No description available.

No description available.

Neisseria meningitidis is the most common cause of bacterial meningitis in the Western world and the second leading cause of mortality in 1-5 year-olds in the United Kingdom. A signature-tagged mutagenesis screen of approximately 3,000 insertional mutants of a serogroup B isolate of N. meningitidis, C311⁺, identified 73 genes required for pathogenesis in an infant rat model of meningococcal septicaemia. Homology-based searches indicate that two of the genes identified, NMB0342 and NMB0345, have homologues in other pathogenic bacteria and exist within a potential operon of seven genes (NMB0342-NMB0348). NBM0342 is a homologue of ispA (intracellular septation protein) of Shigella flexneri, required for effective intercellular spread and plaque formation in epithelial cells. NMB0345 is a homologue of cbf, a Campylobacter jejuni gene that encodes a 29 kDa protein which is a major antigenic peptide. PCR and Southern analyses of genes in the NMB0342-NMB0348 locus show that they are conserved across a wide range of pathogenic isolates and serogroups of N. meningitidis. However, these genes are present only in a subset of commensal strains. N. meningitidis mutants with transpoon insertions in NMB0342 and NMB0345 are highly attenuated when directly competed with the wild-type bacterium in the infant rat model of infection. Mutations have been introduced into other genes within the locus and the resulting mutants analyzed for their ability to cause systemic disease. Mutants with transpoon insertions in the NMB0343 and NMB0344 genes are significantly attenuated, while mutants with insertions in NMB0347 and NMB0348 are attenuated to a lesser degree. Complementation of the NMB0342 mutation by ectopic chromosomal integration of a wild-type copy of NMB0342 almost completely restores the virulence of the bacterium. In vitro cell-culture analyses and microscopic analysis of mutants in association with host cells demonstrate that a mutant with a transpoon insertion in NMB0345 is significantly reduced in its adherence to Chang epithelial cells compared to the wild-type bacterium. Whole blood and serum-sensitivity assays show that the NMB0342 and NMB0345 mutants are highly serum-sensitive compared to the wild-type bacterium. Preliminary experiments have demonstrated that immunization of mice with recombinant NMB0345 protein confers protection against challenge with the serogroup B isolate MC58. In vitro assays demonstrate that recombinant NMB0345 is an active peptidyl polyl cistrans isomerase (PPIase). Together, the results from these investigations support a role for genes of the NMB0342-NMB0348 locus in the pathogenesis of N. meningitidis infections. Further investigation is needed to assess the potential of NMB0345 as a vaccine candidate.

No description available.

Background. Internationally, infectious diseases remain the greatest cause of morbidity among young children. Infectious disease burden is particularly high in low-to-mid income countries (LMIC). South Africa has a high prevalence of bacterial meningitis (BM), especially in children under the age of five. BM is also one of the commonest causes of acquired hearing loss in children. Given the fluctuating and transient nature of BM-related hearing loss, there is a need for an effective audiological protocol to facilitate timeous and appropriate audiological management. There is currently no universally accepted protocol for the audiological referral and management of children diagnosed with BM. Consequently, there is a need for an evidence-based protocol that will ensure timely referral and audiological testing of all children diagnosed with BM. Early identification of BM-related hearing loss in children will allow for timeous, appropriate audiological management and associated benefits, such as an option for placement in mainstream schooling. Objectives. This study aimed to explore the audiological management of children diagnosed with BM at a tertiary hospital in the Western Cape, South Africa, with reference to: patterns of referral for audiological assessment following a diagnosis of BM; current audiological protocols for the management of children diagnosed with BM. It was anticipated that this study would generate evidence that could potentially be used to develop appropriate protocols for the audiological management of children diagnosed with BM in LMICs, specifically South Africa. Methods. A retrospective record review was conducted using patient folders of children between 0 and 6 years who were treated for BM between May 2016 and May 2018. Data collection took place at Red Cross War Memorial Children's Hospital, which has a paediatric infectious diseases unit and an audiology department. Demographic and audiological data were recorded on a self-developed data abstraction form and data were analysed descriptively. Results. A total of 291 patient folders were accessed for review in this study. Of those, 40 (13.7%) met the inclusion criteria for the study and were selected for review. The majority of excluded folders were for patients not referred for audiological testing post-BM diagnosis. For those children referred to audiology, average referral time was 15 days (SD = 24 days) and each patient attended an average of only 2 audiology appointments. Otoacoustic emissions testing and tympanometry were the most commonly performed audiological tests in all children. BM-related hearing loss developed in 2/19 of these patients. All patients who were diagnosed with BM-related hearing loss were subsequently fitted with hearing aids – one of whom was fitted unilaterally with a hearing aid and the other, a cochlear implant candidate, was lost to follow-up. Conclusions. The key challenge experienced in this study was low referral rates to audiology (16%), which was followed by poor adherence to follow-up appointments – both of which were found to impede effective audiological management. Effective management and prevention of BM-related hearing loss pose challenges in LMICs. This study highlights the need for a well-defined referral pathway and an evidence-based protocol for the audiological management of children with BM within the South African health care setting. If this could be achieved, the early identification of hearing loss in these children has the potential to provide them with developmental, scholastic, and working opportunities in line with those of children with normal hearing.

