There is no known cure for the family of diseases known as Transmissible Spongiform Encephalopathies. These include the infamous Mad Cow disease-technically known as Bovine Spongiform Encephalopathy (BSE)--as well as its human form, variant Creutzfeldt-Jakob disease. Although BSE was initially diagnosed in Britain in 1986, the first U.S. regulation to prevent BSE was not enacted until three years later. This delayed reaction proved to be a trend amongst the regulatory agencies responsible for keeping the U.S. food supply safe and BSE-free. The focus of this study is to delineate the degree of U.S. government liability in the event of a BSE outbreak. This study takes into account the various aspects of administrative law as it relates to liability, along with the numerous medical and scientific documents from domestic as well as international authorities, to determine governmental liability. There is sufficient evidence to suggest that the U.S. regulatory agencies concerned with food safety have created legislation consistently favoring industry concerns over those of public health. The legal system of a truly civilized society should be derived from ethical principles, which are then applied to institutions like the economy. When the process is reversed, when laws are based on industrial or economic concerns, ethics becomes an after-thought. This thesis sheds light on the government's handling of the threat of BSE: its shortcomings, competence, failures and successes. - ---

Des variants récessifs touchant le gène PIGB, encodant une enzyme impliquée dans la biosynthèse des ancres GPI, ont récemment été décrits chez des patients présentant une déficience héritée des ancres GPI ainsi qu’une encéphalopathie épileptogène (EE), une forme d’épilepsie infantile sévère associée à des atteintes cognitives. Chez l’humain, plus de 150 protéines, dont certaines sont critiques pour la fonction neuronale, sont localisées à la membrane cellulaire grâce aux ancres GPI. Des données préliminaires du laboratoire Rossignol démontrent que la délétion embryonnaire du gène Pigb dans les interneurones GABAergiques (IN) dérivés de l’éminence ganglionnaire médiale (MGE) est suffisante pour induire des crises d’épilepsie spontanées et des déficits cognitifs chez la souris, suggérant un rôle critique de PIGB dans le développement de l’inhibition corticale. Toutefois, les mécanismes cellulaires et moléculaires sous-tendant les phénotypes cliniques associés aux délétions du gène PIGB sont inconnus. Compte tenu du rôle central joué par les molécules de guidage, dont certaines sont des protéines à ancrage GPI, lors de la migration des IN vers la plaque corticale, nous postulons que la perte sélective des ancres GPI, résultant d’une délétion conditionnelle de Pigb dans les IN, altère leur dynamique de migration, ce qui a pour conséquence de réduire leur nombre dans le cortex postnatal, menant à une désinhibition corticale et au développement de l’épilepsie. L’imagerie en temps réel d’explants cellulaires de MGE a révélé que la perte de fonction du gène Pigb dans les IN dérivés du MGE entraine un défaut de la migration tangentielle et des anomalies morphologiques se traduisant par une réduction de la densité des IN dans le cortex postnatal. Nous avons également démontré que la signalisation motogène EphA4-éphrineA2 est altérée dans les IN déficients en ancres GPI, contribuant au délai de migration observé. En somme, nos travaux ont permis de préciser les mécanismes physiopathologiques sous-tendant les EE associées à des variants pathogéniques du gène PIGB et d’approfondir notre compréhension du rôle des ancres GPI durant le neurodéveloppement et plus précisément, durant la migration des IN. / Recessive variants in the PIGB gene, encoding an enzyme involved in the biosynthesis pathway of GPI anchors, were recently described in children with an inherited GPI anchor defect and epileptic encephalopathy (EE), a neurodevelopmental disorder characterized by early-onset epilepsy with cognitive impairment. GPI anchors are critical for the membrane attachment of at least 150 human proteins, some of which are important for proper neuronal function. Preliminary data from the Rossignol group show that the embryonic deletion of Pigb in GABAergic interneurons (INs) emanating from the medial ganglionic eminence (MGE) causes spontaneous seizures and cognitive deficits in mice, suggesting a critical role of PIGB in the establishment of cortical inhibition. However, the cellular and molecular mechanisms leading to epilepsy remain unknown. Given the central role of guidance molecules, some of which are GPI-anchored proteins, during neuronal migration, we postulate that loss of GPI anchors following the conditional deletion of Pigb in MGE-derived INs disrupts chemotactic guidance and IN migration dynamics, leading to cortical disinhibition and epilepsy post-natally. Time-lapse live imaging of MGE explants revealed that the targeted deletion of Pigb impairs the tangential migration as well as the morphological development of MGE-derived INs, resulting in reduced IN densities in the postnatal cortex. We showed that the kinetic deficits are partly due to a loss of EphA4-ephrinA2 motogenic signaling in PigbcKO INs. In summary, our work helps clarify the physiopathology underlying PIGB associated-EE and deepens our understanding of the roles of GPI-anchor-related pathways in neurodevelopment and more specifically, in the migration of cortical INs.

