Enterovírus (HEV), herpesvírus 1 e 2 (HHV-1 e HHV-2) e adenovírus (HAdV) são importantes agentes de infecções do SNC. Neste trabalho, técnicas moleculares foram aplicadas para a detecção destes vírus em quadros de infecção do SNC. Amostras de líquor foram colhidas de pacientes atendidos no HU-USP entre agosto e novembro/2010 e fevereiro/2012 a janeiro/2013. Através da Nested-PCR HEV foram detectados em 9,8% das amostras, HAdV em 2,5% e HHV-1 e 2 em 1,1%, além de 3 casos de coinfecção, 2 entre HEV e HHV, e 1 entre HEV e HAdV. O material genético viral foi extraído através dos métodos Qiaamp DNA Blood (Qiagen®) e MagMAXTM Viral RNA Isolation (Ambiom), e este último pareceu mais adequado à aplicação na rotina clínica. A análise quimiocitológica do líquor mostrou-se importante no direcionamento da conduta clínica, mas a detecção do vírus é fundamental para a conclusão do diagnóstico. A PCR em tempo real, cuja padronização foi iniciada neste trabalho, consiste em importante ferramenta para a utilização futura no diagnóstico complementar das infecções virais do SNC. / Enteroviruses (HEV), herpesviruses 1 and 2 (HHV-1 and HHV-2) and adenoviruses (HAdV) are important causative agents of infections of the CNS. In this study, molecular techniques were applied to the detection of these viruses. CSF samples were collected from patients treated at the University Hospital of USP, between August and November, 2010, and February 2012 and January 2013. By the Nested-PCR reaction, HEV were detected in 9.8% of the samples, HAdV in 2.5% and HHV-1 and 2 in 1.1%. There were 3 cases of coinfection: 2 with HEV and HHV and other with HEV and HAdV. The viral genetic materials were extracted by QIAamp DNA Blood kit (Qiagen®) and MagMAXTM Viral RNA Isolation (Ambiom), and the second one showed to be more suitable for the application in clinical diagnosis. The CSF chemocytologic analysis proved to be important in directing the clinical conduct, but the detection of viruses is essential for the diagnosis. The real time PCR, which standardization was initiated in this work, will be an important tool for complementary diagnosis of viral infections of the CNS.

INTRODUÇÃO: este trabalho apresenta a arquitetura de um sistema de emissão de alertas para surtos e epidemias em tempo real, baseado em notificações eletrônicas da meningite, e discute os resultados dos testes e simulações realizados. MÉTODOS: esse sistema foi desenvolvido em quatro etapas: Concepção, Análise, Construção e Teste/Simulações. A Concepção contemplou a elicitação de requisitos, a qual definiu o que o sistema deve fazer. A Análise se preocupou com a modelagem e especificação das regras que definem como o sistema deve trabalhar. A Construção abrangeu a transformação das regras definidas e modeladas em linguagem de programação. A última etapa, Teste/Simulação, foi responsável por garantir que o sistema construído estava em conformidade com os requisitos elicitados na etapa de Concepção. RESULTADOS: vários artefatos foram criados e algumas constatações foram verificadas nesta etapa. Sobre os artefatos podemos citar os requisitos, casos de uso, diagrama de classes, modelo físico de dados, casos de teste e programas. Sobre as constatações podemos citar o disparo de alertas nas simulações realizadas pelo sistema dois dias antes que o alerta feito pelas autoridades de saúde do Estado de São Paulo usando os procedimentos habituais. DISCUSSÃO e CONCLUSÃO: O sistema desenvolvido pode ser classificado como um Early Warning System. Nas simulações, observamos que em duas oportunidades ele conseguiu evidenciar ocorrência de surto antecipadamente ao método tradicional utilizado pelo Centro de Vigilância Epidemiológico de São Paulo. Comparando-o com sistemas semelhantes em produção, verificamos que esse sistema se diferencia ao emitir ativamente alertas de surtos em tempo real. / INTRODUCTION: this essay presents the architecture of an alert system for epidemics based on real-time electronic notification of meningococcal meningitis, and discusses the results of tests and simulations made. METHODS: this system was developed in four stages: Conception, Analysis, Construction and Test/Simulation. The Conception covered the requirements elicitation, which defined what the system should do. The Analysis involved the modeling and specification rules that defined how the system should work. The Construction covered the transformation of defined and modeled rules in programming language. The last stage, Test/Simulation, checked the system under known scenarios, comparing the timing of outputs with the Brazilian notification surveillance framework. RESULTS: many artifacts were made and some evidences were verified. About the artifacts we can mention the requirements, use cases, class diagram, physical data model, test cases, and algorithms. About the evidences we can mention the fast alert production in simulations of this system as compared with the current procedure in use by health authorities. DISCUSSION AND CONCLUSION: this system can be classified as an Early Warning System. In simulations we observed that in two opportunities, it managed to put in evidence outbreak occurrence in advance to the traditional used method by Epidemiological Surveillance Center of São Paulo. In comparison with the similar systems under operation, we note this system is distinguished from them in issuing real-time outbreak alerts.

