Tendo sido comprovada a existência da famílias molecularmente distintas de M. avium circulando em suínos de região sul do Brasil, e havendo dúvidas a respeito da importância da transmissão horizontal como mecanismo de manutenção da doença, o presente teve por objetivo estudar a virulência dessas estirpes, informação importente para o aperfeiçoamento dos métodos de controle. As estirpes emergiram do estudo caso-controle, onde as tipagens moleculares por RFLP mostraram a existência de quatro famílias de M. avium (PIG-A, B, C e D). Um estirpe representante de cada família foi inoculada pela via intra-peritoneal em 48 hamsters com uma dose de 30.000 U.F.C. por animal. Após 2, 13, 26 e 40 dias da inoculação, 12 hamsters inoculados de cada família foram anestesiados, sacrificados e os agentes foram quantificados no fígado, baço e pulmão. A presença das estirpes foi verificada no sangue e também foram realizados exames histológicos. As estipers PIG-A, B, C e D desenvolveram lesões granulomatosas no fígado e baço nos quatro tempos experimentais; disseminaram-se pela via linfo-hemática, multiplicando-se em fígado, baço e pulmão. Nos quatro tempos experimentais houve diferença entre as contagens de U.F.C./g entre os órgãos (T1: p<0,001; T2: p<0,001; T3: p<0,001 e T4: p<0,001) e as obtidas do baço foram sempre superiores às do fígado e pulmão. Nos quatro tempos experimentais houve diferença entre as contagens de U.F.C./g entre as estirpes (T1: p<0,001; T2: <0,001; T3: p<0,001 e T4: p<0,001) e foi possível construir a seguinte escala decrescente de virulência: PIG-B > PIG-A > PIG-D > PIG-C. / Given that the existence of molecularly different families of M. avium circulating in swine of the south area of Brazil has been proved, and that some doubts remain regarding the importance of the horizontal transmission as mechanism of maintenance of the disease, this work aimed to study the virulence of those strains, an important information for the improvement of the control methods. The strains emerged from a case-control study, when the RFLP molecular typification showed the existence of four families of M. avium (PIG-A, B, C and D). A strain representative of each family was inoculated by intra-peritoneal route in 48 hamsters with a dose of 30.000 C.F.U./animal. After 2, 13, 26 and 40 days post-infection, 12 inoculated hamsters of each family were anesthetized, euthanized and the bacteria were quantified in the liver, spleen and lung. The presence of the strains was verified in the blood and also histological exams were accomplished. The strains PIG-A, B, C and D developed granulomatous lesions in the liver and spleen in the four experimental times; they were disseminated by the linfo-haematic route, multiplying in liver, spleen and lung. In the four experimental times there was difference among the countings of C.F.U./g among the organs (T1: p<0,001; T2: p<0,001; T3: p<0,001 and T4: p<0,001) and that obtained of the spleen were always superiors to the one of the liver and lung. In the four experimental times there was difference among the countings of C.F.U./g among the ancestries (T1: p<0,001; T2: p<0,001; T3: p<0,001 and T4: p<0,001) and was possible to build the following order of decreasing virulence: PIG-B > PIG-A > PIG-D > PIG-C.

