is much more effective in increasing bone strength. Neural network analysis revealed an increased antiparallel and aggregated beta sheet and random coil in the protein secondary structure of high dose group implying a protein denaturation. Moreover, high dose may induce lipid peroxidation which limit the pleiotropic effects of high dose treatment on bones. This study clearly demonstrated that using low dose simvastatin is safer and more effective for bone health than high dose simvastatin treatment.