O conhecimento dos custos das doenças imunopreveníveis, em especial os custos hospitalares da meningite pneumocócica, objeto de estudo desta tese, são de grande importância para os processos de tomada de decisão no que se refere a intervenções ou estratégias de saúde pública. O objetivo desta tese foi estimar os custos hospitalares relacionados à meningite pelo Streptococcus pneumoniae em crianças com idade até 13 anos (inclusive), na cidade de São José dos Campos, nos últimos dez anos. Foi realizado um estudo retrospectivo de custo-de-doença, a partir dos casos notificados de meningite pneumocócica ocorridos de janeiro de 1999 a dezembro de 2008. O cálculo da estimativa de custos hospitalares foi realizado de acordo com o método misto para a mensuração das quantidades dos itens de custos identificados e também para atribuição de valor aos itens consumidos, fazendo uso do micro-costing quando este era possível, e do gross-costing, como alternativa de viabilidade. Todos os custos foram calculados com os valores monetários referentes a novembro de 2009, e expressos em reais. Para análise das freqüências e médias, foi usado o programa Epi-Info versão 3.5.1. Resultados: De 1999 a 2008, foram notificados ao núcleo municipal de vigilância epidemiológica 41 casos de meningite pneumocócica em menores com até 13 anos de idade (média = 4,8 anos), a maior parte meninos (65,6%; n=27). A prevalência variou entre 0,48 e 5,96%, ao longo do período de estudo, e o número de casos variou de 1 a 9 por ano. O tempo de internação variou entre 8 e 47 dias (média = 23,1 dias). Dez casos evoluíram para o óbito (24,4%; 95%IC = 12,4% - 40,3%). Dois pacientes evoluíram com hidrocefalia já durante a internação por meningite aguda (11,1%; 95% IC = 1,4% - 34,7%). A complicação mais comum foi a infecção secundária ocorrida em 22,2% dos casos (95% IC = 6,4% - 47,6%), sendo um caso de infecção osteo-articular em paciente com anemia falciforme e deficiência de complemento (fração C2), um caso de pericardite purulenta, e dois casos de pneumonia associada a ventilação mecânica. Os custos hospitalares diretos variaram de R$1.277,9 a R$19.887,56, com média de R$5.666,43. Os custos dos honorários profissionais foram os mais relevantes, e variaram de R$311,00 a R$3.844,95 (média = R$1.211,30), seguidos pelos custos dos medicamentos (de R$60,14 a R$2.602,85; média = R$632,95), procedimentos (de R$7,04 a R$1.655,24; média = R$846,77), materiais (de R$15,42 a R$1.083,08; média = R$210,24), e exames laboratoriais (de R$18,3 a R$ 324,67; média = R$161,32). A falta de padronização nas condutas diagnósticas e terapêuticas, somada às diferenças na gravidade e na evolução clínica entre os casos, fez com que os custos fossem muito variáveis caso a caso, e mesmo ano a ano. Conclui-se, então, que os custos do tratamento hospitalar da meningite pneumocócica em São José dos Campos foram muito variáveis, e dependeram da conduta médica e das variações dos casos quanto a gravidade e evolução clínica. Em todos os casos foram considerados altos, cerca de 10 a 20 vezes maiores que o custo médio de internações pago pelo SUS por AIH / The knowledge of the costs of immuno-preventable diseases, mainly the hospital costs of pneumococcal meningitis, object of study of this thesis, are of great importance to the processes of decision making regarding public health interventions or strategies. The aim of this thesis was to estimate the direct hospital costs related to pneumococcal meningitis in children until 13 years of age, in the city of São José dos Campos, from January 1999 to December 2008. A retrospective cost-of-illness study was performed, from the notified cases of pneumococcal meningitis which happened in the period of study. The estimate calculation of the hospital costs was carried out according to the mixed method for the measurement of the quantities of the items of identified costs, and also to value attribution to the items consumed, making use of micro-costing when this was possible, and of the gross-costing, as a