Nas duas últimas décadas, várias espécies de Candida têm surgido como importantes patógenos hospitalares, no mundo e no Brasil. A identificação da origem da infecção tem importância na definição de estratégias de prevenção e controle. As estratégias para a prevenção de candidíase endógena podem focar, parcialmente, em métodos para redução da colonização de mucosas, por exemplo, a restrição ao uso de antibióticos de largo espectro. Entretanto, nos casos nos quais está envolvida uma fonte exógena, um expressivo reforço, na melhoria da qualidade das práticas de assistência à saúde, é prioritário para prevenção da transmissão. O objetivo deste estudo foi avaliar diferentes sítios de colonização por Candida como potenciais fontes de candidemia. O estudo foi desenvolvido em 3 hospitais no Brasil: Instituto Central do Hospital das Clínicas da Faculdade de Medicina de São Paulo, hospital universitário de nível terciário de complexidade, com mil leitos; o Instituto de Infectologia Emílio Ribas, um hospital com 200 leitos, referência para todo o Estado de São Paulo; e o Hospital Geral de Itapecerica da Serra, hospital de cuidados secundários da Grande São Paulo. Foram incluídos no estudo os pacientes com isolamento de Candida em hemocultura obtida de veia periférica após 48 horas de admissão hospitalar. As culturas de vigilância para Candida foram colhidas dos seguintes sítios: urina, reto, cavidade oral, pele (virilha e axila), pele ao redor do cateter e ponta de cateter caso disponível. A tipagem molecular foi realizada quando a mesma espécie de Candida (C. albicans, C. parapsilosis, C. tropicalis and C. glabrata) foi isolada no sangue e nos sítios de vigilância do mesmo paciente. A eletroforese em campo pulsado foi realizada para os isolados de C. albicans, C. parapsilosis e C. glabrata. A amplificação de segmentos polimórficos do DNA foi realizada para C. albicans e C. tropicalis. No total 63 pacientes consecutivos com candidemia foram incluídos no estudo no período de maio de 2004 a outubro de 2005. C. albicans foi isolada em 42% das hemoculturas, C. parapsilosis em 35%, C. tropicalis em 16%, C. guilliermondii, C. krusei, C. glabrata, e C. holmii, em 2% cada uma. Unicamente seis dos 10 isolados de ponta de cateter apresentaram perfil eletroforético idêntico aos isolados de C. parapsilosis do sangue. Os isolados de C. albicans do sangue e de culturas de vigilância do trato gastrintestinal correspondentes, oriundos de 12 pacientes, apresentaram genótipos idênticos. Os resultados sugerem que a colonização do trato gastrintestinal é a provável fonte de candidemia por C. albicans e que a candidemia por C. parasilosis é de origem exógena. / In the last two decades, Candida spp. have emerged as important nosocomial pathogens in the world and in Brazil. The identification of the source of infection is important in approaching prevention and control strategies. Strategies for the prevention of endogenous candidiasis may focus, to a certain extent, on methods for reducing mucosal colonization, for example limitation use of wide-spectrum antibiotics. However, in cases in which an exogenous source is involved, the aggressive reinforcement of adequate healthcare practices is mandatory to prevent transmission. The objective of this study was to evaluate different Candida colonization sites as potential sources for Candida fungemia. The study was done in 3 hospitals in Brazil: the Central Institute of Hospital das Clinicas, a 1000-bed tertiary-care hospital affiliated to the University of São Paulo; the Institute Emilio Ribas, a 200-bed infectious diseases hospital, reference for all the state of São Paulo; and the General Hospital of Itapecerica da Serra, a secondary-care community hospital located in area of the greater São Paulo. The patients with a positive blood culture for Candida, collected from a peripheral vein, were included in the study if they had to be hospitalized for 48 hours or more before candidemia. The following surveillance cultures for Candida were collected from: urine, rectum, oropharynx, skin (groin and axilla), skin around the catheter and catheter tip if available. Molecular typing was performed when the same species of Candida (C. albicans, C. parapsilosis, C. tropicalis and C. glabrata) was isolated from the blood and from surveillance sites of a single patient. Pulsed-field gel electrophoresis was performed for C. albicans, C. parapsilosis and C. glabrata isolates. Randomly amplified polymorphic DNA was performed for C. albicans and C. tropicalis. A total of 63 consecutive patients with candidemia were included in the period from May 2004 to October 2005. C. albicans comprised 42% of the blood isolates, C. parapsilosis 35%, C. tropicalis 16%, C. guilliermondii, C. krusei, C. glabrata, and C. holmii, 2% each. Six of the 10 isolates from catheter tips presented identical electrophoretic profiles to corresponding C. parapsilosis blood cultures and no other surveillance sites were related. C. albicans isolates from blood and from corresponding gastrointestinal surveillance sites from 12 patients presented identical genotypes. In conclusion, our results suggest that tract gastrointestinal colonization is the probable source of C. albicans candidemia and that C. parapsilosis candidemia is not endogenous.