O Granuloma \"lepróide canino\", quadro sindrômico, também denominada lepra canina, foi descrito pela primeira vez em 1973, no Zimbábue, em cães da raça Boxer e Bull mastiff e consiste em um dos tipos de micobacterioses tegumentares encontradas nos animais de companhia. No presente estudo, objetivou-se caracterizar os aspectos clínicos e epidemiológicos da enfermidade, nos animais atendidos no período de 1990 a 2010, no Serviço de Dermatologia do Hospital Veterinário da Faculdade de Medicina Veterinária e Zootecnia da Universidade de São Paulo, bem como determinar a ocorrência de similaridade gênica da micobactéria envolvida, entre os animais brasileiros e os descritos em trabalhos estrangeiros. A amostragem foi composta de 37 animais com diagnóstico estabelecido por exame histopatológico ou citobacterioscópico cutâneo, onde se verificou evidente predisposição racial (83,7%), principalmente da raça Boxer (61,2%), ampla distribuição etária e ausência de predisposição sexual. Os cães apresentavam bom estado geral, sem comprometimento sistêmico, apenas tegumentar, com predomínio das lesões de morfologia nodular (75,6%) e situadas em pavilhões auriculares (86,5%). O diagnóstico foi estabelecido a partir dos seguintes exames subsidiários: histopatologia cutânea (56,8%), citobacterioscopia (21,6%) e por ambas as metodologias (21,6%). Trata-se ainda de enfermidade ocorrente em várias unidades federativas brasileiras, no entanto parece ser pouco diagnosticada e assim submetida a tratamentos equivocados, o que foi verificado em 54% dos cães tratados preteritamente. Os fármacos empregados no tratamento sistêmico, rifampicina ou enrofloxacina, mostraram-se igualmente eficazes, com estabelecimento da alta clínica em tempo médio de 84,1 dias. Já técnica de reação em cadeia de polimerase (PCR) foi executada a partir de cortes histológicos cutâneos, emblocados em parafina, oriundos de 13 animais, sendo que em 09 (69,2%) deles se detectou a presença de Mycobacterium cepa CLGS, pelo método da PCR em tempo real e a confirmação do agente em comum entre os casos do Brasil e de outros países. / Canine leproid granuloma, syndromic, also called \"canine leprosy, was first described in 1973 in Zimbabwe in Boxer dogs and Bull mastiff and consists of a type of soft tissue mycobacterial infections found in pets. In the present study aimed to characterize the clinical and epidemiological aspects of the disease in animals treated between 1990-2010 at the Department of Dermatology, Veterinary Hospital, Faculty of Veterinary Medicine, University of São Paulo, and to determine the occurrence of genetic similarity of mycobacteria involved, of dogs from Brazil and other countries. The sample consisted of 37 animals with diagnosis established by histopathology or cytology skin, where there was clear racial predisposition (83.7%), mainly Boxer (61.2%), broad age distribution and no sexual predisposition. The dogs were in good general condition, without systemic involvement, only cutaneous, with a predominance of nodular lesions morphology (75.6%) located in the ears (86.5%). The diagnosis was established from the following exams: cutaneous histopathology (56.8%), citology (21.6%) and by both methods (21.6%). It is still disease occurring in several Brazilian states, however appears to be underdiagnosed and thus subjected to inappropriate treatment, which was observed in 54% of dogs treated. The drugs used in systemic treatment, rifampin and enrofloxacin, were equally effective, with the establishment of recovery a mean of 84.1 days. Already technique of polymerase chain reaction (PCR) was performed from histological sections of skin, paraffin embedded, from 13 animals, while in 09 (69.2%) of them detected the presence of Mycobacterium strain CLGS by method of real-time PCR and confirmation of the agent in common between the cases of Brazil and other countries.

