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Extracellular vesicles (EVs) are mediators of the immune system response. Encapsulated in EVs, microRNAs can be transferred between cancer and immune cells. To define the potential effects of EVs originated from squamous cell carcinoma cells on immune system response, we performed microRNA profiling of EVs released from two distinct cell lines and treated dendritic cells derived from circulating monocytes (mono-DCs) with these EVs. We confirmed the internalization of EVs by mono-DCs and the down-regulation of microRNA mRNA targets in treated mono-DCs. Differences in surface markers of dendritic cells cultivated in the presence of EVs indicated that their content disrupts the maturation process. Additionally, microRNAs known to interfere with dendritic cell function, and detected in EVs, matched microRNAs from squamous cell carcinoma patients’ plasma: miR-17-5p in oropharyngeal squamous cell carcinoma, miR-21 in oral squamous cell carcinoma, miR-16, miR-24, and miR-181a circulating in both oral and oropharyngeal squamous cell carcinoma, and miR-23b, which has not been previously described in plasma of head and neck squamous cell carcinoma, was found in plasma from patients with these cancer subtypes. This study contributes with insights on EVs in signaling between cancer and immune cells in squamous cell carcinoma of the head and neck.

During the acute phase of Chagas disease

CD8 T cells are regarded as pivotal players in both immunoprotection and immunopathology following Trypanosoma cruzi infection. Previously, we demonstrated the expansion of CD8+ T lymphocytes in the spleen of T. cruzi-infected mice under treatment with benznidazole (N-benzyl-2-nitroimidazole acetamide; Bz), a drug available for clinical therapy. This finding underlies the concept that the beneficial effects of Bz on controlling acute T. cruzi infection are related to a synergistic process between intrinsic trypanocidal effect and indirect triggering of the active immune response. In the present study, we particularly investigated the effect of Bz treatment on the CD8+ T cell subset following T. cruzi infection. Herein we demonstrated that, during acute T. cruzi infection, Bz treatment reduces and abbreviates the parasitemia, but maintains elevated expansion of CD8+ T cells. Within this subset, a remarkable group of CD8low cells was found in both Bz-treated and non-treated infected mice. In Bz-treated mice, early pathogen control paralleled the lower frequency of recently activated CD8low cells, as ascertained by CD69 expression. However, the CD8low subset sustains significant levels of CD44highCD62Llow and CD62LlowT-bethigh effector memory T cells, in both Bz-treated and non-treated infected mice. These CD8low cells also comprise the main group of spontaneous interferon (IFN)-γ-producing CD8+ T cells. Interestingly, following in vitro anti-CD3/CD28 stimulation, CD8+ T cells from Bz-treated T. cruzi-infected mice exhibited higher frequency of IFN-γ+ cells, which bear mostly a CD8low phenotype. Altogether, our results point to the marked presence of CD8low T cells that arise during acute T. cruzi infection, with Bz treatment promoting their significant expansion along with a potential effector program for high IFN-γ production., Author summary Chagas disease is a neglected illness caused by the protozoan Trypanosoma cruzi, which affects 6 to 7 million people worldwide. The current treatment for acutely-infected patients is mostly limited to the benznidazole (Bz) drug, reaching up to 80% of cure. It has been proposed that Bz therapy efficacy involves both trypanocidal and immunonodulatory effects. In this sense, we previously suggested that CD8+ T cells, highly expanded after Bz treatment of acute T. cruzi-infected mice, might play a particular role in parasite control. Here, by further investigating those expanded CD8+ T cells, we observed that they bear a clear-cut effector phenotype and that a significant part of them stand out as a subpopulation bearing low levels of CD8 on their surface. Interestingly, besides the evident parasite control, Bz-treated mice sustain a group of effector CD8low cells with spontaneous IFN-γ production. Moreover, in vitro-stimulated CD8+ T cells, sorted from infected and Bz-treated mice, present a relevant group of IFN-γ+ cells with a CD8low phenotype. Altogether, our data indicate the particular subset of CD8low cells as potentially contributing for a sustained protective immunity in T. cruzi-infected animals under Bz therapy.

Oral transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuen strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease.