Vaginal candidiasis is a disease with high prevalence in adult women. This study aimed to : ( i ) assess the antiCandida activity of essential oil ( EO ) of S. terebinthifolius front lines of cases of recurrent vaginal candidiasis ; ( II ) produce a antiCandida vaginal cream from OE O. basilicum and evaluate the technological process and this cream antiCandida activity in vitro . The major compounds of OE leaves and dried fruits of S. Terebinthifolius were, respectively, the (+) - camphene (20.1%) and R- ? - pinene (22.1%). In terms of minimum inhibitory concentration (MIC ) and minimum fungicidal , OE Fruit S. terebinthifolius showed bands between 25-200 mg / ml , demonstrating activity against C. parapsilosis ( ATCC 22019 ) and a clinical strain , C. albicans (ATCC 18804) and C. glabrata (ATCC 2001) , not being active on these clinical isolates. Regarding OE leaves, no significant action was observed. The OE dried fruit showed fungistatic , however , no fungicide both OE action, in contrast, leaves and fresh fruits showed antiCandida activity, unless the standard strain of C. glabatra the essential oil from fresh fruits . The major compound of OE O. basilicum (Maria - Bonita) was linalol (72.08%). MIC values ranged between this SO 0.78 to 1.56 mg / ml. Before its antifungal action, was produced a vaginal cream. The samples were stored in these distinct conditions: controlled, refrigerator and oven temperature. In controlled and cooler temperatures, no changes in the formula, however, samples at 45 ° C showed slight changes in texture from the 15th day. It can be concluded that the EO of dried leaves and fruits of S.terebinthifolius Raddi not have antiCandida activity, however, the EO extracted from fresh material Botanical demonstrate such activity . The O. basilicum presents antiCandida action. Tests for antimicrobial activity of vaginal cream in its various concentrations showed satisfactory results compared to a synthetic antifungal.Keywords: Vaginal candidiasis, essential oils, Candida spp., Schinus terebinthifolius Raddi, Ocimum basilicum, vaginal cream, anti-candida. / A candidíase vaginal é uma doença com alta prevalência em mulheres na idade adulta. Este trabalho teve como objetivos: (I) avaliar a atividade antiCandida do óleo essencial (OE) de S. terebinthifolius frente a linhagens de casos de candidíase vaginal recorrente; (II) produzir um creme vaginal antiCandida a partir do OE do O. basilicum e avaliar o processo tecnológico e a atividade antiCandida deste creme in vitro. Os compostos majoritários do OE das folhas e frutos secos de S. terebinthifolius, foram respectivamente, o (+) -Camphene (20,1%) e o R-?-pinene (22,1%). Em se tratando das concentrações inibitórias mínimas (CIM) e fungicidas mínimas, o OE do fruto de S. terebinthifolius apresentou faixas entre 25 - 200 mg/ml, demonstrando atividade contra C. parapsilosis (ATCC 22019) e sua linhagem clínica, C. albicans (ATCC 18804) e C. glabrata (ATCC 2001), não sendo ativo aos isolados clínicos destas. Em relação ao OE das folhas, nenhuma ação significativa foi observada. O OE dos frutos secos apresentou ação fungistática, porém, não houve ação fungicida de ambos os OE, em contrapartida, as folhas e frutos frescos apresentaram atividade antiCandida, salvo, a linhagem padrão de C. glabatra pelo óleo essencial dos frutos frescos. O composto majoritário do OE de O. basilicum (Maria-Bonita) foi o linalol (72,08%). Os valores das CIM deste OE variaram entre 0,78 a 1,56 mg/ml. Diante de sua ação fungicida, foi produzido um creme vaginal. As amostras deste foram armazenadas em condições distintas: temperatura controlada, refrigerador e estufa. Em temperatura controlada e refrigerador, não houve modificações na fórmula, entretanto, as amostras à 45º C, apresentaram modificações leves na textura a partir do 15º dia. Pode-se concluir que os OE de folhas e frutos secos da S.terebinthifolius Raddi não apresentam atividade antiCandida, porém, os OE extraídos do material botânico fresco demonstram tal atividade. O O. basilicum apresenta ação antiCandida. Os testes de atividade antimicrobiana do creme vaginal em suas concentrações distintas demonstraram resultados satisfatórios em comparação a um antifúngico sintético. Palavras-Chave: Candidíase vaginal, óleos essenciais, Candida spp., Schinus terebinthifolius Raddi, Ocimum basilicum, creme vaginal, anti-Candida.

La candidose oro-pharyngée (COP) est l’infection fongique opportuniste la plus commune chez les individus infectés par le VIH-1. La production des cytokines Il-17 et Il-22 par les lymphocytes Th17 est importante lors de la résolution de la COP, puisque ces cytokines induisent la production de peptides antifongiques et le recrutement des neutrophiles polymorphonucléaires. Toutefois, les lymphocytes Th17 sont préférentiellement déplétés chez les individus infectés par le VIH-1. Le modèle de COP chez la souris transgénique (Tg) CD4C/HIVMutA, exprimant les gènes nef, env et rev du VIH-1, permettra de déterminer si des altérations quantitatives et/ou fonctionnelles des sous-populations de lymphocytes T CD4+ causent la sensibilité à la candidose. Les sous-populations Th1, Th2, Th1Th17, Th17 et Treg, ainsi que leurs précurseurs, les lymphocytes T CD4+ naïfs, sont sévèrement déplétées dans les ganglions cervicaux de la souris Tg. Cependant, les lymphocytes T CD4+ naïfs conservent la capacité à se différencier in vitro en présence de cytokines polarisantes et à produire les cytokines typiques des diverses sous-populations. De plus, les cytokines requises pour la polarisation des lymphocytes T CD4+ naïfs n’étaient pas réduites dans les ganglions cervicaux des souris Tg, 7 jours après le début de l’infection. Les gènes S100a8, Ccl20, Il17 et Il22 étaient surexprimés en réponse à la COP chez la souris non-Tg, mais pas chez la souris Tg. Le traitement de souris Tg infectées à l’aide de la combinaison des cytokines Il-17 et Il-22 réduit significativement la charge fongique buccale de C. albicans et le nombre d’hyphes dans l’épithélium de la langue et restaure la capacité à surexprimer des gènes S100a8, Ccl20 et Il22. Ces résultats démontrent que la perturbation de l’induction de l’immunité innée par l’Il-17 et l’Il-22 augmente la susceptibilité à la COP chez la souris Tg. / Oropharyngeal candidiasis (OPC) is the most common opportunistic fungal infection in HIV-infected individuals. OPC resolution involves Il-17 and Il-22 production by Th17 cells through oral antifungal peptide production and polymorphonuclear neutrophil recruitment. Conversely, Th17 cells are preferentially depleted in HIV-infected individuals. The OPC model in transgenic (Tg) mice expressing nef, env and rev from the HIV-1 genome enables the study of the quantitative and functional defects of the CD4+ T-cell subpopulations. The Th1, Th2, Th1Th17, Th17 and Treg subpopulations, as well as naïve CD4+ T-cell precursors, are severely depleted in the cervical lymph nodes (CLNs) of Tg mice. However, the differentiation capacity of naïve CD4+ T-cells in response to polarizing cytokines was maintained in vitro in Tg mice, as well as their ability to produce the signature cytokines of the various subpopulations. Moreover, the polarizing cytokines were not reduced in the CLNs of Tg mice, 7 days after infection. The S100a8, Ccl20, Il17 and Il22 genes were up-regulated in response to OPC in non-Tg mice, but not in Tg mice. Treatment of infected Tg mice with a combination of Il-17 and Il-22 cytokines significantly reduced the oral fungal burdens of C. albicans as well as the number of hyphae in the tongue epithelium. Treatment also restored S100a8, Ccl20 and Il22 up-regulation in Tg mice. These results show that defective induction of innate immunity, normally mediated by Il-17 and Il-22, increases the susceptibility to OPC in these Tg mice.

