Infection after trauma complicates the patients clinical course. Infection leads to longer critical care and hospital stays, has been associated with increased mortality rates and places considerable cost pressures on health economies. The predictors of infection after severe injury are not known, and the effects on outcomes other than mortality are under-reported. The overall objective of this research was to characterise factors predictive of infection in severely injured patients admitted to critical care. A prospective cohort study of 271 patients investigated admission factors predictive of the development of infection. A second study of 280 patients evaluated post-injury immune cell changes and the association with infection. Thirdly the relationship between early coagulopathy and infections was investigated in 158 patients. Finally a study of 385 patients examined the use of Tranexamic Acid (TXA) and its association with infection and other outcomes. Infection was a significant burden for severely injured patients. Admission hypoperfusion was the only early characteristic associated with the development of infection, and a dose dependent relationship was observed between severity of shock and increased percentage of infection (p<0.01). Lymphopenia prolonged to day four post injury was strongly predictive infection (OR 0.10, CI 0.02-0.48, p<0.01). At 24 hours, the anticoagulant Protein C was lower in those with infection (Infection: 70.2 iu/dL vs. No infection: 83.3 iu/dL p=0.02), and increased fibrinolysis was also associated with infectious complications (Infection: 6156 μg/L vs. No infection: 3324 μg/L p=0.03). There was a trend to a beneficial relationship between TXA and infection, and it was independently associated with reduced organ failure (OR 0.27, CI: 0.10 – 0.73, p=0.01) and mortality (OR 0.16 CI 0.03 - 0.86, p=0.03). In severely injured patients, admission shock, prolonged lymphopenia and early coagulation dysfunction post severe injury were independent predictors of infection. Timely modulation of these responses after trauma may help to reduce the burden of infection.

The bronchiectatic lung is a diseased state in which the airways are chronically damaged and dilated. This state is found in the clinical entities of cystic fibrosis and non-cystic fibrosis bronchiectasis. These are two highly relevant chronic suppurative lung diseases in which an understanding of the microbiology of these patients is considered key to appropriate management. This has traditionally been via the use of traditional culture techniques. However, with the development of molecular methodologies, the previously perceived wisdom is being challenged. In both cystic fibrosis and non-cystic fibrosis bronchiectasis, Pseudomonas aeruginosa is considered the most significant pathogen. In CF there has been considerable concern surrounding the risk of transmission of Pseudomonas aeruginosa between patients on the basis of a significant quantity of research into this matter. In contrast, there has been very little research performed into the equivalent risk in non-cystic fibrosis bronchiectasis. In this thesis we describe an extensive single-centre epidemiological review of Pseudomonas aeruginosa spanning both these diseases. Via this we have shown evidence of cross-infection within a non-cystic fibrosis bronchiectasis cohort. This epidemiological review has included multiple genotyping methods including multilocus sequence typing and whole genome sequencing, As an extension of the epidemiological review, we have performed an in silico prediction of hypermutator status from the whole genome sequencing data to provide greater understanding of the likelihood of cross-infection, and have also demonstrated a culture-independent adaption of multilocus sequence typing for potential screening for cross-infection. In addition to Pseudomonas aeruginosa, we have also looked at the wider bacterial community in the lungs of patients with these two conditions via culture-independent techniques. We have shown that whilst Pseudomonas aeruginosa is often an important component, these are clearly complex communities. We have primarily investigated the cohort with non-cystic fibrosis bronchiectasis, but we have demonstrated associations between clinically-relevant markers and complexity of the bacterial communities within the lungs of both these cohorts of patients. Whilst we have used the gold-standard technique of 16S rRNA sequencing, we have also shown the validity of a simple and potentially more feasible profiling technique for standard clinical care. In summary, through the application of culture-dependent and independent molecular techniques, this research has shed light on the epidemiology of Pseudomonas aeruginosa within our respiratory cohorts, and the complexity and clinical relevance of the wider microbial communities within these patients. Such studies are essential if we are to advance our understanding of the bronchiectatic lung and optimise strategies for patient management.

