Axonal domains are required for proper neuron function. These domains are unstable and degenerate concurrent with the inflammation in multiple sclerosis (MS) and the inflammatory disease models experimental autoimmune encephalomyelitis (EAE) and lipopolysaccharide (LPS) induced inflammation. Previous studies from our laboratory have shown that the axon initial segment (AIS) is maintained independently of the presence of myelin, but that AIS disruption is seen in MS as well as EAE and LPS-mediated inflammation. AIS loss can be interrupted in the early stage of EAE using the anti-inflammatory drug Didox. However, the potential for Didox directed repair of the AIS in later stages of disease has not been investigated. Here, we utilize two models of CNS inflammation to assess the possibility of reversing AIS pathology. Based on our findings, we present the first evidence that AIS degeneration, an axonal pathology observed in MS and in chronic inflammation, is reversible.

A coqueluche é uma doença contagiosa, causada por Bordetella pertussis e B. parapertussis e as vacinas de células inteiras (WCPs) contra pertussis, embora eficazes, foram associadas a efeitos indesejáveis. Já as vacinas pertussis acelulares são menos reatogênicas, mas caras, o que as torna inviáveis para países em desenvolvimento. Nesse estudo, avaliamos a resposta imune induzida por uma vacina pertussis celular com menor teor de LOS (Plow), desenvolvida pelo Instituto Butantan. Para isso, camundongos C57BL-6 foram imunizados com WCP tradicional ou Plow, formulada com MPL-A de B. pertussis ou com Hidróxido de Alumínio e vacinas tríplice bacterianas com componente pertussis acelular, Pertacel ou Adacel. Após o esquema de imunização, foi avaliada a resposta imune humoral e celular contra a B. pertussis, e B. parapertussis, além de resposta inata a um antígeno não relacionado, BCG. Ensaio de transmissão também foi realizado, após desafio com B. pertussis ou B. parapertussis. Nossos resultados consolidam a avaliação da resposta imune humoral e celular induzida pela Plow, além de apresentar resultados bastante interessantes relativos à atividade da Plow na diminuição da transmissão bacteriana, tanto de pertussis quanto de parapertussis. / Bordetella pertussis and B. parapertussis are the causative agents of whooping cough. Whole cell pertussis (wPs) vaccines, although effective, were associated with undesirable effects. On the other hand, aP vaccines are less reactogenic, but expensive, which made their use unable for developing countries. In this study, we assessed the immunological response, induced by a whole cell pertussis vaccine with low LOS content (Plow), developed by Instituto Butantan. To this, C57BL-6 mice were immunized with traditional whole cell pertussis vaccine or Plow, administrated with Monophosporil lipid A from B.pertussis or Aluminum hydroxide, and diphtheria-tetanus-acellular pertussis vaccines, Pertacel or Adacel. After the immunization scheme, were evaluated humoral and cellular immune responses against B. pertussis and B. parapertussis, in addition to innate response to an unrelated antigen, BCG. Transmission assay was also performed, after B. pertussis or B. parapertussis challenge. Our results consolidated the immune humoral and cellular responses induced by Plow, besides interesting results with regards the efficacy of the vaccine in decreasing the transmission of B. pertussis and B. parapertussis in mice.