Tendo sido comprovada a existência da famílias molecularmente distintas de M. avium circulando em suínos de região sul do Brasil, e havendo dúvidas a respeito da importância da transmissão horizontal como mecanismo de manutenção da doença, o presente teve por objetivo estudar a virulência dessas estirpes, informação importente para o aperfeiçoamento dos métodos de controle. As estirpes emergiram do estudo caso-controle, onde as tipagens moleculares por RFLP mostraram a existência de quatro famílias de M. avium (PIG-A, B, C e D). Um estirpe representante de cada família foi inoculada pela via intra-peritoneal em 48 hamsters com uma dose de 30.000 U.F.C. por animal. Após 2, 13, 26 e 40 dias da inoculação, 12 hamsters inoculados de cada família foram anestesiados, sacrificados e os agentes foram quantificados no fígado, baço e pulmão. A presença das estirpes foi verificada no sangue e também foram realizados exames histológicos. As estipers PIG-A, B, C e D desenvolveram lesões granulomatosas no fígado e baço nos quatro tempos experimentais; disseminaram-se pela via linfo-hemática, multiplicando-se em fígado, baço e pulmão. Nos quatro tempos experimentais houve diferença entre as contagens de U.F.C./g entre os órgãos (T1: p<0,001; T2: p<0,001; T3: p<0,001 e T4: p<0,001) e as obtidas do baço foram sempre superiores às do fígado e pulmão. Nos quatro tempos experimentais houve diferença entre as contagens de U.F.C./g entre as estirpes (T1: p<0,001; T2: <0,001; T3: p<0,001 e T4: p<0,001) e foi possível construir a seguinte escala decrescente de virulência: PIG-B > PIG-A > PIG-D > PIG-C. / Given that the existence of molecularly different families of M. avium circulating in swine of the south area of Brazil has been proved, and that some doubts remain regarding the importance of the horizontal transmission as mechanism of maintenance of the disease, this work aimed to study the virulence of those strains, an important information for the improvement of the control methods. The strains emerged from a case-control study, when the RFLP molecular typification showed the existence of four families of M. avium (PIG-A, B, C and D). A strain representative of each family was inoculated by intra-peritoneal route in 48 hamsters with a dose of 30.000 C.F.U./animal. After 2, 13, 26 and 40 days post-infection, 12 inoculated hamsters of each family were anesthetized, euthanized and the bacteria were quantified in the liver, spleen and lung. The presence of the strains was verified in the blood and also histological exams were accomplished. The strains PIG-A, B, C and D developed granulomatous lesions in the liver and spleen in the four experimental times; they were disseminated by the linfo-haematic route, multiplying in liver, spleen and lung. In the four experimental times there was difference among the countings of C.F.U./g among the organs (T1: p<0,001; T2: p<0,001; T3: p<0,001 and T4: p<0,001) and that obtained of the spleen were always superiors to the one of the liver and lung. In the four experimental times there was difference among the countings of C.F.U./g among the ancestries (T1: p<0,001; T2: p<0,001; T3: p<0,001 and T4: p<0,001) and was possible to build the following order of decreasing virulence: PIG-B > PIG-A > PIG-D > PIG-C.

Foi investigado o valor diagnóstico da resposta alérgica cutânea à tuberculina e do ELISA indireto, com antígeno recombinante MPB 70, em leitões experimentalmente sensibilizados, pela via intramuscular, com suspensões oleosas de M. bovis ou M. avium inativados. Foram utilizados 91 animais divididos em quatro grupos. Os grupos A e B, cada um com 25 indivíduos, grupos C e D com 21 e 20 indivíduos respectivamente, balanceando-se as características de raça, linhagem, faixa etária e sexo. Aos 21 dias de idade, todos os animais foram submetidos a uma triagem com a aplicação de tuberculina PPD de M. bovis, pela via intradérmica na base da orelha e não houve qualquer tipo de reação. Decorridos 60 dias do teste tuberculínico de triagem, o grupo A, recebeu injeção intramuscular de 0,5 mL de uma suspensão oleosa de M. avium estirpe D4; o grupo B, recebeu 0,5 mL de uma suspensão oleosa de M. bovis estirpe AN5; o grupo C (controle I), recebeu 0,5 mL do adjuvante oleoso e o grupo D (controle II), recebeu 0,5 mL de solução fisiológica. Foi realizado o exame histopatológico de biopsias das reações cutâneas e a colheita de sangue para o teste de ELISA de captura. Após 30 dias da sensibilização, foi efetuada a prova de tuberculinização comparativa com reação medida pela variação da espessura da pele com paquímetro às 0h, 24h, 48h e 72h, após