A pele e as mucosas constituem as primeiras barreiras na defesa contra infecções e os macrófagos são componentes essenciais do sistema imune inato, importante neste aspecto. O envolvimento destas células pode ser verificado em grande percentual das imunodeficiências primárias. Desta forma, a avaliação da função fagocitária é de extrema relevância para o reconhecimento dos distúrbios imunológicos que acometem a pele. O objetivo do presente estudo foi avaliar a metodologia laboratorial para a detecção de defeitos funcionais dos fagócitos. Para isto foram estabelecidos os seguintes testes laboratoriais: Nitro Blue Tetrazolium (NBT), Dihidrorodamina (DHR), quimiotaxia, fagocitose e a aderência de S. aureus e C. albicans por citometria de fluxo (CF), além de morte intracelular de S. aureus e C. albicans (CF). Para verificar a integridade do sistema complemento realizou-se ensaios hemolíticos para as vias clássica e alternativa (CH50 e AP50). A metodologia proposta foi aplicada em indivíduos normais para a padronização dos testes. O burst oxidativo avaliado pelo teste da dihidrorodamina (DHR) foi aplicado em 101 indivíduos saudáveis e em paralelo, 50 indivíduos sadios para o teste do NBT. Os mesmos testes foram realizados em pacientes com Candidíase mucocutânea crônica (CMC) (n=9 ), Candidíase persistente (n=5), Suspeita de distúrbios de fagócitos (SDF) (n=14), Doença Granulomatosa Crônica (DGC)(n= 7) e portadores de DGC (n=5). A quimiotaxia foi padronizada em 34 controles para neutrófilos estimulados com Lipopolissacarídeo de E.Coli (LPS) e 5 com fungo Candida albicans. A técnica de fagocitose e aderência de patógenos foi padronizada com os mesmos estímulos (n=7 para fungos/n=5 para bactéria). Após a padronização, o ensaio foi aplicado em pacientes com candidíase persistente (n=5 para bactéria e n=5 para fungo) e em pacientes com CMC (n= 3 para bactéria e n=4 para fungo). Os ensaios de fagocitose e morte intracelular (capacidade bactericida e fungicida) foram padronizados em 18 indivíduos sadios para bactérias e os ensaios de morte intracelular para S. aureus foi aplicado em pacientes com CMC (n=5), com CP (n=6), com SDF (n =9) e com DGC (n=2), para os ensaios de fagocitose com morte intracelular para fungos foram utilizados 22 indivíduos saudáveis e após a padronização do ensaio foram aplicados em pacientes com CMC (n=8), pacientes com CP ( n= 7), pacientes com DGC (n=2) e indivíduos com SDF (n= 13) O ensaio de DHR foi padronizado e estabelecido em 80% de intensidade de fluorescência para células estimuladas com PMA e 15% de intensidade de fluorescência para células sem estímulo. Nos resultados do DHR encontrou-se diferença significativa no grupo de DGC (n=7)(P= 0,0001), no grupo de portadores (n=5)(P=0,0005) e no grupo de SDF (n=14)(P= 0,0053). O ensaio do DHR foi repetido após 24 horas da coleta (n=7), não se verificando alteração da resposta. A quimiotaxia mostrou diferença significativa entre C (n=4) vs SDF (n=3)(P=0,0001) e pacientes com CMC apresentaram redução da capacidade quimiotática para bactérias (n=3)e fungos (n= 4) com soro autólogo (P= 0,0246 e P=0,0109, respectivamente). Na fagocitose e aderência de bactérias inativadas ,os grupos de CMC, CP E SDF não mostraram diferenças significativas com bactérias não opsonizadas ou opsonizadas com soro AB e apresentaram menor índice de fagocitose (C x CMC)(P=0,0357) quando foram opsonizadas com soro autólogo. Na fagocitose e aderência de fungos inativados, controles e grupos de pacientes apresentaram resposta semelhante com fagocitose preservada. Os ensaios de morte intracelular para bactérias não opsonizadas houve menor expressão de fagocitose no grupo de C x SDF (P=0,0044). Na capacidade bactericida verificou-se diferença significativa entre os grupos CxCMC (P=0,0403). A opsonização das bactérias com soro AB foi significativamente diferente entre os grupos CxCP (P=0,0129) e CxSDF (P=0,0048) e com capacidade bactericida diferente entre grupos CxCP (P=0,0258) e CxSDF (P=0,0205). Na avaliação da fagocitose de bactérias opsonizadas com soro autólogo foi verificada diferença significativa entre os grupos CxCP (P=0,0013) e CxSDF (P=0,0048). Não houve diferença na capacidade bactericida dos grupos de pacientes com o controle. Os ensaios de fagocitose e morte intracelular para fungos sem opsonização não mostrou diferença estatisticamente significativa. A morte intracelular mostrou-se diferente para o grupo CxCMC (P=0,0155) e quando opsonizado com soro AB houve diferença CxCP (P=0,0369). A fagocitose com opsonização por soro autólogo significativa no grupo CxSDF (P=0,0001) e um paciente de CMC com sua fagocitose comprometida quando comparado com o controle do dia. A morte intracelular foi diferente nos grupos CxCMC (P=0,0018) e CxCP (p=0,0203). Não houve diferença estatisticamente significativa à avaliação do complemento. O ensaio do DHR mostrou ser sensível e preciso para o diagnóstico de DGC e portadores de DGC, porém pode detectar outras alterações de fagócitos. O ensaio de aderência e fagocitose mostraram-se variáveis dificultando a padronização de valores de normalidade e exclusão de defeitos. Ensaios de fagocitose com morte intracelular mostraram-se como a melhor forma de detectar distúrbios de fagócitos além do diagnóstico de DGC. A aplicação de controles do dia mostrou-se necessária e importante para a detecção de defeitos funcionais. O presente trabalho mostrou que a avaliação de distúrbios de fagócitos por morte intracelular por citometria de fluxo pode ser aplicado em outras situações clínicas com comprometimento imunológico / Skin and mucosa are part of the first barriers in the defense against infections, and the macrophages are essential components of the innate immune system, important when related to this aspect. The involvement of these cells can be seen in a large percentage of the primary immunodeficiencies. Therefore, the assessment of the phagocitary function is extremely important