A terapia endodôntica visa o selamento biológico do complexo sistema apical, contribuindo para isso, as substâncias usadas no tratamento e a resposta imune do paciente. A LILT tem mostrado atividade antiinflamatória, favorecendo o processo reparacional. Sendo assim, este trabalho objetivou analisar o efeito da LILT na atividade secretória de macrófagos, previamente ativados por IFN-? e LPS de E.coli, e estimulados por substâncias liberadas de três tipos de cimentos endodônticos, um a base de óxido de zinco e eugenol, outro a base de hidróxido de cálcio e um terceiro resinoso. A citotoxicidade dessas substâncias foi avaliada usando a técnica de análise do MTT. Macrófagos ativados foram estimulados por essas substâncias ou não (controle) e então, irradiados ou não (controle) e a secreção de proteínas próinflamatórias (interleucina-1 b, fator de necrose tumoral-a e metaloproteinase da matriz-1) foram analisadas pelo teste ELISA. As irradiações foram realizadas com um laser GaAlAs (780 nm, 70 mW, ponta da fibra de 4 mm2, 1.67 seg, 3 J/cm2). Foram usadas duas aplicações de irradiação com intervalo de 6 h. Os dados obtidos foram tratados por Análise de Variância, quando de distribuição normal, ou teste de Friedman, quando de distribuição não normal, com nível de significância de 5 % (p = 0,05). A viabilidade dos controles e células tratados pelos cimentos endodônticos foi similar. Produção de IL-1 b e TNF-a foram observadas. Houve alta produção de MMP-1. Entretanto, sem diferenças estatísticas entre os grupos experimentais. Os grupos irradiados apresentaram resultados similares aos não irradiados. Substâncias liberadas pelos cimentos endodônticos testados não se mostraram citotóxicas nas condições deste experimento. Essas substâncias, bem como a LILT, no parâmetro utilizado, não causam alteração na atividade de secreção de MMP-1, IL-1 b e TNF-a por macrófagos ativados. / The endodontic therapy seeks the dental root canal biological sealing, depending on substances used in this process and patient’s defense immune factors. LILT has shown an anti-inflammatory activity, improving the periapical repair process. This in vitro study aimed to analyze the effect of LILT at the secretory activity of macrophages previously activated by interferon-gamma and lypopolisaccharide from E.coli, and stimulated by substances leached from three endodontic sealers (zinc oxide-eugenol based, resinous and calcium hydroxide-based). Cytotoxicity of these substances was assessed by the MTT test. Activated macrophages were stimulated by the substances or not (control) and then, irradiated or not (control) and the secretion of pro-inflammatory proteins (interleukin-1 b, tumor necrosis factor-a and matrix metalloproteinase-1) was analyzed by ELISA test. The LILT was performed using a GaAlAs laser (780 nm, 70 mW, focal spot of 4.0 mm2, 1.67 sec, 3 J/cm2). Two irradiations with 6 h-intervals were done. The data was compared by either ANOVA test or Friedman’s test. The cell viabilities of controls and cells treated by the sealers were similar. Production of IL -1 b and TNF-a were observed. There was a high production of MMP-1. However, statistical differences were not observed amongst the groups. The irradiated groups presented results similar to those of non irradiated groups. Substances leached from the endodontic sealers are non cytotoxic at these experiments conditions . These substances, as well as the LILT, at the parameter used, were not able to change the secretion of MMP-1, IL-1 b e TNF-a by activated macrophages.

Pesquisa descritivo-explicativa e exploratória sobre a relação entre Turismo e desenvolvimento regional que apresenta o modelo de análise APL Tur, elaborado com base em elementos de referenciais teóricos de economia, geografia, sociologia, administração, comunicação, antropologia e Turismo. O objetivo é mostrar se é possível realizar o desenvolvimento regional por meio do Turismo. Uma região é um contexto territorial delimitado por critérios geográficos, econômicos e políticos. Um dos modelos da análise e gestão do desenvolvimento regional é o Arranjo Produtivo Local APL, uma categoria especial de cluster. Em razão das limitações do APL, elabora-se o modelo particular de análise APL Tur Arranjo Produtivo Local de Turismo. O modelo APL Tur estrutura-se nas dimensões econômica, cultural e organizacional. Os elementos do desenvolvimento regional na dimensão econômica são: delimitação espacial; disparidades intra-regionais; externalidades; sustentabilidade ambiental; e inclusão social. Os elementos do Turismo circunscritos na dimensão econômica são: oferta e demanda; desempenho; priorização; exportação; circuito produtivo; interatividade extra-regional; e acessibilidade. Na dimensão cultural, destacam-se: aspectos históricos; acervos e incentivos; estética; produtos e atrativos; animação; e motivação e satisfação da comunidade. Na dimensão organizacional, têm-se os elementos: poder e capital social; gestão sistêmica; divulgação e imagem; mercadologia e comercialização; planejamento; empreendedorismo e inovação; e conhecimento. Realizou-se o teste do modelo APL Tur, aplicando-o à Região das Hortênsias (Rio Grande do Sul, Brasil), formada pelos municípios de Gramado, Canela, Nova Petrópolis e São Francisco de Paula. Com base no quadro de indicadores dos elementos das dimensões do modelo APL Tur, verifica-se que o Turismo contribui para o desenvolvimento regional, pois proporciona o ingresso, produção e distribuição de riquezas. Para que uma região se desenvolva economicamente por meio do Turismo, é preciso, entretanto, uma gestão adequada das dimensões e elementos do APL Tur, visando à realização dos seus indicadores. O modelo APL Tur é um instrumento adequado para diagnosticar e para identificar oportunidades de melhoria da atividade turística como polarizadora ou como alternativa do desenvolvimento regional. / This is a descriptive-explanatory and exploratory research about the relationship between Tourism and regional development that presents the LPS Tour analysis model and that was worked out taking its basis elements of theoretical references from economics, geography, sociology, administration, communication, anthropology and Tourism. The objective is to show if it is possible to accomplish regional development through Tourism. A region is a territorial context delimitated by geographical, economic, and political criteria. It is taken into consideration that the general model of Local Productive System of Tourism LPS, a especific cathegory of cluster, has limitations to the analysis and management of Tourism. For this reason, the LPS Tour Local Productive System of Tourism - particular model of analysis - is developed. The LPS model is structured in the economic, cultural, and organizational dimensions. The regional development elements in the economic dimension are: spatial delimitation; intra-regional dissimilarities; externalities; environmental sustainability; and social inclusion. The Tourism elements circumscribed in the economic dimension are: supply and demand; performance; prioritization; exportation; productive circuit; extra-regional interactivity; and accessibility. In the cultural dimension, the elements that stand out are: historical aspects; collections and incentives; esthetics; products and attractions; animation; and motivation and satisfaction of the community. In the organizational dimension, we have the following elements: power and stock capital; systemic management; divulgation and image; marketing and commercialization; planning; entrepreneurship and innovation; and knowledge. The test of the LPS Tour model was performed applying it to the Região das Hortênsias (Rio Grande do Sul, Brasil) (The Hydrangeas Region), that is formed by the municipal districts of Gramado, Canela, Nova Petrópolis, and São Francisco de Paula. Based on the panel of indicators of the dimensions elements of the LPS Tour model, it is possible to verify that Tourism contributes to the regional development because it accomplishes the ingression, production and distribution of richness. However, for a region to develop economically through Tourism, an adequate management of its dimensions and elements is necessary, aiming at the accomplishment of the LPS Tour indicators. The LPS Tour model is an adequate instrument to diagnose and to identify opportunities of improvement of the tourist activity, as a polarizer or as an alternative to regional development.