Plasmodium falciparum-specific antibodies tend to be short-lived, but their cognate memory B cells (MBCs) circulate in the peripheral blood of exposed subjects for several months or years after the last infection. However, the time course of antigen-specific antibodies and B-cell responses to the relatively neglected parasite Plasmodium vivax remains largely unexplored. Here, we showed that uncomplicated vivax malaria elicits short-lived antibodies but long-lived MBC responses to a major blood-stage P vivax antigen, apical membrane protein 1 (PvAMA-1), in subjects exposed to declining malaria transmission in the Amazon Basin of Brazil. We found that atypical (CD19+ CD10- CD21- CD27- ) MBCs, which appear to share a common precursor with classical MBCs but are unable to differentiate into antibody-secreting cells, significantly outnumbered classical MBCs by 5:1 in the peripheral blood of adult subjects currently or recently infected with P vivax and by 3:1 in healthy residents in the same endemic communities. We concluded that malaria can drive classical MBCs to differentiate into functionally impaired MBCs not only in subjects repeatedly exposed to P falciparum, but also in subjects living in areas with low levels of P vivax transmission in the Amazon, leading to an impaired B-cell memory that may affect both naturally acquired and vaccine-induced immunity.

Oral transmission of Trypanosoma cruzi, the etiologic agent of Chagas disease, is presently the most important route of infection in Brazilian Amazon. Other South American countries have also reported outbreaks of acute Chagas disease associated with food consumption. A conspicuous feature of this route of transmission is presenting symptoms such as facial and lower limbs edema, in some cases bleeding manifestations and risk of thromboembolism are evident. Notwithstanding, studies that address this route of infection are largely lacking regarding its pathogenesis and, more specifically, the crosstalk between immune and hemostatic systems. Here, BALB/c mice were orally infected with metacyclic trypomastigotes of T. cruzi Tulahuén strain and used to evaluate the cytokine response, primary and secondary hemostasis during acute T. cruzi infection. When compared with control uninfected animals, orally infected mice presented higher pro-inflammatory cytokine (TNF-α, IFN-γ, and IL-6) serum levels. The highest concentrations were obtained concomitantly to the increase of parasitemia, between 14 and 28 days post-infection (dpi). Blood counts in the oral infected group revealed concomitant leukocytosis and thrombocytopenia, the latter resulting in increased bleeding at 21 dpi. Hematological changes paralleled with prolonged activated partial thromboplastin time, Factor VIII consumption and increased D-dimer levels, suggest that oral T. cruzi infection relies on disseminated intravascular coagulation. Remarkably, blockade of the IL-6 receptor blunted hematological abnormalities, revealing a critical role of IL-6 in the course of oral infection. These results unravel that acute T. cruzi oral infection results in significant alterations in the hemostatic system and indicates the relevance of the crosstalk between inflammation and hemostasis in this parasitic disease.

An improved beta differential evolution algorithm is proposed.The improved differential evolution is applied to image threholding segmentation.Simulation results demonstrate that the proposed differential evolution is superior to FODPSO. Image segmentation is the process of partitioning a digital image into multiple regions that have some relevant semantic content. In this context, histogram thresholding is one of the most important techniques for performing image segmentation. This paper proposes a beta differential evolution (BDE) algorithm for determining the n-1 optimal n-level threshold on a given image using Otsu criterion. The efficacy of BDE approach is illustrated by some results when applied to two case studies of image segmentation. Compared with a fractional-order Darwinian particle swarm optimization (PSO), the proposed BDE approach performs better, or at least comparably, in terms of the quality of the final solutions and mean convergence in the evaluated case studies.