for the recognition of immunological disorders which affect the skin. The present study focus on the evaluation of the laboratorial methodology for the detection of functional defects of phagocytes. For this the following laboratorial tests were established: Nitro Blue Tetrazolium (NBT), chemotaxis, phagocytosis and adherence of S. aureus and C. albicans through flow cytometry (FC), besides the intracellular death of S. aureus and C. albicans (FC). To assess the integrity of the complement system hemolytic assays were performed for the classic and alternative pathways (CH50 and AP50). The proposed methodology was applied to normal individuals for the standardization of the assays. The oxidative burst evaluated through the dihydrorodamine essay (DHR) was applied to 101 healthy individuals and in parallel, 50 healthy individuals for the NBT assay. The same assays were performed on patients with Chronic mucocutaneous candidiasis (CMC)(n=9), persistent candidiasis (n=5), Phagocytes disorders suspicious (PDS) (n=14), Chronicle granulomatous disease (CGD)(n=7) and CGD carriers (n=5). Chemotaxis was standardized using 34 controls for neutrophils stimulated by lipopolisacharydes from e. coli (LPS) and 5 by C. albicans. Phagocytosis and adherence of pathogens were standardized using the same stimuli (n=7 for fungi and n=5 for bacteria). Following the standardization, the assay was applied to patients with persistent candidiasis (n=5 for fungi and n=5 for bacteria) and on patients with CMC (n=4 for fungi and n=3 for bacteria). Phagocytosis and intracellular death assays (bactericidal and fungicidal capacity) were standardized using 18 healthy individuals for bacteria and the intracellular death assays for S. aureus were applied on patients suffering from CMC (n=5), from PC (n=6), from PDS (n=9) and from CGD (n=2), for the phagocytosis with fungi intracellular death assays 22 healthy individuals were used, and following the standardization the assay was applied to patients suffering from CMC (n=8), from PC (n=7), from CGD (n=2) and PDS individuals (n=13). The DHR assay was standardized and established according to fluorescence intensity 80% for cells stimulated by PMA and fluorescence intensity 15% for cells without stimuli. In the DHR results a significant difference in the CGD group (n=7)(P= 0,0001), in the carriers group (n=5)(P=0,0005) and in the PDS group (n=14)(P= 0,0053) was found. The DHR assay was performed once again 24 hours after the sample collection (n=7) and no changes in the response were seen. Chemotaxis showed a significant difference between C (n=4) vs PDS (n=3)(P=0,0001) and patients suffering from CMC showed decreased ability in the chemotaxis of bacteria (n=3) and fungi (n=4) with autologous serum (P= 0,0246 e P=0,0109, respectively). In the phagocytosis and adherence of inactivated bacteria, the CMC, PC and PDS groups showed no significant differences with non-opsonizated bacteria or opsonizated with AB serum and presented a lower phagocytosis level (C x CMC)(P=0,0357) when they were opsonizated by autologous serum. In the phagocytosis and adherence of inactivated fungi, controls and patient groups presented a similar response with preserved phagocytosis. In the intracellular death assays for non-opsonizated bacteria there was a lower phagocytosis expression in the C x SDF group (P=0,0044). In the bactericidal ability a significant difference between the groups C x CMC was seen (P=0,0403). The opsonization of bacteria with AB serum showed a significant difference among the groups C x CP (P=0,0129) and C x SDF (P=0,0048) and with different bactericidal ability among the groups C x CP (P=0,0258) and C x SDF (P=0,0205). In the evaluation of the phagocytosis of bacteria opsonizated by autologous serum a significant difference among the groups C x CP (P=0,0013) and C x SDF (P=0,0048) was seen. There was no difference between the bactericidal ability of the patients group and control group. The phagocytosis and intracellular assays for fungi without opsonization presented no significant statistical difference. Intracellular death was different for the C x CMC group (P=0,0155) and when opsonizated by AB serum difference was shown C x CP (P=0,0369). The phagocytosis with opsonization by autologous serum presented significant difference in the C x SDF group (P=0,0001) and in a CMC patient with compromised phagocytosis when compared with the daily control. Intracellular death was different in the C x CMC (P=0,0018) and C x CP (p=0,0203) groups. There was no significant statistical difference according to the complement evaluation. The DHR assay was seen as very sensitive and precise for the diagnosis of CGD, however it can detect other phagocyte alterations. The phagocytosis and adherence assay varied a lot making the standardization of normal values and defects exclusion very difficult. Phagocytosis with intracellular death assays showed the best performance to detect phagocytes disorders besides CGD diagnosis. The use of daily controls was seen as very necessary and important to detect functional disorders. This study demonstrated that phagocytes disorder evaluation through intracellular death using flow cytometry can be applied to other clinical situations which are immunologically compromised