viability alternative. All costs were calculated according to the monetary values of November 2009, and in the Brazilian currency (Real). As for the analysis of frequencies and averages, the Epi-Info program, version 3.5.1, was used. Results: From 1999 to 2008, 41 cases of pneumococcal meningitis in minors until 13 years of age (average = 4.8 years of age), mostly boys (65.6%; n=27) were notified to the municipal nucleus of epidemiological vigilance. The prevalence varied between 0.48 and 5.96%, during the period of study, and the number of cases varied from 1 to 9 per year. The period of permanence in hospital varied between 8 and 47 days (average = 23.1 days). Ten cases resulted in death (24.4%; 95%IC = 12.4% - 40.3%). Two patients acquired hydrocephalus during acute meningitis (11.1%; 95% IC = 1.4% - 34.7%). However, the most common complication was the secondary infection which occurred in 22.2% of the cases (95% IC = 6.4% - 47.6%). There was one case of osteo-articular infection in patient with sickle cell anemia and complement deficiency (C2 fraction), a case of purulent pericarditis, and two cases of pneumonia associated to mechanic ventilation. The direct hospital costs varied from R$1,277.9 to R$19,887.56, with an average of R$5,666.43. Labor costs were more relevant, and varied from R$311.00 to R$3844.95 (average = R$1,211.30), followed by medication costs (from R$60.14 to R$2,602.85; average = R$632.95), procedures (from R$7.04 to R$1,655.24; average = R$846.77), supplies (from R$15.42 to R$1,083.08; average = R$210.24), and lab exams (from R$18.3 to R$ 324.67; average = R$161.32). The lack of standardization in the approach to diagnosis and therapy, added to the differences on the level of seriousness and clinic evolution between the cases, made the costs vary depending on the case, and even to the year. In conclusion, hospital costs for treatment of pneumococcal meningitis in São José dos Campos were very variable, and depend on the medical approach and the variability of clinic conditions. All cases are considered around 10 to 20 times as expensive as the average cost of admissions paid by government for average hospitalization due to other causes

Infecções no sistema nervoso central (SNC) causadas por microrganismos desencadeiam sintomas de moderados a severos, dependendo da região atingida, podendo ser designadas como encefalites ou meningites. Os vírus são os agentes mais comuns nestas infecções. Os agentes virais responsáveis por essas enfermidades que apresentam maior incidência na população mundial são certos herpesvírus, flavivírus, influenza A, enterovírus e vírus da caxumba. Entretanto, essa prevalência varia de acordo com a população, estado imunológico do indivíduo, idade e região estudada. Embora existam dados bem estabelecidos da etiologia dessas doenças em alguns países, ainda há uma carência de informação no que diz respeito à etiologia dessas moléstias no Brasil. Assim, informações mais precisas em relação à prevalência desses agentes em nosso meio são necessárias para o desenvolvimento e aplicação de métodos de diagnósticos mais rápidos e eficientes. Neste trabalho, foram analisadas 120 amostras de liquido cefalorraquidiano (LCR), procedentes de dois centros da cidade de São Paulo (Irmandade Santa Casa de Misericórdia e Hospital das Clínicas da Faculdade de medicina da Universidade de São Paulo), as quais foram submetidas à reação em cadeia de polimerase para o herpesvirus simples 1 e 2 (HSV 1 e 2), vírus da varicela zoster (VZV), herpesvirus humano 6 (HHV-6), influenza A (FLUA), enterovírus, vírus da caxumba, poliomavírus vírus BK (BKV) e vírus JC (JCV) para flavivírus. Do total, 44 amostras (36,7%) apresentaram resultado positivo para algum dos vírus analisados no âmbito desta pesquisa, sendo 15 (12,5%) para poliomavírus BKV, 2 (1,7%) para poliomavírus JCV, 21 (17,5%) para HSV1 e 2, 5 (4,2%) foram positivos para BKV e HSV1 e 2 (coinfecção) e 1 (0,8%) para vírus Epstein-Barr (EBV). Uma parte das amostras negativas foi submetida a sequenciamento