Bacterial infections are a serious problem for patients with burns and other wounds. Such burn wound infection accounts for the pathogenic bacteria by colonising onto burned areas. Therefore, the need for detection and inhibition of such bacterial colonisation requires a methodology for sensing/killing pathogenic bacteria. This research project aims to design a ‗smart‘ wound dressing system which can respond to the microbiological environment of the wound via a simple colour change and will release antimicrobials only when required. Two strains of pathogenic bacteria Staphylococcus aureus (MSSA 476) and Pseudomonas aeruginosa (PAO1) were used in the study. The non-pathogenic bacterium E.coli (DH5α) was used as a control organism as it does not secrete virulence factors and therefore does not lyse membranes of vesicles. The key contributions of this thesis are outlined below. Firstly, an initial responsive nanocapsule system was studied. The fundamental work with giant unilamellar vesicles proved such a responsive system can provide antimicrobial properties when antimicrobial agents were encapsulated within the vesicles. Secondly, partially polymerised vesicles—polydiacetylene/phospholipid vesicles were then developed to improve vesicle stability. The vesicle system was optimised by varying molar concentration of diacetylene monomers (TCDA) in order to obtain relatively stable vesicles as well as sensitivity to the toxins secreted by the pathogenic strains. Measurements proved that the polydiacetylene/phospholipid vesicles can respond to pathogenic bacteria when fluorescent dye/antimcirobials were encapsulated in the vesicles. Finally, a simple prototype dressing was constructed. Plasma polymerised maleic anhydride (pp-MA) deposited onto non-woven polypropylene was shown to be a good method to stabilise vesicles via covalent bonding. Vesicle adhered to pp-MA non-woven polypropylene showed the ability to inhibit/kill the pathogenic strains, quantified by the Japanese Industry Standard assay and also gave a fluorimetric colour response in the presence of pathogenic bacteria when a fluorescent dye is encapsulated within vesicles. Other simple prototypes were also attempted by using hydrogels (gelatine and collagen) to maintain vesicle stability as well as promote tissue healing.

Dental caries is a multifactorial, bacterial, chronic infection that affects millions of people in the world and has become a public health problem. Also referred to as tooth decay, this disease is one of the most common disorders throughout the world, second only to the common cold. Dental caries is the most common chronic childhood disease in the United States and is 5 to 7 times more common than asthma. According to the World Oral Health Report in 2003, dental caries affect 60-80% of school children and a vast majority of adults. Dental caries is a chronic bacterial infection of the hard tissue of the tooth that is characterized by alternating phases of demineralization and remineralization. Dental decay can lead to significant pain and dysfunction that can interfere with basic functions such as eating, sleeping, and speaking. If left untreated, dental caries can result in cavities forming and eventually tooth loss. Although the prevalence and severity of dental caries has decreased over the years, this disease can be better controlled with proper fluoride exposure. Fluoride therapy has become the cornerstone strategy in the prevention of dental caries development and progression. With fluoride being available in various forms, fluoride exposure and/or treatment has greatly increased and has led to decreased incidences of dental caries. Fluoride has the ability to control the initiation and progression of carious lesions, mainly through the promotion of remineralization and the reduction in tooth enamel demineralization. Whether administered systemically or topically, the use of fluoride has proven to be effective in reducing the prevalence of dental caries. The aim of this review is to compare the topical methods of fluoride therapy with systemic applications. The goal is to evaluate the various forms of fluoride treatments based on cost effectiveness, safety, concentration and dosage of fluoride, ease of application, and accessibility to the community. This review will also identify the populations that are most susceptible to dental caries. The purpose of this review is to examine the benefits and risks of the various options of fluoride treatments in order to determine which would be the most the effective, safe, and efficient means of preventing dental caries in high risk populations. Based on the literature review, it was determined that the populations with the greatest risk for dental caries comprised of young children who were from lower socioeconomic backgrounds and elderly adults over the age of 65. After comparing the various forms of fluoride therapies, it was found that systemic fluoride treatments, mainly water fluoridation, would be the most effective in preventing dental caries in high caries risk populations.