Chlamydia trachomatis serovars D-K are the leading cause of bacterially-acquired sexually transmitted infections in the United States. As an obligate intracellular pathogen, C. trachomatis infects columnar epithelial cells of the genital mucosae and can cause deleterious sequelae such as pelvic inflammatory disease, infertility, and ectopic pregnancy. Several chlamydial antigens reach the host cell cytosol prior to the natural release of chlamydiae at the end of the developmental cycle. While some of these extra-inclusion antigens traffic to the host cell surface, others remain intracellular where they are proposed to influence vital host cell functions and antigen trafficking and presentation. The research herein examines the escape and trafficking of the immunodominant chlamydial antigens MOMP, LPS, and cHsp60 within C. trachomatis serovar E-infected polarized human endometrial epithelial cells. Studies using high-resolution transmission electron microscopy (TEM) and immuno-TEM report the novel escape mechanism of chlamydial antigens via vesicles everted/pinched off from the inclusion membrane, an occurrence observed both in the presence and absence of the antibiotic azithromycin. These extra-inclusion vesicles were differentiated from Golgi vesicles and were shown to deliver chlamydial heat shock protein 60 (cHsp60)-homologs 2 and 3, but not homolog 1, to the infected cell surface. Examination of the iron-responsiveness of the three cHsp60 homologs by immuno-TEM revealed a significant increase in cHsp60-2 following iron deprivation. Further investigation of the trafficking of chlamydial MOMP and LPS antigens enveloped within the protective everted inclusion membrane vesicles within host cells involved density gradient centrifugation for the separation of epithelial secretory pathway components followed by SDS-PAGE and Western blot to determine whether the chlamydial antigen-containing vesicles could fuse with and deliver the antigens to host cell organelles. Coupled with immuno-TEM, these data confirmed the presence of major chlamydial antigens within the endoplasmic reticulum of infected host cells. Additionally, chlamydial lipopolysaccharide (LPS) was co-localized with CD1d, a lipid antigen-presenting molecule. Collectively, these studies (i) establish a novel escape mechanism for chlamydial antigens, (ii) identify cHsp60-2 as a marker of iron stress response in C. trachomatis, and (iii) define for the first time the host cell ER as a destination for selected chlamydial antigens during infection.

No description available.