direto de nova geração (n=8 amostras), resultando em amostras positivas para vírus (vírus simio 40), protozoários e bactérias. Este estudo mostrou que infelizmente, menos de 50% das encefalites e meningites assépticas puderam ser relacionadas a algum agente viral. Houve uma alta prevalência de HSV no material estudado, de acordo com o esperado, mas a presença de poliomavírus no LCR destes indivíduos foi acima da observada na literatura. Esses, bem como os resultados de sequenciamento direto e sua associação a etiologia das encefalites e meningites, devem ser interpretados com cautela. / Central nervous system (CNS) infections caused by microorganism trigger moderate to severe symptoms, depending on the region affected and may be referred as encephalitis or meningitis. Viruses are the most common agents in these infections. The viral agents responsible for these diseases with highest incidence worldwide are certain herpesviruses, flaviviruses, influenza A, enteroviruses, and mumps virus. However, their prevalence vary according to the population, immunological state of the individual, age and region studied. Although there are well-established data on the etiology of these diseases in some countries, there is little information regarding the etiology of these diseases in Brazil. Thus, data regarding the prevalence of these agents in our environment is necessary for the development and application of faster and more efficient diagnostic methods. In this study, 120 cerebrospinal fluid (CSF) samples from two centers of the city of São Paulo (Hospital Santa Casa de Misericordia and Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo) were investigated by PCRs for herpes simplex virus (HSV 1 and 2), varicela zoster virus (VZV), human herpesvirus 6 (HHV6), influenza A, enterovirus, mumps virus, polyomavirus BK virus and JC virus and flaviviruses. From these, 44 samples (36.7%) presented positive result for one of the viruses analyzed, being 15 (12.5%) for polyomavirus BKV, 2 (1.7%) for polyomavirus JCV, 21 (17.5%) for HSV 1 and 2, 5 (4.2%) samples were positive for BKV and HSV1 and 2 (coinfection) and 1 (0.8%) for Epstein-Barr virus (EBV). A part of the negative samples (n=8) were submitted to next generation direct sequencing and revealed the presence of agents as viruses (simian virus 40), protozoa and bacteria. This study showed that unfortunately, less than 50% of the aseptic encephalitis and meningitis could be related to some viral agent. It was found high prevalence of HSV, as expected, but the presence of polyomavirus in the CSF of these individuals was higher than that observed in the literature. These results, as well as direct sequencing results and its relationship to the etiology of encephalitis and meningitis should be interpreted with caution.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as lOx the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracistemal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracistemal inoculation of a cephalosporinresistant strain of E. cloacae. Untreated  rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC. Using   the same EEG-model, the neurotoxic potential of imipenem/cilastatin (I) and a new penem derivative, FCE 22101 were compared in a cross-over study. Both I and FCE 22101 were significantly more neurotoxic than BPC. While BTF levels of the three antibiotics could be detected in all tested rabbits, detectable CSF levels were only found in one of twelve rabbits treated with I or FCE 22101, indicating that BTF concentrations rather than CSF ones are decisive for neurotoxicity of ß-lactam antibiotics. The EEG-model used was found to be a suitable model for cross-over studies of intravenously administered antibiotics. Using the "silent-second" as EEG-threshold, a CNS interaction between intraperitoneally administered BPC and intravenous thiopental was demonstrated in rats. The most probably site for this interaction is the organic acid transport system out of the CNS. Thiopental distribution in the rat brain seemed to depend not only on its lipid solubility. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1988, härtill 5 uppsatser.</p> / digitalisering@umu