No description available.

As meningites bacterianas constituem um sério problema de Saúde Pública em todo mundo, por sua incidência, sua letalidade e pela frequência das sequelas que os sobreviventes apresentam. Os agentes etiológicos Haemophilus influenzae, Neisseria meningitidis e Streptococcus pneumoniae são responsáveis por cerca de 60 a 80 por cento dos casos. O presente estudo tem como objetivo conhecer o comportamento epidemiológico das meningites por H.influenzae, S. pneumoniae e por bacilos Gram-negativo, especialmente as enterobactérias 1 no Município de São Paulo no pertodo 1960- 77. O levantamento foi realizado por uma equipe formada por professores do Departamento de Medicina Social da Faculdade de Ciências Médicas da Santa Casa de São Paulo, por médicos sanitaristas e por acadêmicos de medicina. Os dados, colhidos diretamente do prontuário dos pacientes, foram anotados em uma ficha pré-codificada. A meningite por H.influenzae somente foi confirmada quando se identificava o agente na cultura. A confirmação da meningite por S.pneumoniae se dava pela bacterioscopia e/ou pela cultura do líquor. As meningites por bacilo Gram-negativo foram subdivididas em 3 grupos. No primeiro, incluíram-se os casos em que a bacterioscopia e/ou cultura revelaram a presença de um bacilo Gram-negativo sem, contudo, haver a especificação do agente. No segundo, classificaram-se os casos em que, na cultura, foi isolada uma bactéria do gênero Salmonella. O último grupo correspondeu áquele em que se identificou a presença de uma outra enterobactéria. Os subdistritos ou distritos do Municipio de São Paulo foram agrupados de 3 maneiras. As duas primeiras corresponderam às 3 ou 6 áreas homogêneas especificadas pela Fundação SEADE. A última se baseou na distibuição da população economicamente ativa segundo sua participação nos diferentes setores da economia. A população dos subdistritos e distritos do Município de São Paulo segundo faixa etária para os anos compreendidos no estudo foi estimada pelo método geométrico modificado. No período estudado foram confirmados 900 casos de meningite por H.influenzae com um coeficiente médio de 0,89 por 100000 habitantes. Os menores de 5 anos contribuíram com 91,2 por cento dos casos, dos quais 63 por cento eram em menores de um ano. O coeficiente médio para menores de um ano foi de 23,3 por 100000 habitantes. As zonas central, intermediária e periférica não apresentaram incidências significantemente diferentes. Os coeficientes de morbidade padronizados segundo idade foram 0,8, 0,8 e 0,9 para as zonas central, intermediária e periférica, respectivamente. A letalidade média no período de 1960-77 foi de 31 por cento . As crianças menores de um ano apresentaram a maior taxa de letalidade, 40 por cento . No período 1960-77 foram confirmados 1951 casos de meningite por S.pneumoniae com um coeficiente médio de 1,9 por 100000 habitantes. As crianças menores de 5 anos contribuíram com 52 por cento dos casos dos quais 38.5 por cento eram menores de um ano. Os coeficientes médio por 100000 habitantes, para os menores de um ano, foram 37,1 e 29,7 para 1960-69 e 1970-77, respectivamente. A incidência por 100000 habitantes na zona periférica (2,2) na primeira década foi, praticamente, o dobro da zona central, (1,2). Os coeficientes padronizados segundo idade foram 1,6, 1,5 e 2,0 para as zonas central, intermediária e periférica, respectivamente. No período seguinte estes valores foram 1,4, 1,5 e 2,0. A letalidade média no período foi de 44 por cento . Ela foi inversamente proporcional ao número de leucócitos no llquor de entrada. A letalidade na faixa etária menores de um ano foi de 60 por cento no período estudado. No período estudado foram identificados 290 casos de meningite por Salmonella dos quais 10 por cento o foram na primeira década. O coeficiente médio por 100000 habitantes foi de 0,3. A S.typhimurium foi