ResumoObjetivoAnalisar e correlacionar os resultados funcionais e radiográficos e o grau de qualidade de vida em pacientes submetidos a artroplastia total de quadril não cimentada com superfície em cerâmica feita no Hospital Servidor Público Estadual de 2001 a 2006.MétodosFizemos um estudo retrospectivo que analisou 35 quadris tratados com artroplastia total do quadril não cimentada com superfície em cerâmica, com tempo de seguimento mínimo de cinco anos. A avaliação funcional baseou-se no questionário de Harris Hip Score (HHS), a avaliação radiográfica baseou-se no método proposto por Charles Engh para o fêmur e sinais de integração óssea nas zonas de DeLee e Charnley para o acetábulo e a avaliação da qualidade vida baseou-se no questionário SF-36 (Medical Outcomes 36 Item Short-Form Health Survey).ResultadosO questionário HHS apresentou resultados considerados como excelentes e bons em 91% dos pacientes no pós-operatório (média de 93,14 pontos HHS). Quanto à avaliação radiográfica, em 100% dos quadris operados tivemos osteointegração óssea comprovada. Os escores do SF-36 não foram estatisticamente significantes em relação ao grupo controle para os seguintes componentes: dor, vitalidade, aspectos sociais e saúde mental. A variação entre o HHS pré e pós-operatório se correlaciona com a capacidade funcional no SF-36.ConclusãoA artroplastia total com superfície de cerâmica é uma operação que possibilita a melhoria funcional do quadril e o aumento da qualidade de vida do paciente para níveis próximos aos da população sem doenças da articulação.AbstractObjectiveThe aim of the study is to analyze and correlate functional and radiographic results and quality of life in patients undergoing cementless total hip arthroplasty with ceramic surface, performed at Hospital Servidor Publico de Sao Paulo from 2001 to 2006.MethodsWe retrospectively analyzed 35 hips treated with cementless total hip arthroplasty with ceramic surfaces with a minimum follow-up of 5 years. Functional evaluation was based on the Harris Hip Score (HHS). Radiographic evaluation was based on the method proposed by Charles Engh for evaluation of femoral osseointegration and on DeLee and Charnley zones for acetabulum. Quality of life was assessed by SF-36 questionnaire.ResultsThe HHS presented excellent and good results in 91% of patients postoperatively (mean of 93.14 points HHS). As for radiographic evaluation, we found excellent results in 100% of evaluated hips (proven osseointegration). SF-36 scores were not compared to the control group for the following components: pain, vitality, mental health and social aspects. The difference between HHS pre and postoperatively had a statistically significant correlation with physical functioning of the SF-36.ConclusionTotal hip arthroplasty with ceramic surface is a treatment that enables functional improvement of the hip and increases quality of life of patients to levels close to those of people without joint diseases.

In dengue virus (DENV) infection, complement system (CS) activation appears to have protective and pathogenic effects. In severe dengue fever (DF), the levels of DENV non-structural-1 protein and of the products of complement activation, including C3a, C5a and SC5b-9, are higher before vascular leakage occurs, supporting the hypothesis that complement activation contributes to unfavourable outcomes. The clinical manifestations of DF range from asymptomatic to severe and even fatal. Here, we aimed to characterise CS by their receptors or activation product, in vivo in DF patients and in vitro by DENV-2 stimulation on monocytes. In comparison with healthy controls, DF patients showed lower expression of CR3 (CD11b), CR4 (CD11c) and, CD59 on monocytes. The DF patients who were high producers of SC5b-9 were also those that showed more pronounced bleeding or vascular leakage. Those findings encouraged us to investigate the role of CS in vitro, using monocytes isolated from healthy subjects. Prior blocking with CR3 alone (CD11b) or CR3 (CD11b/CD18) reduced viral infection, as quantified by the levels of intracellular viral antigen expression and soluble DENV non-structural viral protein. However, we found that CR3 alone (CD11b) or CR3 (CD11b/CD18) blocking did not influence major histocompatibility complex presentation neither active caspase-1 on monocytes, thus probably ruling out inflammasome-related mechanisms. Although it did impair the secretion of tumour necrosis factor alpha and interferon alpha. Our data provide strategies of blocking CR3 (CD11b) pathways could have implications for the treatment of viral infection by antiviral-related mechanisms.

Objective: The aim of the study is to analyze and correlate functional and radiographic results and quality of life in patients undergoing cementless total hip arthroplasty with ceramic surface, performed at Hospital Servidor Publico de Sao Paulo from 2001 to 2006. Methods: We retrospectively analyzed 35 hips treated with cementless total hip arthroplasty with ceramic surfaces with a minimum follow-up of 5 years. Functional evaluation was based on the Harris Hip Score (HHS). Radiographic evaluation was based on the method proposed by Charles Engh for evaluation of femoral osseointegration and on DeLee and Charnley zones for acetabulum. Quality of life was assessed by SF-36 questionnaire. Results: The HHS presented excellent and good results in 91% of patients postoperatively (mean of 93.14 points HHS). As for radiographic evaluation, we found excellent results in 100% of evaluated hips (proven osseointegration). SF-36 scores were not compared to the control group for the following components: pain, vitality, mental health and social aspects. The difference between HHS pre and postoperatively had a statistically significant correlation with physical functioning of the SF-36. Conclusion: Total hip arthroplasty with ceramic surface is a treatment that enables functional improvement of the hip and increases quality of life of patients to levels close to those of people without joint diseases. Objetivo: Analisar e correlacionar os resultados funcionais e radiográficoseograude qualidade de vida em pacientes submetidos a artroplastia total de quadril não cimentada com superfície em cerâmica feita no Hospital Servidor Público Estadual de 2001 a 2006. Métodos: Fizemos um estudo retrospectivo que analisou 35 quadris tratados com artroplastia total do quadril não cimentada com superfície em cerâmica, com tempo de seguimento mínimo de cinco anos. A avaliação funcional baseou-se no questionário de Harris Hip Score (HHS), a avaliação radiográfica baseou-se no método proposto por Charles Engh para o fêmur e sinaisde integração óssea nas zonasde DeLee eCharnley parao acetábulo ea avaliação da qualidade vida baseou-se no questionário SF-36 (Medical Outcomes 36 Item Short-Form Health Survey). Resultados: O questionário HHS apresentou resultados considerados como excelentes e bons em 91% dos pacientes no pós-operatório (média de 93,14 pontos HHS). Quanto à avaliação radiográfica, em 100% dos quadris operados tivemos osteointegração óssea comprovada. Os escores do SF-36 não foram estatisticamente significantes em relação ao grupo controle para os seguintes componentes: dor, vitalidade, aspectos sociais e saúde mental. A variação entre o HHS pré e pós-operatório se correlaciona com a capacidade funcional no SF-36. Conclusão: A artroplastia total com superfície de cerâmica é uma operação que possibilita a melhoria funcional do quadril e o aumento da qualidade de vida do paciente para níveis próximos aos da população sem doenças da articulação.