Orientador: Elerson Gaetti Jardim Júnior / Banca: Ana Maria Pires Soubhia / Banca: Hélio Massaioshi Tanimoto / Resumo: As doenças infecciosas representam uma das principais causas de perda precoce dos dentes, podendo levar a seqüelas graves. Os microrganismos normalmente envolvidos nessas patologias quase sempre pertencem a microbiota autóctone da cavidade bucal e, quase invariavelmente, são de baixa virulência. Assim, o objetivo desse estudo foi avaliar a susceptibilidade a antimicrobianos de bactérias anaeróbias obrigatórias e anaeróbias facultativas isoladas de processos infecciosos da cavidade bucal, procurando verificar a existência de padrões de susceptibilidade à fármacos nas diferentes espécies e gêneros microbianos. As amostras microbianas foram obtidas de 4 casos de osteomielite crônica da mandíbula, 3 lesões periapicais refratárias ao tratamento endodôntico, 30 infecções endodônticas, 7 casos de periodontite agressiva localizada e 2 casos de periodontite agressiva generalizada. O isolamento dos microbiano foi realizado em meios de cultura seletivos e a identificação dos isolados foi realizada de acordo com suas características morfológicas e bioquímico-fisiológicas. Os isolados, uma vez identificados, foram mantidos em nitrogênio líquido (- 196 oC). Nos testes de susceptibilidade, empregou-se o método de diluição em ágar e o meio de cultura empregado foi o ágar infuso de cérebro coração acrescido de extrato de levedura. Os resultados evidenciaram resistência natural dos anaeróbios facultativos ao metronidazol e níveis moderados de resistência às penicilinas, enquanto a cefoxitina, a associação de amoxicilina/ácido clavulânico e imipenem foram quase que universalmente eficazes. A lincomicina e a clindamicina também se mostraram eficazes, particularmente sobre os anaeróbios obrigatórios. O principal mecanismo de resistência aos b-lactâmicos foi a produção de compostos capazes de degradar essas drogas. / Abstract: Infections diseases represent one of the major causes of early tooth loss, and they can lead to sequels. The microorganisms involved oftenly in these pathologies belong to oral microflora and almost all of them are of virulence potential. Thus, the objective of this study was to evaluate the susceptibility to antimicrobials of obligate and facultative anaerobes recovered from infections in head and neck area, trying to verify the existence of susceptibility patterns to those drugs the different species and microbial goods. Microbials samples were obtained of 4 cases of chronic osteomyelitis, 3 refractary periapical lesions, 30 endodontics infections, 7 cases of localized aggressive periodontitis, 2 cases of generalized aggressive periodontitis. The isolation microbial was accomplished in selective culture means and the identification of the isolated ones was accomplished in agreement with its morphologic and biochemical-physiologic characteristics. The isolates, after identification, were maintained in liquid nitrogen (- 196°C). The susceptibility tests, were carried out throught na agar dilution method and the culture medium employed was brain heart infusion agar supplemented with yeast extract. The results evidenced natural resistance of facultative anaerobes to metronidazole and moderate levels of resistance to penicillin, while cefoxitin, amoxycillin/clavulanic acid and imipenem were almost universally effective, particularly on obligate anaerobes. The main mechanisms of resistance to b-lactams was the production of compounds capable to destroy these drugs. / Mestre

The protozoan parasites Trypanosoma brucei brucei, Trypanosoma congolense and Trypanosoma vivax cause Animal African Trypanosomiasis, a disease responsible for costly livestock pathology and economic losses in Africa. Each of these African trypanosomes are vector-borne and transmitted by the blood-feeding tsetse fly. Additional blood-feeding vectors can spread T. vivax, extending its range into South America. T. b. brucei infection of the mammalian host progresses in waves, with periodic clearance of antigenic variants. Accumulation of slender parasites in the blood is accompanied by accumulation of the density-sensing factor, SIF (stumpy induction factor). SIF drives differentiation from the proliferative slender form to the growth arrested stumpy form at the peak of parasitaemia. This differentiation step aids host survival, and the stumpy form is pre-adapted for continuation of development in the tsetse fly, ensuring transmissibility. Despite facing challenges comparable to T. b. brucei during their life cycle, T. congolense and T. vivax are not found to have morphologically distinguishable slender and stumpy forms. The growth control mechanisms used by these important veterinary pathogens have been investigated in this thesis. Particular focus has been placed on the conservation of quorum sensing pathways within the African Trypanosomes. The potential for cross-species communication has implications for co-infections. T. congolense was found to undergo growth arrest at peak parasitaemia, and transcriptomic changes occurring between ascending and peak parasitaemia were identified and comparisons made to T. b. brucei slender and stumpy transcriptomes. In an examination of the conservation of the SIF-responsive pathway, expression of a T. congolense orthologue was found to rescue stumpy formation in an otherwise SIF-resistant null mutant for the corresponding T. b. brucei gene. The capacity for cross-talk between density-sensing signals in different trypanosome species was tested using conditioned medium from T. congolense bloodstream form cultures. This could activate the expression of a stumpy specific reporter protein in T. b. brucei. A cell line deficient in a SIF-responsive gene showed resistance to the conditioned medium with a delay in reporter expression. These results highlight the unanticipated capacity for different trypanosome species to exhibit intra and inter specific cell-cell communication in the mammalian bloodstream, with possible consequences for their virulence, transmission and evolution.