a espécie mais frequente com 112 casos. Os menores de um ano contribuíram com 91 por cento dos casos, dos quais 52 por cento ocorreram no primeiro trimestre de vida. A incidência média por zona não mostrou diferencas estatisticamente significantes. A letalidade média foi de 87 por cento . Os menores de um ano apresentaram um valor ainda maior, 89 por cento . No período estudado foram identificados 211 casos de meningite por outras enterobactérias com um coeficiente médio de 0,2. A primeira década contribuiu com 32 por cento dos casos. Os gêneros Escherichia e Enterobacter foram os mais frequentes sendo responsáveis por 71 por cento dos casos. Os menores de um ano contribuiram com 57 por cento dos casos, com coeficiente de 4.0 e 4.5 para os períodos 1960-69 e 1970-77 respectivamente. A letalidade média foi de 65 por cento sendo o grupo etário maior de 60 anos o de maior letalidade. A incidência por zona não diferiu significantemente. A meningite por bacilo Gram-negativo apresentou um comportamento epidemiológico distinto da meningite por H.influenzae e das enterobactérias, revelando ser composto por uma miscelânea de agentes. No período de estudo foram identificados 25455 casos de meningite bacteriana, com coeficiente médio de 25 por 100000 habitantes. O coeficiente passaria a ser de 36 por 100000 habitantes se acrecentássemos as meningites bacterianas de etiologia indeterminada. Este índice representou 1 caso para 2782 habitantes. A meningite por N.meningitidis ocupou o primeiro lugar, com 84 por cento dos casos e um coeficiente médio de 21 por 100000. Na primeira década ocorreram 2657 casos, com um coeficiente médio de 5,4 por 100000 habitantes. As três principais etiologias foram responsáveis por 89 por cento dos casos. No octênio seguinte a meningite por meningococo foi responsável por 90 por cento dos casos. No ano de 1974, acme da epidemia de meningite meningocócica, foram identificados 18069 casos de meningite representando um coeficiente de 264 por 100000. Este valor representaria que 1 em cada 379 habitantes foi acometido pela doença naquele ano. / Bacterial meningitis is an intectious disease of major public health throughout the world because of its high incidence and case fatality rates and the permanent sequelae that are seen in the survivors. Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae are the etiologic agents responsible for 60 to 80 per cent of cases. The purpose of this study is to better understand the epidemiology of meningitis caused by H. influenzae, S. pneumoniae and gram-negative bacilli, especially, the Enterobacteriaceae, in the city of São Paulo during the period 1960-77. The survey was performed by a group of professors from the Department of Social Medicine of the \"Faculdade de Ciências Médicas da Santa Casa de São Paulo\", public health physicians and medical students. Data were obtained directly from the patient\'s records and registered on a pre-coded form. Cases of H.influenzae meningitis were confirmed by culture while S.pneumoniae cases were confirmed by gram stain and/or culture of the cerebrospinal fluid (CSP). The cases of gram negative bacillary meningitis were divided into three groups. The first included the cases that were diagnosed by gram stain and culture; the second, the cases where salmonella species were isolated in the culture: and the third, the cases where the presence of other Enterobacteriaceae were identified. The districts of the city of São Paulo were grouped in three ways: two corresponding to the homogenous areas specified by the \"Fundação SEADE\", and the third one based on the distribution of the economically active population according to its participation in the different branches of economic activity. The population of São Paulo by districts included in the study was estimated by the modified geometric method. During the study, 900 cases ot H. influenzae