a aplicação das tuberculinas. No teste comparativo, lido às 72 horas, a reação foi considerada negativa quando a diferença das reações entre o PPD bovino e o PPD aviário foi menor que 6,7 mm; suspeito ou inconclusivo quando a diferença se situou na faixa de 6,7 a 7,5 mm; e positiva para o tipo de PPD, considerando-se tuberculose para PPD M. bovis e micobacteriose para PPD M. avium, quando a diferença da reação foi superior a 7,5 mm. Nos exames histopatológicos, foi observado intenso infiltrado inflamatório linfocitário no local das reações intradérmicas dos animais testados com o PPD homologo ao tipo de micobactéria utilizada na suspensão oleosa sensibilizante. O ensaio de ELISA com antígeno, MPB 70 recombinante, foi capaz de revelar a presença de anticorpos contra o M. bovis, porém não revelou anticorpos para M. avium. / The diagnostic value of the cutaneous allergic response to tuberculin and Indirect ELISA test was investigated using MPB 70 recombinant antigen, in piglets experimentally sensitized intramuscularly with the oily suspensions of inactivated M. bovis or M. avium. The ninety-one animals used were divided into four groups. The groups A and B were formed each with 25 individuals, and groups C and D, with 21 and 20 individuals, respectively, balancing the characteristics of race, ancestry, age and sex. At the age of 21 days, all the animals were submitted to the screening test with the use of M. bovis PPD, by the intradermal route at the base of the ear and no reaction was detected. Sixty days after the screening tuberculin test, animals of the group A were injected intramuscularly with 0.5 mL of oily suspension of M. avium D4 strain; animals of group B received 0.5 mL of an oily suspension of M. bovis, AN5 strain; and the members of group C (control I) received 0.5 mL of an oily adjuvant and the individuals of group D (control II) received 0.5 mL of saline solution. Histological examinations of biopsies of skin reactions were carried out and blood collections made for capture ELISA. Following 30 days of sensitization, comparative skin reactions were measured by the variation in skin thickness with a caliper at 0h, 24h, 48h an 72h after applications of tuberculins. In the comparative test measured at 72h, the reaction was considered negative when the difference of the reactions between bovine PPD and avian PPD was less than 6.7 mm; suspected or inconclusive, when the difference stood in the range of 6.7 to 7.5 mm; and positive according to the type of PPD, considering tuberculosis the M. bovis PPD and mycobacteriosis the M. avium PPD, when the difference of the reaction was greater than 7.5 mm. In histopathological examinations, intense lymphocytic inflammatory infiltrate were observed at the site of intradermal reactions of the animals tested with PPD homologous to the type of mycobacteria used in sensitizing oil suspension. The ELISA assay with MPB 70 recombinant antigen was able to reveal the presence of antibodies against M. bovis, but did not reveal antibodies to M. avium.

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Hospital Universitário Antonio Pedro / A micobacteriose pós-cirúrgica (MPC) vem emergindo nos últimos anos no Brasil e no mundo como uma infecção relacionada à assistência a saúde, representando um grave problema de saúde pública. Em 2006, vários casos foram informados à Secretaria de Estado de Saúde do Rio de Janeiro (SES/RJ). A partir de março daquele ano, teve início um trabalho conjunto dessa Secretaria e do Ministério da Saúde, que definiu diretrizes para a confirmação do surto/epidemia, para o levantamento das causas, para a identificação das espécies do patógeno envolvido e para estabelecer medidas de prevenção e controle. Este estudo teve como objetivo descrever os aspectos clínicos e sociodemográficos dos pacientes atendidos no Serviço de Infectologia do Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense, com diagnóstico de MPC no período 2006-2009. Casuística e métodos: De abril de 2006 a junho de 2009 foram atendidos no Serviço de Infectologia do HUAP 125 pacientes encaminhados pela SES/RJ por serem casos suspeitos ou confirmados de micobacteriose não tuberculosa adquirida após procedimentos cirúrgicos. Os pacientes chegaram ao HUAP