Summary Leishmaniasis is a group of important parasitic diseases affecting millions worldwide. To understand more clearly the quality of T helper type 1 (Th1) response stimulated after Leishmania infection, we applied a multiparametric flow cytometry protocol to evaluate multifunctional T cells induced by crude antigen extracts obtained from promastigotes of Leishmania braziliensis (LbAg) and Leishmania amazonensis (LaAg) in peripheral blood mononuclear cells from healed cutaneous leishmaniasis patients. Although no significant difference was detected in the percentage of total interferon (IFN)-γ-producing CD4+T cells induced by both antigens, multiparametric flow cytometry analysis revealed clear differences in the quality of Th1 responses. LbAg induced an important proportion of multifunctional CD4+ T cells (28% of the total Th1 response evaluated), whereas LaAg induced predominantly single-positive cells (68%), and 57% of those were IFN-γ single-positives. Multifunctional CD4+T cells showed the highest mean fluorescence intensity (MFI) for the three Th1 cytokines assessed and MFIs for IFN-γ and interleukin-2 from those cells stimulated with LbAg were significantly higher than those obtained after LaAg stimulation. These major differences observed in the generation of multifunctional CD4+ T cells suggest that the quality of the Th1 response induced by L. amazonensis antigens can be involved in the mechanisms responsible for the high susceptibility observed in L. amazonensis-infected individuals. Ultimately, our results call attention to the importance of studying a Th1 response regarding its quality, not just its magnitude, and indicate that this kind of evaluation might help understanding of the complex and diverse immunopathogenesis of American tegumentary leishmaniasis.

OBJETIVO: Analisar e correlacionar os resultados clínicos e radiográficos de pacientes com fratura do rádio distal submetidos ao tratamento cirúrgico com placa volar bloqueada de ângulo fixo. MÉTODOS: Avaliou-se 64 pacientes com fraturas do rádio distal submetidos ao tratamento cirúrgico com placa volar bloqueada de rádio distal, com mínimo de seis meses de acompanhamento pós-operatório. Foram submetidos a exame físico com medida do arco de movimento e força de preensão, ao questionário Disabilities of the Arm, Shoulder, and Hand (DASH) e a exames radiográficos. RESULTADOS: No exame físico dos pacientes houve redução de todas as medidas de amplitude de movimento. A força de preensão em kgf medida foi em média 85,8% do valor obtido em relação ao lado não acometido. O valor médio do DASH foi de 15,99. As perdas de extensão e de força de preensão tiveram relação significativa com um DASH inferior. Nas radiografias, as médias dos valores, quando comparados ao do lado não fraturado, foram 84,0% da inclinação radial, 85,4% do comprimento radial e 86,8% do desvio volar do rádio. Perda de comprimento radial se relacionou com perda de extensão e força de preensão. Conclusão: A diminuição da amplitude do movimento está associada à perda do comprimento radial na radiografia. Os resultados subjetivos dos pacientes (DASH) são modificados pela amplitude de extensão e força de preensão, porém não se relacionam com medidas radiográficas. OBJECTIVES: To analyze and correlate the clinical and radiographic results from patients with distal radius fractures who underwent surgical treatment with a fixed-angle volar locked plate. METHODS: Sixty-four patients with distal radius fractures were evaluated. They all underwent surgical treatment with a volar locked plate for the distal radius, with a minimum of six months of postoperative follow-up. They underwent a physical examination that measured range of motion and grip strength, answered the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and underwent radiographic examination. RESULTS: In the physical examination on the patients, all the range-of-motion measurements were reduced. Grip strength measured in kgf was on average 85.8% of the strength on the unaffected side. The mean DASH score was 15.99. A significant relationship was found between lower DASH scores and losses of extension and grip strength. On the radiographs, the mean values in relation to the unfractured side were 84.0% for radial inclination, 85.4% for radial length and 86.8% for volar deviation of the radius. Loss of radial length was correlated with losses of extension and grip strength.