meningitis were confirmed, giving an average rate ot 0.89 cases per 100,000 population. Children <5 years old represented 91 per cent ot the cases, 63 per cent of them being less than one year old . The average rate for children <1 year old was 23.3 cases per 10O,OOO population. The average case fatality rate for the period 1960-77 was 31 per cent . The hightest case fatality rate ocurred in children <1 year old and was 40 per cent . The central, intermediate and peripheria zones didn\'t show significant different rates of incidence. The age standartized morbidity rates for these zones were, respectively, 0.8, 0.8 and 0.9. During 1960-77, 1,951 cases of S.pneumoniae meningitis were confirmed, giving an average rate of 1.9 per 100,000 population. Children <5 years old accounted for 52.4 per cent ot cases and 38.5 per cent were <l year old. The average rates for children <1 year of age were 37.1 and 29.7 per 100,000 population, for the periods of 1960-69 and 1970- 77, respectively. The incidence rate for the peripheria zone -2.2 per 100000 population- pratically doubled the rate for the central area- 1.2 per 100000 population- in the 1960\'s. The age standardized rates were 1.6, 1.5 and 2.0 tor central, intermediate, and peripheric zones, respectively. In the 1970\'s these rates were 1.4, 1.5 and 2.0. The average case fatality rate for the period was 46.9 per cent , which inversely proportional to the number ot CSF leucocytes at first examination. For children <1 year old, the case tatality rate was 60 per cent during the same period. Two hundred ninety cases of Salmonella meningitis were indentitied during the study, 10 per cent of them during the first decade. The average rate was 0.3 cases per 100,000 population. S. typhimurium was the most frequently isolated species, with 112 cases. Children <1 year old represented 91 per cent of the cases and 52 per cent ot these ocurred in children <3 months of age. The averages rates of incidence in the different zones didn\'t show statistically significant differences. The average case fatality rate was 87 per cent children <1 year old had a rate of 89 per cent . During the study period, 211 cases of meningites by other Enterobacteriaceae were indentified , giving an average rate of 0.2 per 100,000. Almost one-third of these cases ocurred in the first decade of the study period. The genus Escherichia and the genus Enterobacter were the most frequent, being responsible for 32 per cent of the cases. For children under one year 1 the rates were 4.0 and 4.5 for the periods of 1960-69 and 1970-77, respectively, representing 57 per cent of the total of cases. The average case fatality rate was 65 per cent , the hightest being among persons >60 years old. The rates of incidence by zone didn\'t show significant differences. The epidemiology of gram-negative bacillary meningitis was distinct from that of H.influenzae meningitis and meningitis due to the Enterobacteriaceae, giving evidence of being composed by a mixture of agents. In the same period, 25,455 cases of bacterial meningitis were identified, giving an average rate of 25 cases per 100,000 population. This rate would be 36.0 per 100,000 if we added the cases ot bacterial meningitis of unknown etiology. This represents one case per 2,782 inhabitants. N. meningitidis meningitis was the most frequent etiologic agent representing 84 per cent of the total, giving an average rate of 21 per 100,000. From 1960-69, 2,657 cases ocurred, giving an average rate of 5,4. The three principal etiologies were responsible for 89 per cent of cases. During the next eight years, 90 per cent of cases of meningitis were meningococcal. In year of 19/4, during the peak of the meningoccocal meningitis epidemic, 18,069 cases of meningitis were identified, representing a rate of 264 per 100,000. Put another way, 1 in 379 inhabitants developed menngitis.