com a ficha própria de notificação de caso de MPC preenchida com os dados da identificação, do procedimento relacionado à infecção, da abordagem diagnóstica e da terapêutica prévia. O tratamento medicamentoso obedeceu às diretrizes estabelecidas pela SES/RJ e pela Agência Nacional de Saúde. Os dados contidos nestas fichas, bem como outras informações concernentes à evolução clínica, tratamento dispensado no HUAP e resposta terapêutica, foram inseridos em um banco de dados especialmente desenvolvido para a pesquisa. Resultados: A maior parte dos casos de MPC ocorreu em pacientes do sexo feminino (77,6%) e a colecistectomia laparoscópica foi o procedimento cirúrgico mais frequente (48,8%). A média do período de incubação foi de 41 dias e a mediana de 31 dias, O sinal clínico mais comum foi a presença de secreção (86,5%), seguida da de nodulações (65,6%). A maior parte dos casos apresentou lesões superficiais e múltiplas (44,8%). Em 45,6% dos casos foram colhidos suabes e tecido para cultura antes do início do tratamento e a positividade deste material foi de 43,5%, valor significantemente maior que o observado quando a coleta de material foi feita após o início do tratamento (16,7%). O tratamento com três fármacos (claritromicina, etambutol e terizidona) foi feito em 90,4% (113/125) dos pacientes, com duração média de 226 dias e mediana de 229 dias. Foram submetidos a pelo menos uma abordagem cirúrgica 77,6% (97/125) dos casos, principalmente aqueles que apresentavam lesões profundas (44/56). Efeitos adversos foram observados em 62,4% (78/125) dos casos, sendo boca amarga o mais frequente. Conclusão: Apesar do longo tempo de tratamento com múltiplos fármacos, a grande maioria dos pacientes aderiu ao tratamento e evoluiu para a cura sem recidivas. / Post-surgical mycobacteriosis (PSM) is emerging as a serious public health problem in Brazil and in the world. In 2006 a number of infections were reported to the Secretary of Health in the Rio de Janeiro State. Starting in March of this year, a joint effort was initiated by this Secretary and the Ministry of Health, in order to set up guidelines to confirm the outbreak/epidemic, to identify its causes, to identify the species of the pathogen involved, and to establish measures of prevention and control. The aim of this work was to describe the clinical and sociodemographic findings of the patients treated at the Infectious Diseases Service of Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense, who had PSM from 2006 to 2009. Patients and Methods: From April 2006 to June 2009, 125 patients were referred by the Secretary of Health of the Rio de Janeiro State to HUAP with suspected or confirmed PSM. Each patient arrived at HUAP had a PSM case report form with data on identification, infection-related procedures, diagnostic approaches, and previous therapy. The treatment was defined by the Secretary of Health of the Rio de Janeiro State and the Health National Agency. The data from these case report forms, as well as other information associated with clinical evolution, treatment at HUAP, and therapeutic response were inserted into a database specially developed for this research. Results: Most PSM cases occurred in female patients (77.6%) and laparoscopic cholecystectomy was the most frequent surgery (48.8%). The mean incubation period was 41 days (median: 31 days). The most common presentation was drainage (86.5%) and nodules (65.6%). Most cases had multiple and superficial lesions (44.8%). Swab and tissue cultures were performed before treatment in 45.6% of the patients and their positivity was 43.5%, value significantly higher than that found when the specimens were obtained after the onset of treatment (16,7%). Most patients (90.4% - 113/125) were treated with a combined therapy using 3 drugs (clarithromycin, ethambutol and terizidone), with a mean duration of 226 days (median: 229 days). Surgical debridement was performed in 77.6% (97/125) of the cases, mainly in those with deep tissues lesions (44/56). Drug adverse effects occurred in 62.4% (78/125) of the cases, and bitter taste was the most common. Conclusion: In spite of multiple-drug and long-term treatment, most patients adhered to therapy and evolved to cure without relapses.