Introdução: As infecções são importantes causas de morbidade e mortalidade em pacientes com lúpus eritematoso sistêmico juvenil (LESJ). No entanto, estudos avaliando somente infecções fúngicas invasivas (IFI) em pacientes com LESJ são restritos a relatos de casos ou série de casos, sem qualquer avaliação sistemática dos possíveis fatores de risco ou desfechos associados. A escassez de dados referentes às IFI em pacientes com LESJ e seu impacto sobre as características da doença em uma grande população levou ao desenvolvimento deste estudo multicêntrico. Objetivos: Estudar a prevalência, fatores de risco e mortalidade de IFI em pacientes com LESJ. Método: Um estudo de coorte multicêntrico retrospectivo foi realizado com 852 pacientes com LESJ de 10 Serviços de Reumatologia Pediátrica do Estado de São Paulo. Uma reunião foi realizada e todos os pesquisadores foram treinados para o preenchimento do banco de dados. As IFI foram diagnosticadas de acordo com as definições revisadas pelo grupo de consenso EORTC/MSG (comprovadas, prováveis ou possíveis). Foram coletados dados acerca de dados demográficos, características clínico-laboratoriais, atividade da doença (SLEDAI-2K), dano cumulativo (SLICC/ACR-DI) e tratamento, além de características e complicações das IFI. Resultados: IFI foram diagnosticadas em 33/852 (3,9%) pacientes com LESJ. IFI comprovadas foram diagnosticadas em 22 pacientes, IFI prováveis em 5 e IFI possíveis em 6. Os tipos de IFI encontradas foram: candidíase em 20 pacientes, aspergilose em 9, criptococose em 2, histoplasmose disseminada em um e paracoccidioidomicose em um. A mediana de duração da doença foi menor (1,0 vs. 4,7 anos, p < 0,0001), com maiores escores de SLEDAI-2K atual [19,5 (0-44) vs. 2 (0-45), p < 0,0001] e dose atual de prednisona [50 (10-60) vs. 10 (2-90) mg/dia, p < 0,0001] em pacientes com IFI em comparação com os pacientes sem IFI. A frequência de óbito foi maior no grupo com IFI (51% vs. 6%, p < 0,0001). A análise de regressão logística revelou que SLEDAI-2K atual (OR=1,108, IC 95%=1,057- 1,163, p < 0,0001), dose atual de prednisona (OR=1,046, IC 95%=1,021-1,071; p < 0,0001) e duração da doença (OR=0,984, IC 95%=0,969-0,998, p=0,030) foram fatores de risco independentes para IFI (R2 Nagelkerke 0,425). Conclusão: Este foi o primeiro estudo que caracterizou IFI em pacientes com LESJ. Identificou-se que a atividade da doença e uso de glicocorticoides foram os principais fatores de risco para estas infecções potencialmente graves, principalmente nos primeiros anos de curso da doença e com uma elevada taxa mortalidade / Introduction: Infections are an important cause of morbidity and mortality in childhoodonset systemic lupus erythematosus (cSLE) patients. However, studies evaluating solely invasive fungal infections (IFI) in cSLE patients are restricted to case reports or case series without any systematic evaluation of the possible associated risk factors and outcome in pediatric lupus population. The scarcity of data regarding IFI in cSLE patients and its impact on disease characteristics in a large population led to the development of this multicenter study. Objective: To study the prevalence, risk factors and mortality of IFI in cSLE patients. Methods: A retrospective multicenter cohort study was performed in 852 cSLE patients from 10 Pediatric Rheumatology services. An investigator meeting was held and all participants received database training. IFI were diagnosed according to EORTC/MSG Consensus Group criteria (proven, probable and possible). Demographic data, clinical, laboratorial, disease activity (SLEDAI-2K), cumulative damage (SLICC/ACR-DI) and treatment were collected. IFI were characterized and its outcome were also evaluated. Results: IFI were observed in 33/852 (3.9%) cSLE patients. Proven IFI was diagnosed in 22 cSLE patients, probable IFI in 5 and possible IFI in 6. Types of IFI were: 20 candidiasis, 9 aspergillosis, 2 cryptococcosis, one disseminated histoplasmosis and one paracoccidioidomycosis. The median of disease duration was lower (1.0 vs. 4.7 years, p < 0.0001), with a higher current SLEDAI-2K [19.5 (0-44) vs. 2 (0-45), p < 0.0001] and current prednisone dose [50 (10-60) vs. 10 (2-90) mg/day, p < 0.0001] in patients with IFI compared to those without IFI. The frequency of death was higher in the former group (51% vs. 6%, p < 0.0001). Logistic regression analysis revealed that current SLEDAI-2K (OR=1.108; 95%CI=1.057-1.163; p < 0.0001), prednisone current dose (OR=1.046; 95%CI=1.021-1.071; p < 0.0001) and disease duration (OR=0.984; 95%CI=0.969-0.998; p=0.03) were independent risk factors for IFI (R2 Nagelkerke 0.425). Conclusion: This was the first study that characterized IFI in cSLE patients. We identified that disease activity and glucocorticoid use were the main risk factors for these life-threatening infections, mainly in the first years of disease course and with a high rate of fatal outcome

Le cancer de la cavité orale représente un problème important de santé publique en France où les taux d’incidence sont parmi les plus élevés au monde. Bien qu’une détection précoce soit possible, ces tumeurs sont souvent diagnostiquées à un stade avancé et sont ainsi responsables de plus de 1500 décès par an. L’objectif général est de clarifier le rôle et l’impact des différents facteurs de risque dans la survenue des cancers de la cavité orale en France, notamment d’examiner de façon détaillée le rôle du tabac et de l’alcool par localisation anatomique précise, et d’étudier les associations avec d’autres facteurs de risque potentiels (indice de masse corporelle, antécédents médicaux, antécédents familiaux de cancer, consommations de café et de thé). Ce travail s’appuie sur les données d’une large étude cas-témoins en population générale, l’étude ICARE. Il porte sur un sous-ensemble de ces sujets (772 cas de cancer de la cavité orale et 3555 témoins). Les résultats montrent que le tabac augmente le risque de cancer de la cavité orale même pour des quantités et/ou durées faibles, alors que l’augmentation de risque liée à l’alcool n’est observée que pour de fortes consommations. L’effet conjoint du tabac et de l’alcool est plus que multiplicatif. Les associations avec les consommations d’alcool et de tabac varient selon la sous localisation : les associations les plus fortes sont observées pour le plancher buccal, les plus faibles pour les gencives. L’étude des autres facteurs de risque a mis en évidence : une association inverse entre risque de cancer de la cavité orale et indice de masse corporelle, avec un risque plus faible chez les