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of- function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

La documentation scientifique fait état de la présence, chez l’adulte, de cellules souches et progénitrices neurales (CSPN) endogènes dans les zones sous-ventriculaire et sous-granulaire du cerveau ainsi que dans le gyrus denté de l’hippocampe. De plus, un postulat selon lequel il serait également possible de retrouver ce type de cellules dans la moelle épinière et le néocortex des mammifères adultes a été énoncé. L’encéphalopathie de Wernicke, un trouble neurologique grave toutefois réversible qui entraîne un dysfonctionnement, voire une défaillance du cerveau, est causée principalement par une carence importante en thiamine (CT). Des observations récentes laissent envisager que les facteurs en cause dans la prolifération et la différenciation des CSPN pourraient également jouer un rôle important lors d’un épisode de CT. L’hypothèse, selon laquelle l’identification de nouveaux métabolites entrant dans le mécanisme ou la séquence de réactions se soldant en une CT pourraient en faciliter la compréhension, a été émise au moyen d'une démarche en cours permettant d’établir le profil des modifications métaboliques qui surviennent en de telles situations. Cette approche a été utilisée pour constater les changements métaboliques survenus au niveau du foyer cérébral dans un modèle de rats déficients en thiamine (rats DT), particulièrement au niveau du thalamus et du colliculus inférieur (CI). La greffe de CSPN a quant à elle été envisagée afin d’apporter de nouvelles informations sur la participation des CSPN lors d’un épisode de CT et de déterminer les bénéfices thérapeutiques potentiels offerts par cette intervention. Les sujets de l’étude étaient répartis en quatre groupes expérimentaux : un premier groupe constitué de rats dont la CT était induite par la pyrithiamine (rats DTiP), un deuxième groupe constitué de rats-contrôles nourris ensemble (« pair-fed control rats » ou rats PFC) ainsi que deux groupes de rats ayant subi une greffe de CSPN, soit un groupe de rats DTiP greffés et un dernier groupe constitué de rats-contrôles (rats PFC) greffés. Les échantillons de foyers cérébraux (thalamus et CI) des quatre groupes de rats ont été prélevés et soumis à des analyses métabolomiques non ciblées ainsi qu’à une analyse visuelle par microscopie à balayage électronique (SEM). Une variété de métabolites-clés a été observée chez les groupes de rats déficients en thiamine (rats DTiP) en plus de plusieurs métabolites dont la documentation ne faisait pas mention. On a notamment constaté la présence d’acides biliaires, d’acide cynurénique et d’acide 1,9— diméthylurique dans le thalamus, alors que la présence de taurine et de carnosine a été observée dans le colliculus inférieur. L’étude a de plus démontré une possible implication des CSPN endogènes dans les foyers cérébraux du thalamus et du colliculus inférieur en identifiant les métabolites-clés ciblant les CSPN. Enfin, les analyses par SEM ont montré une amélioration notable des tissus à la suite de la greffe de CSPN. Ces constatations suggèrent que l’utilisation de CSPN pourrait s’avérer une avenue thérapeutique intéressante pour soulager la dégénérescence symptomatique liée à une grave carence en thiamine chez l’humain. / Endogenous neural-stem progenitor cells (NSPC) have been documented to be found in the subventricular and subgranular zones, the dentate gyrus, and suggestions of the possibility of these cells being found in the spinal cord and neocortex in adult mammalian brain have been postulated. Thiamine deficiency (TD) is the major cause of Wernicke's Encephalopathy, a reversible neurological disorder that results in cerebral dysfunction and impairment. Recent evidence suggests factors involved in neural NSPC proliferation and differentiation are involved during TD. By means of a current approach for profiling metabolic changes occurring in focal areas of the TD rat brain, specifically the thalamus and the inferior colliculus (IC), it was hypothesized that new metabolites that might offer a better understanding into the sequel and/or mechanism of TD could be identified. It was also considered that