L'ulcère de Buruli (UB), infection à Mycobacterium ulcerans, troisième mycobactériose mondiale, connait une émergence rapide depuis 1980, essentiellement dans les pays d'Afrique subsaharienne. Jusqu’ici, les connaissances épidémiologiques sur l’UB étaient fondées sur des séries de cas cliniques non confirmés par laboratoire. Nous avons constitué la plus grande cohorte de cas confirmés à ce jour rassemblant plus de 1200 patients traités au CDTUB de Pobè au Bénin entre 2005 et 2011, afin de décrire l'épidémiologie clinique de la maladie et d'explorer l’architecture génétique de la susceptibilité à cette maladie. Les patients atteints d’UB sont des enfants (âge médian au diagnostic de 12 ans), présentant une lésion unique (96%), large (plus de 15 cm, 36%), ulcérative (66%) du membre inférieur (60%). Nous rapportons une présentation clinique atypique de l’UB, dans laquelle les patients présentent exclusivement une ostéomyélite à M. ulcerans. Le sex-ratio varie avec l’âge : les garçons sont majoritaires parmi les enfants (57% de patients masculins chez les moins de 15 ans), et les femmes parmi les adultes (33% de patients masculins). La présentation clinique dépend de l’âge et du sexe. 9% des patients masculins ont présenté une ostéomyélite contre 4% des patients féminins. Un an après la fin du traitement, 22% des patients présentent des séquelles fonctionnelles fixées. Une présentation clinique comportant une lésion oedémateuse, osseuse, de grande taille ou plusieurs lésions est significativement associée avec le développement de séquelles fonctionnelles (OR 7.64, IC95% [5.29-11.31]). Les patients coinfectés par le VIH ont un risque significativement plus élevé de développer un UB sévère (OR 2.77, IC95% [1.32-6.33]). Nous avons exploré l’architecture génétique de la susceptibilité à l’UB dans une perspective mendélienne et une perspective complexe. Le cas le plus sévère de la maladie observé dans ce centre appartient à une famille consanguine dans laquelle la ségrégation du phénotype suggère un défaut génétique mendélien récessif. Une analyse de liaison génétique par cartographie d'homozygotie suggère l’implication du locus des béta-défensines sur le chromosome 8 dans la pathogénèse de l'UB, et mène à l’identification d’une délétion homozygote ségrégeant parfaitement avec la maladie. Dans une perspective complexe, une étude d’association pangénomique a été réalisée après génotypage d’une cohorte de 400 cas et 400 témoins exposés sur plus de 2 millions de SNPs par la puce Illumina Omni2.5 et a permis l’identification de nombreux signaux d’intérêt. L’étude de réplication est en cours. La compréhension de la physiopathologie de l'infection à M. ulcerans est cruciale pour générer de nouvelles pistes thérapeutiques et vaccinales. La dissection du contrôle génétique de l'infection par l'hôte est en ce sens indispensable. / Buruli ulcer (BU), caused by Mycobacterium ulcerans, is the third most frequent mycobacteriosis worldwide. It has been rapidly emerging in sub-Saharan African countries since 1980. Until now, knowledge of BU epidemiology relied on series of non laboratory-confirmed clinical cases. From 2005-2011, we recruited the current largest cohort of laboratory-confirmed cases (more than 1,200 patients) at the Pobe CDTUB, Benin, to describe the clinical epidemiology of the disease and to explore the genetic architecture of human susceptibility to BU. Typically, patients with BU were children (median age at diagnosis 12 years) presenting with a unique (96%) large (≥15 cm, 36%) ulcerative (66%) lesion of the lower limb (60%). Atypical clinical presentation of BU included osteomyelitis with no identifiable present or past BU skin lesions. The sex ratio of BU widely varied with age, with male patients accounting for 57% of patients aged 15 years and younger, but only 33% of those older than 15 years. Clinical presentation of BU was significantly dependent on age and sex. 9% male patients had BU osteomyelitis, whereas only 4% of female patients did. 1 year after treatment, 22% of patients with follow-up information presented with permanent functional sequelae. Presentation with oedema, osteomyelitis, or large (≥15 cm in diameter), or multifocal lesions was significantly associated with occurrence of permanent functional sequelae (OR 7•64, 95% CI 5•29–11•31) and operationally defines severe BU. When coinfected with HIV, patients had a significantly higher risk to develop severe BU (OR 2.77, IC95% [1.32-6.33]). We explored the genetic architecture of susceptibility to BU in both mendelian and complex genetic frameworks. The most severe case of the disease to have been treated at the Pobe CDTUB belonged to a consanguineous family in which the segregation of the phenotype was indicative of a recessive mendelian genetic defect. Genetic linkage analysis by homozygosity mapping suggested the implication of the beta-defensin locus on chromosome 8 in BU pathogenesis and lead to the identification of a homozygous deletion, which co-segregated perfectly with the disease in the family. In a complex genetics approach, we undertook a genome-wide association study, which involved the genotyping of more than 2 million SNPs (Illumina Omni2.5) in a cohort of 400 cases and 400 exposed controls. We identified many signals of interest. The replication study is ongoing. Understanding BU physiopathology is crucial to the development of efficient vaccines and drugs. Dissection of the genetic control of the infection by M. ulcerans by its human host therefore constitutes an indispensable step.