Cardiac autonomic impairment and chronotropic incompetence in fibromyalgia

Abstract\ud \ud \ud \ud Introduction\ud \ud We aimed to gather knowledge on the cardiac autonomic modulation in patients with fibromyalgia (FM) in response to exercise and to investigate whether this population suffers from chronotropic incompetence (CI).\ud \ud \ud \ud Methods\ud \ud Fourteen women with FM (age: 46 ± 3 years; body mass index (BMI): 26.6 ± 1.4 kg/m2) and 14 gender-, BMI- (25.4 ± 1.3 kg/m2), and age-matched (age: 41 ± 4 years) healthy individuals (CTRL) took part in this cross-sectional study. A treadmill cardiorespiratory test was performed and heart-rate (HR) response during exercise was evaluated by the chronotropic reserve. HR recovery (deltaHRR) was defined as the difference between HR at peak exercise and at both first (deltaHRR1) and second (deltaHRR2) minutes after the exercise test.\ud \ud \ud \ud Results\ud \ud FM patients presented lower maximal oxygen consumption (VO2 max) when compared with healthy subjects (22 ± 1 versus CTRL: 32 ± 2 mL/kg/minute, respectively; P < 0.001). Additionally, FM patients presented lower chronotropic reserve (72.5 ± 5 versus CTRL: 106.1 ± 6, P < 0.001), deltaHRR1 (24.5 ± 3 versus CTRL: 32.6 ± 2, P = 0.059) and deltaHRR2 (34.3 ± 4 versus CTRL: 50.8 ± 3, P = 0.002) than their healthy peers. The prevalence of CI was 57.1% among patients with FM.\ud \ud \ud \ud Conclusions\ud \ud Patients with FM who undertook a graded exercise test may present CI and delayed HR recovery, both being indicative of cardiac autonomic impairment and higher risk of cardiovascular events and mortality.This work was supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo (Grant 2009/51897-5)

O PAPEL DO BRASIL COMO INDUTOR DO PROCESSO DE INTEGRAÇÃO ENERGÉTICA REGIONAL NA AMÉRICA DO SUL

O presente artigo tem como objetivo analisar qual o papel do Brasil como indutor do processo de integração energética regional na América do Sul. Tem-se como hipótese que o Brasil exerce função de liderança na integração energética sul-americana. Destaca-se, para tal, o papel do Conselho Energético Sul-Americano (UNASUL), da Petrobrás e da integração via hidrelétricas no subcontinente sul-americano. Entretanto, ainda são identificadas diversas dificuldades e insuficiências, como a ausência de um marco regulatório, a falta de capacidade de financiamento e a falta de medidas tomadas no âmbito multilateral para a conquista de uma integração energética efetiva na América do Sul

Valor preditivo da medida da cintura e da relação cintura-quadril no diagnóstico do diabetes melito e da dislipidemia