Padronizou-se a PCR-Multiplex para a detecção do DNA de Neisseria meningitidis. Para tanto os primers escolhidos foram: RW01, DG74 e COR28 baseados na subunidade menor do ribossomo (16S rRNA) que apresenta regiões de seqüências conservadas encontradas em todas as bactérias conhecidas. Os primers RW01 e DG74 amplificaram o fragmento universal bacteriano de 370 bp e, os primers RW01 e COR28, o fragmento específico de N. meningitidis de 279 bp em uma única etapa. Os resultados obtidos nas amostras de LCR de 168 pacientes pelos métodos de cultura e PCR-Multiplex quando comparados à bacterioscopia mostraram que tal técnica apresentou alta sensibilidade (91,3%) no estudo de amostras de LCR de bacterioscopia positiva, enquanto que a cultura apresentou resultados menores (19,7%). Nas amostras de LCR com bacterioscopia negativa a sensibilidade da PCR-Multiplex (57,8%) também foi mais elevada do que da cultura (10%). Estes dados sugerem que a técnica aqui padronizada é altamente promissora para ser utilizada como método diagnóstico da meningite meningocócica, especialmente nos casos de pacientes submetidos à terapia antibiótica prévia. / The PCR-multiplex technique was standardized to detect N.meningitidis DNA. It was used universal primer for all bacteria showing sequence of minor subunit of 16S ribossome regions (RW01, DG74) by amplification of 370bp fragment and another (COR28) for specific sequence of N. meningitidis, amplifying 279bp fragment in one step. The results obtained in CSF samples of 168 patients by culture and PCR-Multiplex technique when compared with microscopy showed high sensitivity (91,3%) in samples with positive microscopy (81) to Gram negative diplococcus, however the culture presented only 19, 7% of positivity in the same samples. In other hand the CSF samples with negative bacterioscopy (67) the PCR-Multiplex sensitivity (57,8%) was higher to culture (10,0%) too. These data indicate a high sensitivity and specificity of PCR as a tool for a rapid diagnosis of meningococcal meningitis, mainly in that patient submitted to previous antibiotic therapy as in case of this work (90% of patients) besides the possibility of a rational practice of specific treatment.

Σκοπός. Η δραστηριότητα της β-γλυκουρονιδάσης στο εγκεφαλονωτιαίο υγρό (ΕΝΥ) είναι αυξημένη στην βακτηριακή μηνιγγίτιδα, αλλά η πορεία της κατά τη διάρκεια της θεραπείας είναι άγνωστη. Σκοπός της μελέτης ήταν η μέτρηση της δραστηριότητας της β-γλυκουρονιδάσης κατά τη διάρκεια της θεραπείας και η σύγκρισή της με άλλες κυτταρικές και βιοχημικές παραμέτρους του ΕΝΥ. Μέθοδος. H δραστηριότητα της β-γλυκουρονιδάσης, ο αριθμός κυττάρων, η συγκέντρωση πρωτεΐνης και ο λόγος γλυκόζης ΕΝΥ/αίματος μετρήθηκαν κατά τη διάρκεια της θεραπείας σε 47 ασθενείς με βακτηριακή μηνιγγίτιδα, από τους οποίους 4 ήταν νεογνά και 97 μάρτυρες. Οι ασθενείς υποβλήθηκαν σε 1 ή 2 επαναληπτικές οσφυονωτιαίες παρακεντήσεις. Επίσης η δραστηριότητα της β-γλυκουρονιδάσης μετρήθηκε σε 8 ασθενείς με πυελονεφρίτιδα και στείρα πλειοκυττάρωση ΕΝΥ. Αποτελέσματα. Πριν τη θεραπεία η διάμεση δραστηριότητα της β-γλυκουρονιδάσης σε ασθενείς βρεφικής μέχρι εφηβικής ηλικίας ήταν 136 moles 4-methylumbelliferone/ml/ώρα (με διακύμανση από 44 έως 826), ενώ στους μάρτυρες ήταν 14 nmoles/ml/ώρα (με διακύμανση 7 έως 23) (p<0,000001). Σε όλους τους ασθενείς με κλινική βελτίωση, η δραστηριότητα της β- γλυκουρονιδάσης ήταν χαμηλότερη σε δείγματα ΕΝΥ, τα οποία ελήφθησαν μετά πάροδο τουλάχιστον 6 ωρών από την έναρξη της θεραπείας. Έξι μέχρι 12 ώρες μετά την έναρξη της θεραπείας η διάμεση δραστηριότητα της β-γλυκουρονιδάσης είχε ήδη μειωθεί κατά 59%. Αντιθέτως, οι υπόλοιποι παράμετροι του ΕΝΥ έδειξαν μεταβλητότητα των τιμών τους, κατά τις πρώτες 24 ώρες της θεραπείας, η οποία ήταν ανεξάρτητη από την πορεία της νόσου. Σε 1 ασθενή με πνευμονιοκοκκική μηνιγγίτιδα, ο