the use of NSPC transplantation could offer new information into the involvement of NSPC and potential therapeutic benefit in TD. Non-targeted metabolomics analysis, fluorescences microscopy, and scanning election microscopy (SEM) analysis visualization was performed on samples of the focal areas (thalamus and IC) of pyrithiamine induced TD rats (PTD), pair-fed controls (PFC) rats, and NSPC transplanted TD and PFC rats. Various key metabolites were identified in rats with TD, including previous undocumented metabolites such as bile acids, kynurenic acid, and 1,9-dimethyluric acid in the thalamus and taurine and carnosine in the IC. The study also demonstrated a possible involvement of endogenous NSPC in focal areas of the thalamus and IC identifying key metabolites targeting NSPC and showed tissue amelioration (observed through SEM) following NSPC transplantation. The findings suggested that NSPC could offer a therapeutic alternative to alleviate some of symptomatic degeneration of TD.

Les virus sont les causes principales d’encéphalites et plus d’une centaine d’entre eux sont impliquées dans ces pathologies. Cependant, plus de 50% des encéphalites restent sans étiologie, dû en partie à des techniques de diagnostic mal adaptées ou à une méconnaissance de l’agent infectieux impliqué. Nous rapportons les cas de deux enfants d’une même famille qui ont développé une encéphalite nécrosante aiguë (ANE) conduisant à une hospitalisation de plusieurs semaines en soin intensif. Les virus communément recherchés dans les cas d’encéphalites n’ont pas été retrouvés chez ces patients. Par contre, la culture réalisée à partir des prélèvements d’urine des enfants et d’un prélèvement de gorge pour l’un des deux, a permis d’isoler un nouveau réovirus nommé MRV2Tou05. L’analyse moléculaire des 10 segments du génome viral a indiqué qu’un nouveau réovirus de sérotype 2 avait été isolé chez ces patients et qu’il s’agissait d’un virus réassortant entre une souche isolée de porc et une souche humaine. Le virus se réplique dans des cellules neuronales humaines et a été retrouvé par amplification de gène dans les prélèvements d’urine et dans certains prélèvements de sérum des deux enfants. De plus, une réponse anticorps spécifique dirigée contre MRV2Tou05 a été détectée dans les sérums des patients de l’étude alors qu’aucune réponse anticorps n’a été observée dans 40 sérums de donneurs sains. Toutes ces données sont en faveur de l’implication du nouveau réovirus isolé dans l’encéphalopathie observée. Des études supplémentaires réalisées in vivo dans un modèle animal permettront de mieux comprendre le rôle étiologique de ce nouveau réovirus dans les cas d’encéphalites / Viruses remain the main cause of Acute Encephalitis and more hundred of them are implicated in these pathologies. However, the etiologic agent is not determined in approximately 50% of cases, owed partially to not well adapted techniques of diagnosis or to misunderstanding of the involved infectious agent. We report the cases of two children in a same family who developed an acute necrotizing encephalopathy (ANE) leading to hospitalization in intensive care unit. Viruses commonly found in encephalitis were not detected in cerebrospinal fluid of these patients. However, a new reovirus strain of serotype 2, MRV2Tou05 was isolated from urine and throat swab samples on epithelium cells and was identified by electron microscopy and genome sequencing. Molecular characterization of its segmented genome indicates that MRV2Tou05 is a reassortant issued from swine and human strains. This new reovirus strain was directly detected by a specific sensitive molecular test in urine and serum samples from the two children. A specific antibody response directed against this new reovirus strain was detected in patient sera, whereas no response was observed in 38 healthy adult sera. Both its isolation and molecular detection from samples of the patients and the specific immune response toward this strain suggest an etiologic role of this reovirus in the ANE cases described herein. The reproduction of symptoms in an animal model will help understanding the exact role of this strain in ANE cases