<p>Toxic products, such as endotoxin from the gram-negative and exotoxin from the gram-positive bacteria, are the most important initiators of the inflammatory host response in sepsis. In addition to antibacterial treatment, numerous attempts have been made to interfere with the exaggerated proinflammatory cascade initiated by the toxins. As most antitoxic and anti-inflammatory agents have shown no clear efficacy, an attractive alternative has been to prevent or minimise their release. Therefore, it was of interest to further study the antibiotic-induced release of toxins after exposure to antibiotics used for the treatment of the most severe infections, especially if protein synthesis inhibitors could reduce the release induced by PBP 3-specific β-lactam antibiotics.</p><p>There were significant reductions in endotoxin release from gram-negative bacteria when the combination of the PBP 3-specific β-lactam antibiotic, cefuroxime, and the protein synthesis inhibitor, tobramycin, was compared with cefuroxime alone. Increasing doses of tobramycin reduced endotoxin release and increased the killing rate. In a kinetic <i>in vitro</i> model the endotoxin release from <i>E.coli</i> was higher after the second dose of cefuroxime. Nevertheless, it was reduced after addition of tobramycin.</p><p>No binding of tobramycin to endotoxin was observed, either <i>in vivo</i> or <i>in vitro</i>. In a porcine sepsis model, a possible anti-inflammatory effect of ceftazidime and tobramycin, expressed as late cytokine inhibition, was seen.</p><p>The protein synthesis inhibitor, clindamycin, released less streptococcal pyrogenic exotoxin A (SpeA) from a group A streptococcus strain than penicillin, and addition of clindamycin to penicillin resulted in less toxin production than penicillin alone. The SpeA production was dependent on the bacterial number at the start of treatment. Higher doses of penicillin also led to less SpeA. </p><p>The choice of antibiotic class and dose may be important in the severely ill septic patient in whom an additional toxin release could be deleterious. A combination of a β-lactam antibiotic and a protein synthesis inhibitor seems beneficial but further investigations are needed.</p>

<p>In patients with sepsis, the activation of the cascade systems, for example the complement system with the generation of C5a, is followed by a state of immunosuppression with impaired bactericidal capacity caused by suppression of the neutrophil granulocytes. To inhibit the C5a-induced systemic inflammatory and the following anti-inflammatory responses, different anti-C5a strategies have been successful in experimental models of sepsis. In animals and in healthy volunteers after injection of lipopolysaccharide (LPS), an up-regulation of the C5a receptor (C5aR) has been reported. Before designing clinical studies, it was of importance to increase the knowledge of C5a and C5aR regulation in humans. </p><p>At the time when the diagnosis of severe sepsis or septic shock can be established clinically, granulocyte C5aR expression, analysed by flow cytometer, was shown to be reduced, whereas monocyte C5aR expression was unchanged. There was a correlation between granulocyte C5aR expression and the severity of disease, as measured by the APACHE II score. </p><p><i>Ex vivo</i> incubation of whole blood with LPS resulted in a reduction in granulocyte C5aR expression. Such a reduction was not found in isolated cells, indicating that the effect was mediated via plasma factors, such as C5a, IL-8 and TNF-α which all were shown to reduce C5aR expression <i>ex vivo</i>.</p><p>Although there was a trend between chemotaxis, as measured by migration in a modified Boyden chamber, and C5aR expression on granulocytes from patients with severe sepsis or septic shock or from healthy individuals, the correlation failed to reach statistical significance.</p><p>It is concluded that granulocyte C5aR expression is affected by several plasma factors and that a reduction is clinically evident at the time of the sepsis diagnosis. Reduced granulocyte C5aR expression is associated with an impaired chemotaxis but does not alone limit the chemotactic response.</p>

No description available.

Toxic products, such as endotoxin from the gram-negative and exotoxin from the gram-positive bacteria, are the most important initiators of the inflammatory host response in sepsis. In addition to antibacterial treatment, numerous attempts have been made to interfere with the exaggerated proinflammatory cascade initiated by the toxins. As most antitoxic and anti-inflammatory agents have shown no clear efficacy, an attractive alternative has been to prevent or minimise their release. Therefore, it was of interest to further study the antibiotic-induced release of toxins after exposure to antibiotics used for the treatment of the most severe infections, especially if protein synthesis inhibitors could reduce the release induced by PBP 3-specific β-lactam antibiotics. There were significant reductions in endotoxin release from gram-negative bacteria when the combination of the PBP 3-specific β-lactam antibiotic, cefuroxime, and the protein synthesis inhibitor, tobramycin, was compared with cefuroxime alone. Increasing doses of tobramycin reduced endotoxin release and increased the killing rate. In a kinetic in vitro model the endotoxin release from E.coli was higher after the second dose of cefuroxime. Nevertheless, it was reduced after addition of tobramycin. No binding of tobramycin to endotoxin was observed, either in vivo or in vitro. In a porcine sepsis model, a possible anti-inflammatory effect of ceftazidime and tobramycin, expressed as late cytokine inhibition, was seen. The protein synthesis inhibitor, clindamycin, released less streptococcal pyrogenic exotoxin A (SpeA) from a group A streptococcus strain than penicillin, and addition of clindamycin to penicillin resulted in less toxin production than penicillin alone. The SpeA production was dependent on the bacterial number at the start of treatment. Higher doses of penicillin also led to less SpeA. The choice of antibiotic class and dose may be important in the severely ill septic patient in whom an additional toxin release could be deleterious. A combination of a β-lactam antibiotic and a protein synthesis inhibitor seems beneficial but further investigations are needed.