A pesquisa se propõe a analisar a literatura judaica da Baixa Idade Média cujo conteúdo procura assimilar a memória formativa da tradiçáo do povo estabelecendo-se sobre os temas de perseguiçáo e sofrimento como resultado da reflexáo de uma comunidade em condiçáo de exílio. Também se propõe, através desta análise, entender porque há uma tendência pronunciada em subordinar mesmo os novos acontecimentos a arquétipos familiares, pois mesmo os mais terríveis sáo de algum modo menos aterrorizantes quando observados à luz de antigos padrões do que em sua realidade desnorteante. Assim, demonstraremos como os ramos da literatura judaica da Idade Baixa Média estabelecem grande quantidade de pensamentos sobre a posiçáo do povo judeu na história, e uma riqueza de idéias acerca da história judaica, de reflexões freqüentemente profundas e por vezes até ousadas a respeito do exílio e redençáo. &nbsp

Este artigo se propõe a investigar as causas pelas quais o processo de dominação romana foi se degradando aos poucos na Judeia do século I. O Evergetismo romano era um princípio político em que, através de um acordo entre interessados, geralmente um nobre e um vassalo, ou o rei e um nobre, o de mais alto escalão oferece favores e espera algum tipo de retribuição e reconhecimento da outra parte a fim de impor sua autoridade pela consensualidade. No caso da Judeia, este acordo foi feito pelo imperador romano e a classe dirigente da Judeia, a qual, por sua vez, deveria reproduzir o modelo ao povo. Contudo, vários fatores neste processo impediram o Império Romano e a classe dirigente da Judeia de colocar em prática este modelo de dominação, levando à fatídica guerra do ano 70.The failure of Roman evergetism in Judea - Abstract: This article aims at investigating why the Roman domination process gradually degraded in Judaea duringthe 1st Century. Roman Evergetism was a political principle according to which, by agreement between the interested parties, generally a noble and a vassal or the king and a noble, the one who is higher on the social scale offers favors and expects some kind of retribution and acknowledgment from the other party in order to impose his authority by consensus. In the case of Judaea this agreement was made between the Roman Emperor and the leading class of Judaea, which in turn was to reproduce this model toward the people. However, several factors in this process prevented the Roman Empire and the leading class of Judaea from putting this model of domination into practice, which thus led to the fateful war of 70 C.E.

Aim: To compare the hemodynamic effects and myocardial oxygen consumption (MVO 2) during bathing in bed without hydrothermal handling and positioning in the case of patients with acute myocardial infarction (AMI) and not infarcted by thoracic electrical bioimpedance. Method: Clinical, parallel, randomized and controlled trial. The dimensioning of a discrete and finite sample was carried out and the resulting sample is composed of 30 infarcted patients classified as Killip class I or II, admitted to a private hospital, and assisted up to 72 hours after the cardiac event; 30 hospitalized controls with no cardiac cause, matched by age and sex, with pulse pressure

Objectives: To analyze and correlate the clinical and radiographic results from patients with distal radius fractures who underwent surgical treatment with a fixed-angle volar locked plate. Methods: Sixty-four patients with distal radius fractures were evaluated. They all underwent surgical treatment with a volar locked plate for the distal radius, with a minimum of six months of postoperative follow-up. They underwent a physical examination that measured range of motion and grip strength, answered the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and underwent radiographic examination. Results: In the physical examination on the patients, all the range-of-motion measurements were reduced. Grip strength measured in kgf was on average 85.8% of the strength on the unaffected side. The mean DASH score was 15.99. A significant relationship was found between lower DASH scores and losses of extension and grip strength. On the radiographs, the mean values in relation to the unfractured side were 84.0% for radial inclination, 85.4% for radial length and 86.8% for volar deviation of the radius. Loss of radial length was correlated with losses of extension and grip strength.