Hepatitis C virus (HCV) infection has become a global public health concern with over 130 million people chronically infected and over 350,000 deaths every year from HCV-related liver diseases. GB virus-B (GBV-B) infection in tamarins is a surrogate model for acute HCV infection. Whilst HCV infection commonly leads to chronicity, GBV-B is naturally cleared. To better understand this natural clearance, this project aimed to study the associated humoral immune response to GBV-B. Additionally, GBV-B-specific antibodies were produced with the aim of characterising the pathology of the virus. Previously, there was no available GBV-B neutralisation assay to identify antibodies in this animal model. Therefore, a GBV-B neutralisation assay, based on a method that is known to be successful for the closely-related HCV, was developed. This method involved producing pseudotyped retroviral particles (PV) expressing the GBV-B envelope that could infect a human hepatocarcinoma cell line. GBV-B PV production was confirmed by western blotting. Future studies can now test archived tamarin sera in this assay for the presence of neutralising antibodies. Neutralising antibodies found through this model could be epitope mapped, and incorporated into HCV vaccine design strategies. To study the pathology of GBV-B infection, GBV-B-specific antibodies were also produced using two techniques in parallel- classical hybridoma technology and ribosome display. Antibodies targeting the nucleocapsid core protein of GBV-B have been previously detected in tamarins and served as the target for production of GBV-B antibodies using both aforementioned technologies. GBV-B core-specific antibodies were successfully isolated using both technologies and can now be used in downstream techniques, such as immunohistochemistry, to characterise the pathology of GBV-B infection thereby further validating the use of the animal model.

Orientador: Alvimar José da Costa / Coorientador: Carolina Buzzulini / Banca: Fernando de Almeida Borges / Banca: Carlos Noriyuki Kaneto / Resumo: O sistema de criação conjunta ovinos/bovinos, visando melhor aproveitamento da pastagem, provendo diversificação lucrativa, pode deparar com problemas graves nas propriedades rurais, tais como as parasitoses. Dentre as mais importantes, destaca-se a hemoncose. As espécies Haemonchus placei e Haemonchus contortus são comumente encontradas parasitando bovinos e ovinos, respectivamente. A infecção de bovinos por H. contortus constitui, ainda, uma incógnita na literatura, sobretudo a brasileira. Este helminto tem sido descrito parasitando principalmente ovinos e caprinos. As espécies mais citadas parasitando bovinos são H. placei e H. similis. Portanto, objetivou-se no presente estudo avaliar a infectividade de H. contortus para bovinos e comparar sua patogenicidade à de H. placei. Para tal, foram utilizados 10 bezerros, criados e mantidos sem contato com helmintos, assim distribuídos: GI - dois bezerros não inoculados (controle), GII - quatro bezerros inoculados com larvas infectantes (L3) de H. contortus e GIII - quatro bezerros infectados com larvas (L3) de H. placei. Cada bovino recebeu 10.000 L3, de acordo com o grupo experimental, em dose única. Exames coproparasitológicos (McMaster e coproculturas) foram realizados diariamente após o 60 dia da inoculação, objetivando estabelecer o período pré-patente. Foram colhidas, semanalmente, amostras de sangue para hemogramas e dosagens bioquímicas. Decorridos 42 dias pós-infecção, os 10 bovinos foram eutanasiados e necropsiados, sendo colhido "in totum" todos os exemplares de Haemonchus. Nos abomasos foram realizados estudos anátomo-histopatológicos. O período pré patente para H. contortus foi de 20 dias e para H. placei foi de 27 dias. Dentre os parâmetros hematológicos, apenas as quantificações de hemácias apresentaram diferenças significativas (P<0,05), entre os grupos. As concentrações séricas médias de proteínas totais, albumina, ureia ... / Abstract: The ovine/bovine joint breeding system, which aims for a better use of pastures, providing profitable diversification, can face severe problems in rural properties, such as parasites, amongst which Haemonchus infections stand out. H. placei and H. contortus species are commonly found parasitizing cattle and sheep, respectively. Bovine infections by H. contortus still persist as an unknown possibility in literature, especially in Brazil. Such helminth has been described parasitizing sheep and goats, while