Made available in DSpace on 2014-12-17T14:05:23Z (GMT). No. of bitstreams: 1 ThayseAS_TESE.pdf: 2133799 bytes, checksum: c236c1e72798e2c7e1008d1c78d046a4 (MD5) Previous issue date: 2013-03-21 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis and also developed a system to enable the functional analysis of polymorphic proteins. Patients with bacterial meningitis (BM), aseptic meningitis (AM) and controls (non-infected) genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. The levels of NF-?B and c-Jun were measured in CSF by dot blot assays. A significant (P<0.05) increase in the frequency of APE1 148Glu allele in BM and AM patients was observed. A significant increase in the genotypes Asn/Asn in control group and Asn/Glu in BM group was also found. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs increased significantly in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 148Glu allele or OGG1 326Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1Asn148Glu, OGG1Ser326Cys or PARP-1Val762Ala. Reductions in the levels ofIL-6, IL-1Ra, MCP-1/CCL2and IL-8/CXCL8 were observed in the presence of APE1148Glu allele in BM patients, however no differences were observed in the levels of NF-?B and c-Jun considering genotypes and analyzed groups. Using APE1 as model, a system to enable the analysis of cellular effects and functional characterization of polymorphic proteins was developed using strategies of cloning APE1 cDNA in pIRES2-EGFP vector, cellular transfection of the construction obtained, siRNA for endogenous APE1 and cellular cultures genotyping. In conclusion, we obtained evidences of an effect of SNPs in DNA repair genes on the regulation of immune response. This is a pioneering work in the field that shows association of BER variant enzymes with an infectious disease in human patients, suggesting that the SNPs analyzed may affect immune response and damage by oxidative stress level during brain infection. Considering these data, new approaches of functional characterization must be developed to better analysis and interactions of polymorphic proteins in response to this context / Estudos in vitro e em modelos animais sugerem que as prote?nas de reparo de DNA da via de reparo por excis?o de bases (do ingl?s, BER) APE1, OGG1 e PARP-1 est?o envolvidas tamb?m na resposta inflamat?ria. Neste trabalho foi investigado se os SNPs APE1 Asn148Glu, OGG1 Ser326Cys e PARP-1 Val762Ala associam-se ? meningite, e foi desenvolvido um sistema para an?lise funcional destas variantes polim?rficas. Os gen?tipos de pacientes com meningite bacteriana (MB), meningite ass?ptica (MA) e n?o infectados (controles) foram investigados por PIRA-PCR ou PCR-RFLP. Danos no DNA gen?mico foram detectados por meio de tratamento com Fpg. IgG e IgA foram titulados no plasma e citocinas e quimiocinas foram mensuradas em amostras de l?quor atrav?s de ensaios em Bio-Plex. Os n?veis de NF-?B e c-Jun foram dosados no l?quor dos pacientes por meio de dot blot. Foi observado um aumento significativo (P<0.05) na frequ?ncia do alelo APE1 148Glu nos casos de MB e MA. Os gen?tipos Asn/Asn no grupo controle e Asn/Glu no grupo da MB tamb?m apresentaram relevante aumento em suas frequ?ncias (P<0.05). Para o SNP OGG1 Ser326Cys, o gen?tipo Cys/Cys esteve mais frequente (P<0.05) nos casos de MB. A frequ?ncia do gen?tipo PARP-1 Val/Val foi mais alta no grupo controle (P<0.05). A ocorr?ncia combinada dos SNPs foi significativamente alta nos pacientes com MB, indicando que estes SNPs podem estar associados ? doen?a. Os portadores do alelo APE1 148Glu ou OGG1 326Cys apresentaram um n?mero maior de s?tios sens?veis ? Fpg, sugerindo que os SNPs afetam a atividade de reparo do DNA. Altera??es na s?ntese de IgG foram observadas na presen?a dos SNPs APE1 Asn148Glu, OGG1 Ser326Cys ou PARP-1 Val762Ala. Redu??es nos n?veis de IL-6, IL-1Ra, MCP-1/CCL2 e IL-8/CXCL8 