Title: Functional consequences of perinatal hypoxia-ischemia in rat Objectives: The aim of this diploma thesis is to design a set of behavioral tests which provide an effective assessment of motor and cognitive-behavioural deficits in adults rats after experimental hypoxic-ischemic insult during the perinatal period (P7). Supposed benefit is to establish a model of motor and cognitive-behavioural abilities of individuals after this procedure. Methods: The present thesis has a theoretical-empirical character. The practical part describes how the experiment was performed. 32 long Evans Rats were randomly devided into two groups: experimental group (HIE) and control group (Ctrl). The method to produce hypoxic-ischemic brain damage in the 7 day-old rats consisted of right common carotid ligation followed by systemic hypoxia by the inhalation of 8% oxygen and 92% nitrogen. The adult animals (55-75 days old) were tested by the following list of behavioral tests: Bar holding test, Rotarod test, Ladder rung walking test, Reaching test, Open field test and Morris water maze test. Sigma Plot and Microsoft Excel 2010 were the programs used for statistical analysis. Results: Results of Open field test, Ladder rung walking test and Morris water maze test confirmed that hypoxic-ischemic insult affects the...

Anomalies de structure du génome et Déficience Intellectuelle : Recherche des gènes candidats de Déficience intellectuelle en utilisant l'analyse chromosomique sur microréseau d'ADN pangénomique 180K et l'analyse chromosomique sur microréseau d'ADN de haute résolution 1M ciblée des gènes candidats de Déficience intellectuelle. L'analyse chromosomique sur microréseau d'ADN (ACM) de haute résolution est une innovation technologique puissante afin de détecter les aberrations chromosomiques concernant les variations du nombre de copies. En utilisant l'ACM 180K, l'ACM 1M et la PCR quantitative, nous avons identifié les 5 variations du nombre de copies (CNV) intragéniques pathogènes de novo impliquant les gènes : RUNX1T1, KIAA1468, FABP7, ZEB2 (syndrome de Mowat-Wilson) et ANKRD11 (syndrome de KBG). Les 5 patients ayant une DI et une dysmorphie faciale. L'ACM 180K a révélé une délétion d'une taille de 92 kb emportant le gène KIAA1468 candidat pour le syndrome de West chez un enfant de 3 ans présentant une DI sévère et une encéphalopathie épileptique infantile précoce. Le criblage des mutations du gène KIAA1468 a été réalisé chez 35 patients atteints de syndrome de West. Un variant intronique c.2761-7 T>C et un variant faux-sens hérité de la mère c.3547 G>A avec signification clinque inconnue ont été identifiés. En utilisant des approches par l'ACM 1M de haute résolution chez 45 patients atteints de DI idiopathique modérée à sévère, un seul CNV causal a été identifié, une délétion intragénique d'une taille de 28.37 kb du gène ZEB2. Notre étude confirme une fréquence très faible des délétions/duplications intragéniques avec la détection d'une seule aberration chromosomique (1/45). En conclusion, si la fréquence des mutations ponctuelles est élevée, nous avons également souligné l'application de la technique de séquençage à haut débit avec un rendement diagnostique jusqu'à 45%-55% des cas de DI sévère idiopathique chez lesquels aucun CNV n'a été détecté sur ACM / Chromosomal structural abnormalities and Intellectual Disability : In search of intellectual disability candidate genes by using pangenomic comparative genomic hybridization 180 K and high resolution comparative genomic hybridization 1M targeting intellectual disability candidate gene.High resolution microarray-based comparative genomic hybridization (a-CGH) has been a powerful technical innovation in order to detect submicroscopic chromosomal aberrations related to copy number variations. By using a-CGH 180K, 1M high resolution a-CGH and quantitative PCR, we have identified 5 pathogenic intragenic copy number variations (CNVs) de novo : RUNX1T1, KIAA1468, FABP7, ZEB2 (Mowat-Wilson syndrome) and ANKRD11 (KBG syndrome). All five patients had intellectual disability (ID) and facial dysmorphism. Interestingly, a-CGH 180K has revealed a 92 kb deletion of a candidate gene KIAA1468 for West syndrome in a 3 year-old boy with severe ID and early infantile epileptic