personnes en surpoids ou obèses ; un risque augmenté lorsqu’un parent du 1er degré a été atteint d’un cancer des voies aéro-digestives supérieures ; un risque élevé chez les personnes présentant des antécédents de candidose buccale ; un risque diminué chez les consommateurs de thé ou de café. A partir de ces premiers résultats, il est envisagé de construire un score prédictif de cancer de la cavité orale permettant d’identifier les sujets à risque élevé sur lesquels cibler préférentiellement les actions de dépistage. / Cancer of the oral cavity is a major public health problem in France. Incidence rates are among the highest in the world. Although early detection is possible and effective, these tumors are often diagnosed at an advanced stage and are thus responsible for over 1,500 deaths per year. The objective of this work was to clarify the role and impact of several risk factors in the development of cancers of the oral cavity in France, particularly to examine the role of tobacco smoking and alcohol drinking by subsite, and to explore associations with other potential risk factors (body mass index, medical history, family history of cancer, tea and coffee consumption). We analyzed detailed data from 772 cases of cancer of the oral cavity and 3555 controls included in a large population-based case-control study, the ICARE study. Tobacco smoking increased the risk of oral cavity cancer even for low quantities and/or durations, while alcohol drinking increased this risk only in heavy drinkers. The combined effect of tobacco and alcohol was greater than multiplicative. Associations with alcohol and tobacco consumption varied depending on subsite: the strongest associations were observed for the floor of the mouth, the lowest for the gums. The analysis of other risk factors showed: an inverse association between oral cancer risk and body mass index with a lowered risk among overweight or obese; an increased risk associated with an history of head and neck cancer in 1st degree relatives; an elevated risk in people with a history of oral candidiasis and a decreased risk among consumers of tea or coffee. From these first results, it is planned to develop an oral cancer risk score to identify high-risk individuals for screening.

Introdução: As infecções são importantes causas de morbidade e mortalidade em pacientes com lúpus eritematoso sistêmico juvenil (LESJ). No entanto, estudos avaliando somente infecções fúngicas invasivas (IFI) em pacientes com LESJ são restritos a relatos de casos ou série de casos, sem qualquer avaliação sistemática dos possíveis fatores de risco ou desfechos associados. A escassez de dados referentes às IFI em pacientes com LESJ e seu impacto sobre as características da doença em uma grande população levou ao desenvolvimento deste estudo multicêntrico. Objetivos: Estudar a prevalência, fatores de risco e mortalidade de IFI em pacientes com LESJ. Método: Um estudo de coorte multicêntrico retrospectivo foi realizado com 852 pacientes com LESJ de 10 Serviços de Reumatologia Pediátrica do Estado de São Paulo. Uma reunião foi realizada e todos os pesquisadores foram treinados para o preenchimento do banco de dados. As IFI foram diagnosticadas de acordo com as definições revisadas pelo grupo de consenso EORTC/MSG (comprovadas, prováveis ou possíveis). Foram coletados dados acerca de dados demográficos, características clínico-laboratoriais, atividade da doença (SLEDAI-2K), dano cumulativo (SLICC/ACR-DI) e tratamento, além de características e complicações das IFI. Resultados: IFI foram diagnosticadas em 33/852 (3,9%) pacientes com LESJ. IFI comprovadas foram diagnosticadas em 22 pacientes, IFI prováveis em 5 e IFI possíveis em 6. Os tipos de IFI encontradas foram: candidíase em 20 pacientes, aspergilose em 9, criptococose em 2, histoplasmose disseminada em um e paracoccidioidomicose em um. A mediana de duração da doença foi menor (1,0 vs. 4,7 anos, p < 0,0001), com maiores escores de SLEDAI-2K atual [19,5 (0-44) vs. 2 (0-45), p < 0,0001] e dose atual de prednisona [50 (10-60) vs. 10 (2-90) mg/dia, p < 0,0001] em pacientes com IFI em comparação com os pacientes sem IFI. A frequência de óbito foi maior no grupo com IFI (51% vs. 6%, p < 0,0001). A análise de regressão logística revelou que SLEDAI-2K atual (OR=1,108, IC 95%=1,057- 1,163, p < 0,0001), dose atual de prednisona (OR=1,046, IC 95%=1,021-1,071; p < 0,0001) e duração da doença (OR=0,984, IC 95%=0,969-0,998, p=0,030) foram fatores de risco independentes para IFI (R2 Nagelkerke 0,425). Conclusão: Este foi o primeiro estudo que caracterizou IFI em pacientes com LESJ. Identificou-se que a atividade da doença e uso de glicocorticoides foram os principais fatores de risco para estas infecções potencialmente graves, principalmente nos primeiros anos de curso da doença e com uma elevada taxa mortalidade / Introduction: Infections are an important cause of morbidity and mortality in childhoodonset systemic lupus erythematosus (cSLE) patients. However, studies evaluating solely invasive fungal infections (IFI) in cSLE patients are restricted to case reports or case series without any systematic evaluation of the possible associated risk factors and outcome in pediatric lupus population. The scarcity of data regarding IFI in cSLE patients and its impact on disease characteristics in a large population led to the development of this multicenter study. Objective: To study the prevalence, risk factors and mortality of IFI in cSLE patients. Methods: A retrospective multicenter cohort study was performed in 852 cSLE patients from 10 Pediatric Rheumatology services. An investigator meeting was held and all participants received database training. IFI were diagnosed according to EORTC/MSG Consensus Group criteria (proven, probable and possible). Demographic data, clinical, laboratorial, disease activity (SLEDAI-2K), cumulative damage (SLICC/ACR-DI) and treatment were collected. IFI were characterized