Purpose: Obesity rates are increasing in Brazil. Waist measurement (WM) is a good measure to evaluatelocalized obesity and it is easier to perform when compared to wait-hip-ratio (WHR). However the effects of regionalobesity were better described between WHR and cardiovascular risk factors. Aim: to test whether waist measurement alone is better than WHR to predict diabetes and high cholesterol. Methods: We analyzed positive and negative likelihood ratio (LR)of WM and WHR in a sample of 202 apparently healthy men and women aged 20-74 years as a predictive factor for diabetes and dislipidemia. Results: (1) For women, WHR was a better predictive factor for diabetes(LHR+ = 2,5 e LHR- = 0,2) and dislipidemia (LHR+ = 2,5, LHR- = 0,2) diagnosis than WM (diabetes, LHR+ = 1,9 eLHR- = 0,4; dislipidemia, LHR+ = 1,6 e LHR- = 0,6); (2) For men, WM was a better predictive factor for diabetes (LHR+ = 2,4e LHR- = 0,6) and dislipidemia (LHR+ = 5 e LHR- = 0,5) than for WHR (diabetes, LHR+ = 1,0 e LHR- = 0,9;dislipidemia, LHR+ = 2,1 e LHR- = 0,7 diagnosis. Conclusion: WM and WHR have different behaviors in men and women.Introdução: O índice de obesidade está aumentando no Brasil.A medida da cintura (MC) é uma boa medida para a avaliação da obesidade localizada e é mais fácil de ser adquirida do que a relação cintura quadril (RCQ). Entretanto, os efeitos da obesidade regional foram melhores descritos entre a RCQ e fatores de risco cardiovasculares. Objetivo: testar se a medida da cintura isolada é melhor do que a RCQ para predizer diabetes e dislipidemia. Métodos: analisamos a razão de verossimilhança positiva e negativa da MC e RCQ numa amostra de 202 homens e mulheres com idade variando de 20 a 74 anos e aparentemente saudáveis como fator preditivo para diabetes e dislipidemia. Resultados: (1) Para mulheres, a RCQ foi melhor fator preditivo para o diagnostico dediabetes (RV+ = 2,5 e RV- = 0,2) e dislipidemia (RV+2,5 e RV-=0,2) comparado a MC (diabetes, RV+ = 1,9 e RV- = 0,4; dislipidemia, RV+ = 1,6 e RV- = 0,6); (2) Para homens, a MC foi melhor fator preditivo para o diagnostico de diabetes (RV+ = 2,4 e RV- = 0,6) e dislipidemia (RV+ = 5 e RV- = 0,5) do que a RCQ (diabetes, RV+ = 1,0 e RV- = 0,9; dislipidemia, RV+ = 2,1 e RV- = 0,7). Conclusão: A MC e a RCQ se comportam diferentes entre homens e mulheres

Resistance to P. brasiliensis

Paracoccidioidomycosis (PCM) is a systemic fungal infection, endemic in Brazil, that leads to severe morbidity and even mortality if not correctly treated. Patients may respond differently to PCM depending on the pattern of the acquired immune response developed. The onset of protective immune response is notably mediated by neutrophils (PMN) that play an important role through directly killing the fungi and also by interacting with other cell types to modulate the acquired protective immune response that may follow. In that way, this study aimed to present and compare different experimental models of PCM (intraperitoneal and subcutaneous) regarding PMN production and maturation inside femoral bone marrow and also PMN infiltration in peritoneal and subcutaneous exudates of resistant and susceptible mice. We also assessed the fungal colony forming units and the levels of soluble inflammatory mediators (LTB4, KC, IFN-γ, GM-CSF, and IL-10) inside subcutaneous air-pouches to compare the efficiency of the PMN present at this site in relation to the two main neutrophil functions: initial lysis of the invading pathogen and modulation of the acquired immune response. P. brasiliensis inoculated intraperitoneally was able to disseminate to the bone marrow of susceptible mice, causing a more marked alteration of PMN production and maturation than that observed after resistant mice infection by the same route. Subcutaneous air-pouch inoculation of P. brasiliensis elicited a controlled and limited infection that produced a PMN-rich exudate, thus favoring the study of the interaction between the fungus and the neutrophils. Susceptible mice produced higher numbers of PMN; however, these cells were less effective in killing the fungi. Inflammatory cytokines were more pronounced in resistant mice, which supports their PCM raised resistance

Paracoccidoides brasiliensis 30 kDa adhesin: identification as a 14-3-3 protein, cloning and subcellular localization in infection models