foram encontradas na presen?a do alelo APE1 148Glu em amostras de pacientes com MB, no entanto n?o foram encontradas diferen?as nos n?veis de NF-?B e c-Jun considerando os gen?tipos e os grupos analisados. Utilizando APE1 como modelo, foi desenvolvido um sistema que possibilita a express?o e caracteriza??o funcional das enzimas polim?rficas estudadas e seus efeitos na c?lula, por meio de clonagem, utilizando o vetor pIRES2-EGFP e cDNA de APE1, transfec??o celular da constru??o obtida, inibi??o por siRNA de APE1 end?gena e genotipagem de culturas celulares. Em conclus?o, foram obtidas evid?ncias de um efeito significativo dos SNPs nos genes de reparo de DNA na regula??o da resposta imunol?gica. Este ? um trabalho pioneiro na ?rea, que demonstra a associa??o de variantes das enzimas da via BER com uma doen?a infecciosa em humanos, sugerindo que os SNPs estudados podem afetar a resposta imune e o impacto do n?vel de estresse oxidativo durante a infec??o cerebral. Desta forma, novos meios de an?lise funcional devem ser desenvolvidos para estudo de prote?nas polim?rficas e suas intera??es neste contexto / 2020-01-01

Distúrbios do sistema nervoso central (SNC) em ruminantes abrangem um importante grupo de enfermidades responsáveis por grandes perdas econômicas em todo o mundo. As principais doenças neurológicas causadas por bactérias em ruminantes e que envolvem processos inflamatórios incluem listeriose, leptomeningites e meningoencefalites supurativas, abscessos cerebrais e medulares, empiema basilar e neurotuberculose. Esta dissertação teve por objetivo a caracterização epidemiológica, patológica, microbiológica e imuno-histoquímica das doenças inflamatórias de origem bacteriana que afetam o SNC de ruminantes no Rio Grande do Sul. Foi realizado um estudo retrospectivo no período compreendido entre janeiro de 1996 a dezembro de 2015, onde um total de 3.274 bovinos, 596 ovinos e 391 caprinos foram avaliados. Destes, 219 bovinos, 21 ovinos e sete caprinos foram diagnosticados com doenças inflamatórias no SNC. As doenças neurológicas inflamatórias de origem bacteriana totalizaram 60 casos divididos em 34 bovinos, 19 ovinos e sete caprinos, os quais foram subdivididas em: meningoencefalite por L. monocytogenes (oito ovinos, cinco caprinos e quatro bovinos), leptomeningite e meningoencefalite supurativa (14 bovinos, dois caprinos e um ovino), abscessos cerebrais (seis bovinos e dois ovinos) e medulares (sete ovinos), empiema basilar (quatro bovinos e um ovino) e neurotuberculose (seis bovinos). O exame imuno-histoquímica foi realizado em todos os casos diagnosticados com listeriose (anticorpo anti-L. monocytogenes), meningite e meningoencefalite supurativa (anticorpo anti-Escherichia coli) e neurotuberculose (anticorpo anti-Mycobacterium tuberculosis). A meningoencefalite por L. monocytogenes representou a principal enfermidade neurológica em ovinos e caprinos, seguido dos abscessos medulares em ovinos. Nos bovinos, a leptomeningite e meningoencefalite supurativa foi a doença neurológica mais prevalente para a espécie, frequentemente relacionada com a falha na transmissão da imunidade passiva. O empiema basilar, frequentemente diagnosticado em bezerros, está diretamente relacionado com o manejo do desmame interrompido através da utilização de tabuletas nasais. A neurotuberculose causada por Mycobacterium spp. é uma importante doença neurológica em bovinos jovens e deve ser considerada como diagnóstico diferencial de doenças neurológicas. Dos dados analisados neste período, as doenças neurológicas inflamatórias bacterianas representaram um total de 24,3% entre as doenças neurológicas inflamatórias diagnosticadas neste período e, com isso, conclui-se que representam importantes causas de mortalidade para os ruminantes domésticos. / Central nervous system (CNS) diseases are worldwide economically important conditions in ruminants. The main neurological bacterial diseases which involve inflammation in ruminants are listeriosis, suppurative leptomeningitis and meningoencephalitis, brain