encephalopathy. Mutational screening for candidate gene KIAA1468 was performed in 35 patients with West syndrome. An intronic variant c.2761-7 T>C and a non synonymous maternally inherited variant c.3547 G>A with unknown clinical significance were identified. By using 1M high-resolution a-CGH approach in 45 patients presenting moderate to severe idiopathic ID, only one causal CNV was identified, a 28.37 kb intragenic ZEB2 deletion. Our study has confirmed the low frequency of intragenic deletion/duplication with the detection of only one chromosomal aberration (1/45). In conclusion, providing that the high frequency of intragenic point mutation, we also stressed the application of next-generation sequencing technology with 45-55% diagnostic yield in patients with idiopathic severe ID in case of no apparent CNV(s) on high-resolution a-CGH

Dentre as manifestações clínicas observadas em pacientes sépticos, as disfunções neurológicas são, provavelmente, as de fisiopatologia mais obscura e pobremente explorada, o que consequentemente as torna de difícil entendimento e tratamento médico. Adicionalmente, estudos epidemiológicos indicam que a síndrome séptica é mais frequente e mais letal em pacientes idosos. Nesse contexto, este trabalho objetivou comparar os efeitos da sepse, induzida pelo modelo de ligadura e perfuração cecal, no encéfalo de ratos jovens e idosos por meio da análise da expressão gênica de larga escala (transcriptoma), a fim de averiguar como as alterações no padrão de expressão podem estar relacionadas a disfunções neurológicas. Os resultados deste estudo indicaram a diminuição da expressão dos genes Bcl-3, S100A8 e uridina fosforilase 1, bem como o aumento da expressão de Stefin A3, sendo tais efeitos característicos das manifestações comuns da sepse no sistema nervoso central, independentemente da idade dos animais; por outro lado, a diminuição da expressão do gene da haptoglobina foi observada apenas nos animais idosos com sepse. De forma geral, na comparação entre animais idosos e jovens, os resultados desta pesquisa apontaram que animais idosos apresentam uma quantidade menor de genes modificados pela sepse, o que sugere menor capacidade de ativar mecanismos neuroprotetores / Among the clinical manifestations observed in septic patients, the neurological dysfunctions are probably the most obscure and poorly explored pathophysiology, which consequently makes them difficult to understand and to treat. Additionally, epidemiological studies indicate that septic syndrome is more frequent and more lethal in elderly patients. In this context, this article is aimed at comparing the effects of sepsis, induced by the ligature model and cecal perforation, on the brain of young and elderly rats by means of the analysis of the large scale gene expression (transcriptome), in order to investigate how the changes in this expression may be related to neurological dysfunctions. The results of this study indicated decreased expression of the Bcl-3, S100A8 and uridine phosphorylase 1 genes, as well as increased expression of Stefin A3, these effects being characteristic of the common manifestations of central nervous system sepsis regardless of the age of the animals; on the other hand, decreased haptoglobin gene expression was observed only in the elderly animals with sepsis. In general, in the comparison between old and young animals, the results of this research indicated that elderly animals present a smaller amount of genes modified by sepsis, which suggests a smaller capacity to activate neuroprotective mechanisms

O presente estudo avaliou a autorregulação encefálica (ARE) em doentes com insuficiência hepática fulminante (IHF) antes e após transplante hepático. Foram avaliados 25 pacientes com diagnóstico de IHF, 17 foram avaliados antes e após o transplante hepático, sendo seis (24,0%) do sexo masculino e 19 (76,0%) feminino. A média de idade foi de 33,8 anos, que variou de 14 a 56 anos, com desvio padrão de 13,1 anos. A hemodinâmica encefálica foi avaliada pela velocidade de fluxo sanguíneo encefálico (VFSE) nas artérias cerebrais médias e artéria basilar (AB), que usou o ultrassom Doppler transcraniano (DTC), dispositivo de dois canais, com transdutores de 2 mega