οποίος ενεμφάνισε επιδείνωση των συμπτωμάτων του 22 ώρες μετά την έναρξη της θεραπείας, η δραστηριότητα της β-γλυκουρονιδάσης αυξήθηκε κατά 89%. Στη νεογνική μηνιγγίτιδα η δραστηριότητα της β-γλυκουρονιδάσης πριν τη θεραπεία ήταν αυξημένη, αλλά η παρακολούθηση της πορείας της νόσου απαιτεί παρατεταμένη περίοδο ενζυμικών μετρήσεων, για έγκαιρη ρύθμιση της θεραπείας επί υποτροπών και αναμολύνσεων. Συμπεράσματα. Η δραστηριότητα της β-γλυκουρονιδάσης του ΕΝΥ είναι αξιόπιστος δείκτης βακτηριακής μηνιγγίτιδας, που μπορεί να προσδιορίσει, νωρίς στην πορεία της νόσου, την ανταπόκριση στην θεραπεία. / Aim: β-Glucuronidase activity is increased in the cerebrospinal fluid (CSF) of patients with bacterial meningitis. The aim of this study was to investigate the β-glucuronidase activity in the cell-free CSF of bacterial meningitis, its course during treatment and compare it to other CSF parameters. Methods: The β-glucuronidase activity, cell number, protein concentration and CSF/blood glucose ratio were measured in 47 consecutive infants and children with bacterial meningitis, and 97 control subjects. Patients had 1 or 2 follow-up lumbar punctures. Results: The β-glucuronidase activity was increased early in bacterial meningitis, even when the other CSF parameters were undisturbed. Before treatment, the median activity in affected children was 136 moles 4-methylumbelliferone/L/h (range 44-826) and in controls 14 (7-23). In all patients who improved, the activity was lower in the follow-up CSF samples. Six to 12 hours after starting treatment, the median activity was already reduced by 59%. The other CSF parameters showed a variability during the first 24 hours of treatment independently of the course of the disease. Multiple comparisons of the CSF parameters in 17 patients who had 2 follow-up punctures showed that the β-glucuronidase activity was the best prognostic index. Conclusion: β-Glucuronidase activity in the CSF is a reliable indicator of bacterial meningitis, which can identify the response to treatment early in the course of illness. The enzyme activity is increased early in the disease, even when the other laboratory parameters from the CSF remain normal.

Made available in DSpace on 2014-12-17T14:05:22Z (GMT). No. of bitstreams: 1 LeonamGC_TESE.pdf: 2406262 bytes, checksum: 604659dd8ff62335f952679dda971b6e (MD5) Previous issue date: 2013-03-19 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Despite advances in antibiotic therapy, bacterial meningitis (BM) remains with high mortality and morbidity rates in worldwide. One important mechanism associated to sequels during disease is the intense inflammatory response which promotes an oxidative burst and release of reactive oxygen species, consequently leading to cell death. Activation of DNA repair enzymes during oxidative stress has been demonstrated in several neurological disorders. APE1/Ref-1 is a multifunctional protein involved in DNA repair and plays a redox function on transcription factors such as NFkB and AP-1.The aim of this study was assess the role of APE1/Ref-1 on inflammatory response and the possibility of its modulation to reduce the sequels of the disease. Firstly it was performed an assay to measure cytokine in cerebrospinal fluid of patients with BM due to Streptococcus pneumoniae and Neisseriae meningitides. Further, a cellular model of inflammation was used to observe the effect of the inhibition of the endonuclease and redox activity of APE1/Ref-1 on cytokine levels. Additionally, APE1/Ref-1 expression in cortex and hippocampus of rat with MB after vitamin B6 treatment was evaluated. Altogether, results showed a similar profile of cytokines in the cerebrospinal fluid of patients from both pathogens, although IFNy showed higher expression in patients with BM caused by S. pneumoniae. On