and spinal cord abscesses, basilar empyema and neurotuberculosis. This study aim to describe the epidemiological, pathological, microbiological and immunohistochemical findings of the bacterial inflammatory diseases that affect the CNS of ruminants in Rio Grande do Sul state. A retrospective study was performed from January 1996 to December 2015, during which samples of 3.274 cattle, 596 sheep and 391 goats were evaluated. Of these, 219 cattle, 21 sheep and seven goats were diagnosed with inflammatory diseases affecting the CNS. The neurological inflammatory bacterial diseases accounted for 60 cases, which corresponded to 34 cases in cattle, 19 in sheep and seven in goats. These were further subdivided in: meningoencephalitis by L. monocytogenes (eigth sheep, five goats and four cattle), suppurative leptomeningitis and meningoencephalitis (14 cattle, two goats and one sheep), brain abscesses (six cattle and two sheep) and spinal cord (seven sheep), basilar empyema (four cattle and one sheep) and neurotuberculosis (six cattle). Immunohistochemical exam was performed in all cases diagnosed as listeriosis (antibody anti-L. monocytogenes), as suppurative leptomeningitis and meningoencephalitis (antibody anti-E. coli), and as neurotuberculosis (antibody anti-Mycobacterium tuberculosis). L. monocytogenes meningoencephalitis was the main neurological disease in sheep and goats, followed by spinal cord abscesses in sheep. In cattle, suppurative leptomeningitis and meningoencephalitis was the most frequent neurological disease, and its ocorrunce is related to the failure in passive immunity transmission. Basilar empyema is frequently diagnosed in calves and is directly related to early weaning handling through the use of nose-flaps. Neurotuberculosis caused by Mycobacterium spp. is an important neurological disease in young cattle and should be consired as a differential diagnosis of granulomatous meningoencephalitis. During the described period, neurological inflammatory bacterial diseases accounted for 24.3% of the neurological inflammatory diseases, and, thus, these are important causes of death in domestic ruminants.

Meningitis is an infection of the meninges, a layer of tissue surrounding the brain. In cases of pneumococcal meningitis (where the bacterium Streptococcus pneumoniae is the causat- ive agent) this causes severe inflammation, requiring intensive care and rapid antibiotic treatment. The contribution of variation in host and pathogen genetics to pneumococcal meningitis is unknown. In this thesis I develop and apply statistical genetics techniques to identify genomic variation associated with the various stages of pneumococcal meningitis, including colonisation, invasion and severity. I start by describing the development of a method to perform genome-wide association studies (GWAS) in bacteria, which can find variation in bacterial genomes associated with bacterial traits such as antibiotic resistance and virulence. I then applied this method to longitudinal samples from asymptomatic carriage, and found lineages and specific variants associated with altered duration of carriage. To assess meningitis versus carriage samples I applied similar analysis techniques, and found that the bacterial genome is crucial in determining invasive potential. As well as bacterial serotype, which I found to be the main effect, I discovered many independent sequence variants associated with disease. Separately, I analysed within host-diversity during the invasive phase of disease and found it to be of less relevance to disease progression. Finally, I analysed host genotype data from four independent studies using GWAS and heritability estimates to determine the contribution of human sequence variation to pneumococcal meningitis. Host sequence accounted for some variation in susceptibility to and severity of meningitis. The work concludes with a combined analysis of pairs of bacterial and human sequences from meningitis cases, and finds variation correlated between the two.