the main species cited as parasites of bovines are H. placei and H. similis. Therefore, the present study aimed to evaluate infectivity of H. contortus for bovines and compare its pathogenicity to that of H. placei. To achieve this goal, 10 calves were utilized, all created and maintained free of any contact with helminths, distributed as follows: GI - two non-inoculated calves (control group); GII - four animals inoculated with infecting larvae (L3) of H. contortus; and GIII - four bovines infected with larvae (L3) of H. placei. Each inoculated calf received 10,000 L3, according to its experimental group, in a single dose. Coproparasitological exams (McMaster and coprocultures) were performed daily, starting at the 6th post-inoculation day, seeking to establish prepatent periods. Blood samples, for cell counts and biochemical dosages, were collected on a weekly basis. 42 days after infection of experimental animals, all 10 calves were euthanized and necropsied, for subsequent "in totum" collection of all Haemonchus specimens. Anatomical and histopathological examinations were performed on all abomasums. Prepatent period for H. contortus was 20 days, and 27 days for H. placei. Amongst hematological parameters, only erythrocyte counts presented significant differences (P < 0.05) between experimental groups. Average serum concentrations of total proteins, albumin, urea, creatinin, AST and GGT presented significant ... / Mestre

Orientador: Henrique Nunes de Oliveira / Coorientador: Márcia Cristina de Sena Oliveira / Banca: Simone Cristina Méo Niciura / Banca: Rodrigo Giglioti / Resumo: A bovinocultura é um setor com importante destaque no agronegócio brasileiro. O carrapato Ripicephalus (Boophilus) microplus é responsável por perdas econômicas significativas aos pecuaristas e é vetor de hemoparasitoses como Anaplasma spp e Babesia spp. Sabe-se que os bovinos Bos taurus taurus são mais susceptíveis à infestação por carrapatos do que Bos taurus indicus. Acredita-se que o mesmo ocorra para a infecção por Babesia bovis. Neste trabalho, foram avaliados, em duas colheitas, 355 bovinos da raça Angus, pertencentes a uma fazenda de Uruguaiana-RS, nos quais foram realizadas contagens de carrapatos e colheitas de amostras de sangue para quantificação de B. bovis, pela técnica de qPCR, e genotipagem com chip de 150.000 marcadores SNP. Para qPCR utilizaram-se sequências iniciadoras que flanqueiam um fragmento do gene do citocromo B (mt-cytB), como oligonucleotídeos iniciadores. Após genotipagem dos bovinos com o chip Gene Seek Genomic Profiler™ (GGP-HD) da Illumina Infinium®, foi realizado imputação de genótipos, para recuperação de genótipos faltantes, e controle de qualidade. Foi realizada análise de associação genômica ampla (GWAS), para cada uma das características, infecção por B. bovis e resistência a carrapatos, através do método denominado "Single Step Genomic BLUP" (ssGBLUP). Todos os animais apresentaram infestação por carrapatos e infecção por B. bovis, determinada pela qPCR, e altos valores médios para ambas as características. Algumas regiões cromossômicas ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The cattle industry is a sector with importance in the Brazilian agribusiness. The Ripicephalus (Boophilus) microplus is responsible for economic losses and is a vector for hemoparasitoses, such as Anaplasma spp and Babesia spp. It is known that the Bos tauros animals are more susceptible to infestation by ticks when compared with infestation in Bos indicus animals. It is believed that the same behavior keeps for infection by Babesia bovis. They were evaluated, in two collections, 355 Angus cattle, from a farm in Uruguaiana city, estate of Rio Grande do Sul, where were performed tick counts, quantification of B. bovis by qPCR and genotyping with a 150K chip. Were used as primers, in the qPCR, sequences that flanking the fragment of the cytochrome b gene. The technique was standardized and optimized using specimens of isolates of B. bovis. After genotyping, imputation was carried out, for recovery of missing genotypes, and quality control. Genome association analysis was performed (GWAS), to each of the characteristics, through the method called "Single Step Genomic BLUP" (ssGBLUP). All animals showed tick infestation and infection by B. bovis and high average values for both characteristics. Some regions on chromosomes were identified as significant to the characteristics tick infestation and infection by B. bovis, and seven chromosomes, identified in the present study, were already described in other studies. The present study agrees with other results indicating that the qP... (Complete abstract click electronic access below) / Mestre