and its outcome were also evaluated. Results: IFI were observed in 33/852 (3.9%) cSLE patients. Proven IFI was diagnosed in 22 cSLE patients, probable IFI in 5 and possible IFI in 6. Types of IFI were: 20 candidiasis, 9 aspergillosis, 2 cryptococcosis, one disseminated histoplasmosis and one paracoccidioidomycosis. The median of disease duration was lower (1.0 vs. 4.7 years, p < 0.0001), with a higher current SLEDAI-2K [19.5 (0-44) vs. 2 (0-45), p < 0.0001] and current prednisone dose [50 (10-60) vs. 10 (2-90) mg/day, p < 0.0001] in patients with IFI compared to those without IFI. The frequency of death was higher in the former group (51% vs. 6%, p < 0.0001). Logistic regression analysis revealed that current SLEDAI-2K (OR=1.108; 95%CI=1.057-1.163; p < 0.0001), prednisone current dose (OR=1.046; 95%CI=1.021-1.071; p < 0.0001) and disease duration (OR=0.984; 95%CI=0.969-0.998; p=0.03) were independent risk factors for IFI (R2 Nagelkerke 0.425). Conclusion: This was the first study that characterized IFI in cSLE patients. We identified that disease activity and glucocorticoid use were the main risk factors for these life-threatening infections, mainly in the first years of disease course and with a high rate of fatal outcome

On t.p.: Degree MSc Dental Science (Community Dentistry) / Thesis (MSc)--Stellenbosch University, 2002. / ENGLISH ABSTRACT: The purpose of this review was to investigate the management of oral candidiasis in HIV/AIDS patients and to evaluate the different guidelines that are available for its management. To achieve this aim, three objectives were identified: (i) to identify and report on the different interventions used to manage oral candidiasis, in patients with HIV/AIDS, (ii) to determine the efficacy of these interventions, and (iii) to provide guidelines for management. A thorough systematic search of the literature was carried out and all relevant papers were graded into three levels of evidence (A, B, and C) and scored for quality according to set criteria. A number of topical and systemic antifungal medications are used to treat oral candidiasis in HIV-positive patients. These include the poleyne antibiotics, nystatin and amphotericin B. Milder episodes of oral candidiasis respond to topical therapy with nystatin, clotrimazole troches or oral ketoconazole. Fluconazole has been extensively evaluated as a treatment for candidiasis. With HIV-infection, a cure rate of 82% has been achieved with a daily oral dose of 50 mg. Fluconazole was found to be a better choice of treatment for relapsing oropharyngeal candidiasis, resulting in either better cure rates or better prevention of relapse. Intravenous amphotericin B has been found to be effective therapy in azole refractory candidiasis where it was shown to be safe and well tolerated. Topical therapies were found to be effective treatment for uncomplicated oropharyngeal candidiasis, however patients relapsed more quickly than those treated with oral systemic antifungal therapy. Overall, nystatin appears less effective than clotrimazole and the azoles in the treatment of oropharyngeal candidiasis. With regard to the resolution of clinical symptoms, clotrimazole was found to be just as effective as the azoles, except when patient compliance was poor. Fluconazole-treated patients were more likely to remain disease-free during the fluconazole follow-up period than with those treated with other interventions. Relatively few studies were qualified to address the provision of guidelines for the management of oral candidiasis in primary health care settings. Most of the studies found were of moderate and low quality level of evidence. These studies included the assessment of different guidelines for identification, treatment and dental needs. They stressed that patients with HN need dentists who will act as primary health care providers, together with other providers to ensure adequate overall care. Given the level of interest and importance of candidiasis associated with treatment of HN -positive patients, it is surprising to find that little high quality research has been undertaken. As such, it is hoped that this review would provide researchers, oral health care workers and other health care providers with an overview of the management of oral candidiasis associated with HN/AIDS. / AFRIKAANSE OPSOMMING: Die doelstelling van die oorsig was om ondersoek in te stel na die hantering van orale kandidiase in HIV/AIDS pasiënte asook om die verskillende beskikbare riglyne vir die behandeling daarvan te evalueer. Ter verwesenliking van hierdie doelstelling is drie doelwitte geïdentifiseer: (i) om die intervensies wat gebruik word in die hantering van orale kandidiase behandeling te identifiseer, (ii) om die effektiwiteit van hierdie intervensies te identifiseer en (iii) om op grond hiervan riglyne vir die hantering voor te stel. 'n Sistematiese literatuursoektog is uitgevoer en alle relevante artikels is in drie groepe geklassifiseer (A, B en C) op grond van die data kwaliteit. 'n Verskeidenheid topikale en sistemiese antifungale middels word gebruik om orale kandidiase in HIV-positiewe pasiënte te behandel. 'n Sukseskoers van 82% is met die gebruik van 'n daaglikse dosis van 50 mg medikament gerapporteer. Fluconazole was die beter keuse van middel vir die behandeling van terugkerende orofaringeale kandidiase. Topikale behandeling was effektief in die behandeling van ongekompliseerde orofaringeale kandidiase, hoewel die kans op terugkeer van die toestand groter was as met die sistemiese middels. Pasiënte wat met flukonasool behandel is, het 'n groter kans gehad om siektevry te bly vergeleke met pasiënte op die ander intervensies. Meeste van die studies was van middelmatige tot lae kwaliteit en gevolglik was dit moeilik om behandelingsriglyne te stel. Wat egter wel duidelik is, is dat HIV pasiënte primêre mondsorg benodig wat saam met ander versorging omvattende sorg sal verseker.