Hertz (MHz). A autorregulação encefálica foi mensurada pelo índice de autorregulação (IARE) estática que leva em conta os efeitos do aumento da pressão arterial média (PAM) sobre a VFSE. Para isso, promoveu-se o aumento da PAM (20 mmHg a 30 mmHg) com infusão de noradrenalina.. Ao se avaliar o IARE considerando a velocidade de fluxo sanguíneo em quatro momentos (pré-transplante, 1°, 2° e 3° dia após o transplante), observou-se que houve diferença estatística em artéria cerebral média (ACM) à direita (p=0,008), esquerda (p=0,007), máxima (p=0,005), e AB (p=0,006); assim como na análise em cada tempo do IARE, observou-se diferença estatística em ACM à direita (p=0,012), esquerda (p=0,009), máxima (p=0,006), e AB (p=0,011). A análise categórica do IARE na artéria cerebral média e basilar descreveu que a maioria dos doentes reestabeleceu a AR no 2° dia em ACM e 3° na AB (índice > 0,6), enquanto com o índice > 0,8 em ambas as artérias a ARE reestabeleceu no 2° dia. As variáveis sistêmicas como pressão parcial de CO2 e hemoglobina nos tempos da avaliação não apresentaram diferença estatística p=0,100 e p=0,093 respectivamente. Os resultados obtidos apontam para o comprometimento da ARE antes e após transplante hepático, tanto em circulação anterior como posterior, e que tende a ser reestabelecido entre 48 a 72 horas. Os achados deste estudo favorecem o manejo adequado de doentes nestas fases (antes e após transplante) e podem evitar a evolução para complicações neurológicas, como tumefação encefálica e hipertensão intracraniana, que indicam prognóstico ruim para a evolução clínica destes doentes. Estudos futuros necessitam ser realizados para que se consolide o uso da monitoração contínua com métodos não invasivos como o DTC para direcionar o manejo hemodinâmico encefálico na IHF / This study evaluated cerebral autoregulation in patients with fulminant hepatic failure (FHF) before and after liver transplantation. A total of 25 patients comprising six (24.0%) males and 19 (76.0%) females with FHF were evaluated. Seventeen patients were evaluated both before and after liver transplantation. Mean age of the patients was 33.8 years, with a range of 14-56 years and standard deviation of 13.1 years. Brain hemodynamics was assessed by cerebral blood flow velocity in the middle cerebral arteries (MCA) and basilar artery (BA) using transcranial Doppler ultrasound on a two-channel device with 2 MHz transducers. Cerebral autoregulation was measured by static cerebral autoregulation index (SCAI), which accounts for the effects of increase in mean arterial blood pressure (ABP) on cerebral blood flow velocity. An increase in ABP (20 mmHg to 30 mmHg) was induced with norepinephrine infusion. Evaluation of SCAI based on blood flow velocity (BVF) at four timepoints (pre-transplant and on 1st, 2nd and 3rd days post-transplant) revealed a statistical difference in the MCA right (p = 0.008) left (p = 0.007), maximum (p = 0.005) and the BA (p = 0.006). In addition, analysis by timepoint showed a statistical difference in MCA (p = 0.012), left (p = 0.009), maximum (p = 0.006) and in the BA (p = 0.011). Categorical analysis of autoregulation in the MCA and BA showed that most patients reestablished autoregulation in the MCA on the 2nd day post-transplant and in the BA (index > 0.6) on the 3rd day, while autoregulation was reestablished in both arteries (index > 0.8) on the 2nd day. On the assessment by timepoint, the systemic variables CO2 partial pressure and hemoglobin showed no statistically significant differences (p = 0.100 and p = 0.093, respectively). The results reveal impaired SCAI before and after liver transplantation, both in anterior and posterior circulation, with a tendency to reestablish at 48 to72 hours. The findings of this study can help improve management of patients at these stages (pre and post transplantation), preventing neurological complications such as brain swelling and intracranial hypertension, associated with poor prognosis for the clinical course. Future studies should be conducted to consolidate the use of continuous monitoring with noninvasive method (TCD), to provide more accurate information to guide brain hemodynamic management in FHF