Distúrbios do sistema nervoso central (SNC) em ruminantes abrangem um importante grupo de enfermidades responsáveis por grandes perdas econômicas em todo o mundo. As principais doenças neurológicas causadas por bactérias em ruminantes e que envolvem processos inflamatórios incluem listeriose, leptomeningites e meningoencefalites supurativas, abscessos cerebrais e medulares, empiema basilar e neurotuberculose. Esta dissertação teve por objetivo a caracterização epidemiológica, patológica, microbiológica e imuno-histoquímica das doenças inflamatórias de origem bacteriana que afetam o SNC de ruminantes no Rio Grande do Sul. Foi realizado um estudo retrospectivo no período compreendido entre janeiro de 1996 a dezembro de 2015, onde um total de 3.274 bovinos, 596 ovinos e 391 caprinos foram avaliados. Destes, 219 bovinos, 21 ovinos e sete caprinos foram diagnosticados com doenças inflamatórias no SNC. As doenças neurológicas inflamatórias de origem bacteriana totalizaram 60 casos divididos em 34 bovinos, 19 ovinos e sete caprinos, os quais foram subdivididas em: meningoencefalite por L. monocytogenes (oito ovinos, cinco caprinos e quatro bovinos), leptomeningite e meningoencefalite supurativa (14 bovinos, dois caprinos e um ovino), abscessos cerebrais (seis bovinos e dois ovinos) e medulares (sete ovinos), empiema basilar (quatro bovinos e um ovino) e neurotuberculose (seis bovinos). O exame imuno-histoquímica foi realizado em todos os casos diagnosticados com listeriose (anticorpo anti-L. monocytogenes), meningite e meningoencefalite supurativa (anticorpo anti-Escherichia coli) e neurotuberculose (anticorpo anti-Mycobacterium tuberculosis). A meningoencefalite por L. monocytogenes representou a principal enfermidade neurológica em ovinos e caprinos, seguido dos abscessos medulares em ovinos. Nos bovinos, a leptomeningite e meningoencefalite supurativa foi a doença neurológica mais prevalente para a espécie, frequentemente relacionada com a falha na transmissão da imunidade passiva. O empiema basilar, frequentemente diagnosticado em bezerros, está diretamente relacionado com o manejo do desmame interrompido através da utilização de tabuletas nasais. A neurotuberculose causada por Mycobacterium spp. é uma importante doença neurológica em bovinos jovens e deve ser considerada como diagnóstico diferencial de doenças neurológicas. Dos dados analisados neste período, as doenças neurológicas inflamatórias bacterianas representaram um total de 24,3% entre as doenças neurológicas inflamatórias diagnosticadas neste período e, com isso, conclui-se que representam importantes causas de mortalidade para os ruminantes domésticos. / Central nervous system (CNS) diseases are worldwide economically important conditions in ruminants. The main neurological bacterial diseases which involve inflammation in ruminants are listeriosis, suppurative leptomeningitis and meningoencephalitis, brain and spinal cord abscesses, basilar empyema and neurotuberculosis. This study aim to describe the epidemiological, pathological, microbiological and immunohistochemical findings of the bacterial inflammatory diseases that affect the CNS of ruminants in Rio Grande do Sul state. A retrospective study was performed from January 1996 to December 2015, during which samples of 3.274 cattle, 596 sheep and 391 goats were evaluated. Of these, 219 cattle, 21 sheep and seven goats were diagnosed with inflammatory diseases affecting the CNS. The neurological inflammatory bacterial diseases accounted for 60 cases, which corresponded to 34 cases in cattle, 19 in sheep and seven in goats. These were further subdivided in: meningoencephalitis by L. monocytogenes (eigth sheep, five goats and four cattle), suppurative leptomeningitis and meningoencephalitis (14 cattle, two goats and one sheep), brain abscesses (six cattle and two sheep) and spinal cord (seven sheep), basilar empyema (four cattle and one sheep) and neurotuberculosis (six cattle). Immunohistochemical exam was performed in all cases diagnosed as listeriosis (antibody anti-L. monocytogenes), as suppurative leptomeningitis and meningoencephalitis (antibody anti-E. coli), and as neurotuberculosis (antibody anti-Mycobacterium tuberculosis). L. monocytogenes meningoencephalitis was the main neurological disease in sheep and goats, followed by spinal cord abscesses in sheep. In cattle, suppurative leptomeningitis and meningoencephalitis was the most frequent neurological disease, and its ocorrunce is related to the failure in passive immunity transmission. Basilar empyema is frequently diagnosed in calves and is directly related to early weaning handling through the use of nose-flaps. Neurotuberculosis caused by Mycobacterium spp. is an important neurological disease in young cattle and should be consired as a differential diagnosis of granulomatous meningoencephalitis. During the described period, neurological inflammatory bacterial diseases accounted for 24.3% of the neurological inflammatory diseases, and, thus, these are important causes of death in domestic ruminants.