Les levures du genre Candida figurent parmi les pathogènes majeurs isolés chez les patients en soins intensifs et sont responsables d'infections systémiques : les candidoses invasives. Le retard et le manque de fiabilité du diagnostic sont susceptibles d'aggraver l'état du patient et d'augmenter le risque de décès à court terme. Pour respecter les objectifs de traitement, les experts recommandent de traiter le plus précocement possible les patients à haut risque de candidose invasive. Cette attitude permet de proposer un traitement précoce aux malades atteints, mais peut entraîner un traitement inutile et coûteux et favoriser l'émergence de souches de moindre sensibilité aux antifongiques utilisés.Ce travail applique des méthodes statistiques modernes à des données observationnelles longitudinales. Il étudie l'impact des traitements antifongiques systémiques sur la répartition des quatre principales espèces de Candida dans les différents prélèvements de patients en réanimation médicale, sur leur sensibilité à ces antifongiques, sur le diagnostic des candidémies ainsi que sur le pronostic des patients. Les analyses de séries de données temporelles à l'aide de modèles ARIMA (moyenne mobile autorégressive intégrée) ont confirmé l'impact négatif de l'utilisation des antifongiques sur la sensibilité des principales espèces de Candida ainsi que la modification de leur répartition sur une période de dix ans. L'utilisation de modèles hiérarchiques sur données répétées a montré que le traitement influence négativement la détection des levures et augmente le délai de positivité des hémocultures dans le diagnostic des candidémies. Enfin, l'utilisation des méthodes d'inférence causale a montré qu'un traitement antifongique préventif n'a pas d'impact sur le pronostic des patients non neutropéniques, non transplantés et qu'il est possible de commencer une désescalade précoce du traitement antifongique entre le premier et le cinquième jour après son initiation sans aggraver le pronostic. / Candida species are among the main pathogens isolated from patients in intensive care units (ICUs) and are responsible for a serious systemic infection: invasive candidiasis. A late and unreliable diagnosis of invasive candidiasis aggravates the patient's status and increases the risk of short-term death. The current guidelines recommend an early treatment of patients with high risks of invasive candidiasis, even in absence of documented fungal infection. However, increased antifungal drug consumption is correlated with increased costs and the emergence of drug resistance whereas there is yet no consensus about the benefits of the probabilistic antifungal treatment.The present work used modern statistical methods on longitudinal observational data. It investigated the impact of systemic antifungal treatment (SAT) on the distribution of the four Candida species most frequently isolated from ICU patients', their susceptibilities to SATs, the diagnosis of candidemia, and the prognosis of ICU patients. The use of autoregressive integrated moving average (ARIMA) models for time series confirmed the negative impact of SAT use on the susceptibilities of the four Candida species and on their relative distribution over a ten-year period. Hierarchical models for repeated measures showed that SAT has a negative impact on the diagnosis of candidemia: it decreases the rate of positive blood cultures and increases the time to positivity of these cultures. Finally, the use of causal inference models showed that early SAT has no impact on non-neutropenic, non-transplanted patient prognosis and that SAT de-escalation within 5 days after its initiation in critically ill patients is safe and does not influence the prognosis.

Made available in DSpace on 2014-12-17T14:16:35Z (GMT). No. of bitstreams: 1 WalicyranisonPS_DISSERT.pdf: 2780035 bytes, checksum: 20a70f53e533bfb0816b6d9b02b8af32 (MD5) Previous issue date: 2013-06-11 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Candida albicans is a diploid yeast that in some circumstances may cause oral or oropharyngeal infections. The investigation of natural products is mandatory for the discovery of new targets for antifungal drugs development. This study aimed to determine the genotypes of 48 clinical isolates of C. albicans obtained from the oral cavity of kidney transplant patients from two distinct geographic regions of Brazil. In addition, we investigated three virulence factors in vitro: phospholipase activity, morphogenesis and the ability to evade from polymorphonuclear neutrophils. The expression of these virulence factors in vitro was also investigated in the presence of the crude extract of Eugenia uniflora. The genotype A was the most prevalent (30 isolates; 62.5%), followed by genotype C (15 isolates; 31.5%) and genotype B (3 isolates; 6.25%). When microsatellite technique with primer M13 was applied, 80% of the isolates from the South were placed within the same cluster. All Genotype C strains were grouped together within two different clusters. Genotype C was considered more resistant to PMNs attack than genotypes A and B. Strains isolated from the South of Brazil showed higher ability to combat PMNs phagocytosis. We found a high rate of genotype C strains isolated from the oral cavity of this group of patients. The crude extract of E. uniflora inhibited proper hypha formation and phagocytosis by PMNs, but had no significant effect on phospholipase activity. This study characterized oral C. albicans strains isolated from kidney transplant recipients and will contribute for the better understanding of the pathogenesis and alternative therapeutics for oral candidiasis / Candida albicans ? uma levedura dipl?ide que em certas circunst?ncias pode causar infec??es da cavidade oral e da orofaringe. A investiga??o de produtos naturais ? fundamental para a descoberta de novos alvos para o desenvolvimento de drogas antif?ngicas. Este estudo objetivou determinar os gen?tipos de 48 isolados cl?nicos de C. albicans obtidos da cavidade oral de pacientes transplantados renais de duas distintas regi?es geogr?ficas do Brasil. Al?m disso, foram investigados tr?s fatores de virul?ncia in vitro: atividade de fosfolipase, morfog?nese e a capacidade de escapar do ataque de neutr?filos polimorfonucleares. A express?o destes fatores de virul?ncia tamb?m foi investigada na presen?a do extrato bruto de Eugenia uniflora. O gen?tipo A foi o mais prevalente (30 isolados; 62,5%), seguido do gen?tipo C (15 isolados; 31,5%) e do gen?tipo B (3 isolados; 6,25%). Quando a t?cnica do microssat?lite com o primer M13 foi empregada, 80% dos isolados da regi?o Sul foram agrupados no mesmo cluster. Todos os isolados do gen?tipo C foram agrupados juntos em dois diferentes clusters bem definidos. Isolados do gen?tipo C foram considerados mais resistentes ? a??o de PMNs do que os dos gen?tipos A e B. As cepas isoladas do Sul do Brasil demonstraram maior habilidade em combater a fagocitose por PMNs. Encontrou-se uma alta taxa de isolados do gen?tipo C da cavidade oral deste grupo de pacientes. O extrato bruto de E. uniflora inibiu a forma??o de hifa e fagocitose por PMNs, mas n?o apresentou efeito significativo na atividade de fosfolipase. Este estudo caracterizou isolados cl?nicos de C. albicans da cavidade oral de pacientes transplantados renais, contribuindo para um melhor entendimento da patog?nese e terap?utica alternativa para a candid?ase oral