Este estudo caracteriza a intoxicação por Trema micrantha em equinos, até então desconhecida nesta espécie. No primeiro artigo (artigo 1), é descrito um surto espontâneo de intoxicação por T. micrantha em equinos que ocorreu em junho de 2007, no Município de São José do Herval, na região da encosta da serra do Rio Grande do Sul. Dois equinos morreram na propriedade, após uma árvore de T. micrantha ter sido derrubada por um temporal e suas folhas terem sido consumidas pelos animais. O quadro clínico patológico apresentado foi característico de insuficiência hepática aguda, com desenvolvimento de encefalopatia hepática. Subsequentemente, para melhor caracterizar a intoxicação por Trema micrantha em equinos, desenvolveu-se um experimento (artigo 2). Quatro pôneis receberam e consumiram espontaneamente folhas de T. micrantha, em doses únicas de 30, 25 e 20g/kg. Um equino recebeu uma dose de 15 e outra de 25g/kg, 30 dias após. Três animais adoeceram e evoluíram para morte. Os principais sinais clínicos apresentados foram apatia, desequilíbrios, dificuldade de deglutição, decúbito esternal, decúbito lateral, movimentos de pedalagem coma e morte. Os três equinos afetados apresentaram elevação na atividade sérica de gama glutamil transferase (GGT), nos níveis séricos de amônia, além de diminuição da glicemia. Os principais achados patológicos foram encontrados no fígado e no encéfalo dos três animais. O fígado apresentava macroscopicamente acentuação do padrão lobular, enquanto que no encéfalo havia áreas amareladas na superfície de corte, mais evidentes na substância branca do cerebelo. Microscopicamente, o fígado apresentava necrose, predominantemente centrolobular e hemorragia. No encéfalo, havia edema perivascular generalizado e astrócitos Alzheimer tipo II na substância cinzenta. Esses astrócitos apresentaram marcação fraca ou negativa na imuno-histoquímica anti-GFAP e marcação positiva do antígeno S-100. A dose letal mínima de folhas de T. micrantha estabelecida nesse experimento foi de 20g/kg. A maior sensibilidade da espécie equina constatada nesse estudo, a ampla distribuição de T. micrantha, bem como sua palatabilidade reforçam a importância da planta em casos acidentais de intoxicação nessa espécie. / This study characterizes Trema micrantha poisoning in horses, previously unknown in this species. The first article (Article 1) describes an outbreak of T. micrantha poisoning in horses. The disease occurred in June 2007, in the Municipality of São José do Herval, Rio Grande do Sul State. Two horses died after consuming the leaves of the branches from a T. micrantha tree, which had been felled by a storm. Clinical pathology presented by the animals was characteristic of an acute liver failure with development of hepatic encephalopathy. To further characterize the Trema micrantha poisoning in horses, an experiment was carried out (Article 2). Four ponies received and spontaneously consumed green leaves of T. micrantha, at the doses of 30, 25, and 20 g/kg. One horse received two doses, 15 and 25 g/kg, 30 days apart. Three animals were affected and died. The main clinical signs were apathy, equilibrium deficit, deglutition difficulty, sternal or lateral recumbency, paddling, coma and death. These tree diseased ponies had also enhanced seric activity of gamma-glutamyl transferase (GGT), seric ammonia apart of diminished glycemia. The main pathological findings were observed in the liver and encephalon. There were enhanced lobular pattern of the livers and yellowish areas in the cut surface of the encephalon, especially visualized in the cerebral white matter. Microscopically, there was hepatic necrosis predominantly centrilobular apart of hemorrhages. Generalized perivascular edema and Alzheimer type II astrocytes were observed in the encephalon. The Alzheimer type II astrocytes showed weak or absent anti-glial fibrillar acid protein immunostaining associated with positive immunostaining for S-100 protein. The minimal lethal dose of Trema micrantha leaves was established at 20 g/kg. The high sensibility of this species to this plant, its wide distribution, and the high palatability of the plant reinforce the importance of Trema micrantha in accidental episodes of intoxication in horses.