the other hand, inhibitors of APE1/Ref-1 reduced cytokine levels, mainly TNF-?. Reduction of oxidative stress markers was also observed after introduction of inhibitors in the LPS-stimulated cell. In the animal model, BM increased the expression of the protein APE1/Ref-1, while vitamin B6 promoted reduction. Thereby, this data rise important factors to be considered in pathogenesis of BM, e.g., IFNy can be used as prognostic factor during corticosteroid therapy, APE1/Ref-1 can be an important target to modulate the level of inflammation and VIII oxidative stress, and vitamin B6 seems modulates several proteins related to cell death. So, this study highlights a new understanding on the role of APE1/Ref-1 on the inflammation and the oxidative stress during inflammation condition / A meningite bacteriana (MB) ? uma doen?a infecciosa que permanece com altas taxas de mortalidade e morbidade em todo o mundo, principalmente em pa?ses subdesenvolvidos, apesar dos avan?os na antibioticoterapia. Um dos principais mecanismos associados ?s sequelas durante a MB ? a elevada resposta inflamat?ria, que promove uma exacerbada quantidade de esp?cies reativas de oxig?nio (ERO) levando ?s c?lulas a apoptose ou necrose. A ativa??o de enzimas de reparo de DNA durante o estresse oxidativo tem sido demonstrada nas mais diversas desordens. Uma importante enzima envolvida neste processo ? a endonuclease apur?nica/apirimidinica1/fator redox-1 (APE1/Ref-1). Ela ? uma prote?na multifuncional envolvida no reparo de DNA e na redu??o de fatores envolvidos com a resposta inflamat?ria, tais como o fator nuclear kappa B (NFkB) e prote?na ativadora 1 (AP-1). Este estudo teve como objetivo identificar o envolvimento de APE1/Ref-1 na resposta inflamat?ria visando a possibilidade de sua utiliza??o como alvo terap?utico na redu??o de sequelas durante a MB. Para isto, inicialmente foi realizado uma an?lise no perfil de express?o de citocinas em l?quor de pacientes com meningite causada por Streptococcus pneumoniae e Neisseriae meningitidis visando selecionar moduladores inflamat?rios de interesse para ensaios em cultura de c?lula subsequentes. Em seguida, utilizando um modelo celular de indu??o com LPS foi avaliado o efeito da inibi??o da atividade de reparo e redox de APE1 sobre a express?o de citocinas inflamat?rias. Por fim, foi observada a express?o de APE1 no c?rtex (CX) e hipocampo (HC) de ratos com MB frente a uma terapia adjuvante com vitamina B6. Nossos resultados mostraram um perfil de moduladores inflamat?rios muito semelhante no l?quor dos pacientes com MB causada pelos pat?genos estudados, embora interferon gama (IFNy) tenha sido VI significativamente mais expresso em pacientes com S. pneumoniae do que N. meningitidis. Quanto ao uso dos inibidores das fun??es, redox e de reparo, de APE1/Ref-1 no modelo in vitro, houve redu??o significativa na express?o de algumas citocinas, principalmente o fator de necrose tumoral-alfa (TNF-?). Al?m disso, os inibidores demonstraram uma redu??o nos n?veis de ERO nas c?lulas estimuladas com LPS. No modelo animal, a express?o prot?ica de APE1/Ref-1, no CX e HC dos ratos, foi modulada ap?s introdu??o da vitamina B6. Portanto, esses dados fornecem um novo olhar para a fisiopatologia da MB, em que citocinas como IFNy podem ser usadas em um diagn?stico diferencial entre meningites causadas por S. pneumoniae e N. meningitidis. A prote?na de reparo de DNA, APE1/Ref-1, parece ser um alvo potencial na modula??o da resposta inflamat?ria e do estresse oxidativo, bem como a terapia adjuvante com vitamina B6 mostra ter um papel sobre a express?o de APE1/Ref-1. Consequentemente, o conhecimento obtido neste estudo pode ser importante na melhoria do progn?stico da MB, al?m de contribuir para entender a associa??o entre o reparo de DNA e inflama??o / 2020-01-01 / 2020-01-01