Os leucotrienos (LTs) e as citocinas são mediadores inflamatórios produzidos durante a sepse e que podem apresentar uma tarefa moduladora na secreção de arginina-vasopressina (AVP). Na fase aguda da sepse as concentrações plasmáticas de AVP encontram-se aumentadas e na fase tardia em níveis basais, apesar da hipotensão progressiva. Nosso objetivo foi analisar o efeito da injeção intraperitoneal de MK-886, (inibidor da síntese de leucotrienos), sobre a produção de LTs e de citocinas no sítio infeccioso e plasma de animais sépticos. Foram usados ratos Wistar que receberam injeções intraperitoneais de MK-886 (4mg/kg) ou veículo (DMSO 5%) 1h antes da indução de sepse experimental por ligadura e perfuração cecal (CLP) ou da operação fictícia (OF). Os animais foram decapitados 0, 4 e 24h após CLP ou OF. O sangue foi coletado para a determinação do sódio sérico, hematócrito, citocinas, LTB4. O lavado peritoneal foi coletado para dosagem de citocinas. O hipotálamo foi removido e incubado para a análise de cis-LTs. O sódio sérico diminuiu, o hematócrito aumentou e os cis-leucotrienos hipotalâmicos não apresentaram alterações significantes após 4 horas de CLP. A sepse provocou um aumento nas concentrações de TNF-a, no sítio infeccioso, mas não foi detectada no plasma. As citocinas IL-1b e a IL-6 aumentaram em 4 horas tanto no sítio infeccioso como no plasma. A análise dos resultados de LTB4 plasmático mostrou uma diminuição das concentrações 24 horas após o CLP. A administração do MK-886 não modificou o sódio, o hematócrito e aparentemente nem os cis-leucotrienos hipotalâmicos. No sítio infeccioso a droga causou um aumento nas concentrações de TNF-a 4 e 24 horas enquanto as de IL-1b não se modificaram e as de IL-6 aumentaram apenas 4 horas após o CLP. Entretanto, no plasma, a droga diminuiu acentuadamente as concentrações tanto de IL-1b como de IL-6. A análise do LTB4 plasmático mostrou efeito da droga em 4 horas, mas não em 24 horas da sepse. Os resultados deste estudo sugerem que os LTS regulam de maneira diferente a produção de citocinas no plasma e no foco infeccioso e podem explicar os efeitos destes mediadores sobre a secreção de AVP durante a sepse. / Leukotrienes (LTs) and cytokines are inflammatory mediators produced during sepsis and may have a task in modulating the secretion of vasopressin (VP). In the acute phase of sepsis, the plasma AVP concentrations are increased and in the late stage at basal levels, despite the progressive hypotension. Our goal was to analyze the effect of intraperitoneal injection of MK-886 (leukotriene synthesis inhibitor) on the production of LTs and cytokines in the infectious site and plasma of septic animals. We used Wistar rats that received intraperitoneal injection of MK-886 (4.0mg/kg) or vehicle (DMSO 5%) 1 h before induction of experimental sepsis by cecal ligation and puncture (CLP) or sham operation (OF).The animals were decapitated at 0, 4 and 24 h after surgeries and blood was collected for determination of serum sodium, hematocrit, cytokines and LTB4. The peritoneal fluid was collected for cytokine assay. The hypothalamus was removed and incubated for the analysis of cis-LTs. Serum sodium decreased, hematocrit increased and hypothalamic cis-leukotrienes did not show significant changes after 4 hours of CLP. Sepsis caused increase in the TNF-a concentrations in the site of infection, but was not detected in plasma. The cytokines IL-1b and IL-6 increased by 4 hours both in the plasma as in the site of infection. The results of LTB4 showed a decrease in plasma concentrations 24 hours after CLP. The administration of MK-886 did not alter sodium, hematocrit, and apparently neither the cis-hypothalamic leukotrienes. At the site of infection the drug caused an increase in the concentrations of TNF-a 4 and 24 hours while IL-1b remained unchanged and IL-6 increased only 4 hours after CLP. However, in the plasma the drug markedly diminished the concentrations of IL-1b and IL-6. The analysis of LTB4 in plasma showed effects of the drug in 4 hours but not 24 hours of sepsis. The results of this study suggest that LTs differentially regulate the cytokine production in the plasma and in the site of infection, and may explain the effects of these mediators in AVP secretion during sepsis.