Paracoccidoides brasiliensis adhesion to lung epithelial cells is considered an essential event for the establishment of infection and different proteins participate in this process. One of these proteins is a 30 kDa adhesin, pI 4.9 that was described as a laminin ligand in previous studies, and it was more highly expressed in more virulent P. brasiliensis isolates. This protein may contribute to the virulence of this important fungal pathogen. Using Edman degradation and mass spectrometry analysis, this 30 kDa adhesin was identified as a 14-3-3 protein. These proteins are a conserved group of small acidic proteins involved in a variety of processes in eukaryotic organisms. However, the exact function of these proteins in some processes remains unknown. Thus, the goal of the present study was to characterize the role of this protein during the interaction between the fungus and its host. To achieve this goal, we cloned, expressed the 14-3-3 protein in a heterologous system and determined its subcellular localization in in vitro and in vivo infection models. Immunocytochemical analysis revealed the ubiquitous distribution of this protein in the yeast form of P. brasiliensis, with some concentration in the cytoplasm. Additionally, this 14-3-3 protein was also present in P. brasiliensis cells at the sites of infection in C57BL/6 mice intratracheally infected with P. brasiliensis yeast cells for 72 h (acute infections) and 30 days (chronic infection). An apparent increase in the levels of the 14-3-3 protein in the cell wall of the fungus was also noted during the interaction between P. brasiliensis and A549 cells, suggesting that this protein may be involved in host-parasite interactions, since inhibition assays with the protein and this antibody decreased P. brasiliensis adhesion to A549 epithelial cells. Our data may lead to a better understanding of P. brasiliensis interactions with host tissues and paracoccidioidomycosis pathogenesis.FAPESP, 2011/18038-9National Council for Scientific and Technological Development, 473119/2010-2Coordenação de Aperfeiçoamento de Pessoal de Nível Superio

Cell-Free Antigens from Paracoccidioides brasiliensis Drive IL-4 Production and Increase the Severity of Paracoccidioidomycosis

The thermally dimorphic fungus Paracoccidioides brasiliensis (Pb) is the causative agent of paracoccidioidomycosis (PCM), one of the most frequent systemic mycosis that affects the rural population in Latin America. PCM is characterized by a chronic inflammatory granulomatous reaction, which is consequence of a Th1-mediated adaptive immune response. In the present study we investigated the mechanisms involved in the immunoregulation triggered after a prior contact with cell-free antigens (CFA) during a murine model of PCM. The results showed that the inoculation of CFA prior to the infection resulted in disorganized granulomatous lesions and increased fungal replication in the lungs, liver and spleen, that paralleled with the higher levels of IL-4 when compared with the control group. The role of IL-4 in facilitating the fungal growth was demonstrated in IL-4-deficient- and neutralizing anti-IL-4 mAb-treated mice. The injection of CFA did not affect the fungal growth in these mice, which, in fact, exhibited a significant diminished amount of fungus in the tissues and smaller granulomas. Considering that in vivo anti-IL-4-application started one week after the CFA-inoculum, it implicates that IL-4-CFA-induced is responsible by the mediation of the observed unresponsiveness. Further, the characterization of CFA indicated that a proteic fraction is required for triggering the immunosuppressive mechanisms, while glycosylation or glycosphingolipids moieties are not. Taken together, our data suggest that the prior contact with soluble Pb antigens leads to severe PCM in an IL-4 dependent manner

In vitro and in situ activation of the complement system by the fungus Lacazia loboi

Since there are no studies evaluating the participation of the complement system (CS) in Jorge Lobo's disease and its activity on the fungus Lacazia loboi, we carried out the present investigation. Fungal cells with a viability index of 48% were obtained from the footpads of BALB/c mice and incubated with a pool of inactivated serum from patients with the mycosis or with sterile saline for 30 min at 37 ºC. Next, the tubes were incubated for 2 h with a pool of noninactivated AB+ serum, inactivated serum, serum diluted in EGTA-MgCl2, and serum diluted in EDTA. The viability of L. loboi was evaluated and the fungal suspension was cytocentrifuged. The slides were submitted to immunofluorescence staining using human anti-C3 antibody. The results revealed that 98% of the fungi activated the CS by the alternative pathway and no significant difference in L. loboi viability was observed after CS activation. In parallel, frozen histological sections from 11 patients were analyzed regarding the presence of C3 and IgG by immunofluorescence staining. C3 and IgG deposits were observed in the fungal wall of 100% and 91% of the lesions evaluated, respectively. The results suggest that the CS and immunoglobulins may contribute to the defense mechanisms of the host against L. loboi

TLR9 activation dampens the early inflammatory response to paracoccidioides brasiliensis, Impacting host survival

Background: Paracoccidioides brasiliensis causes paracoccidioidomycosis, one of the most prevalent systemic mycosis in Latin America. Thus, understanding the characteristics of the protective immune response to P. brasiliensis is of interest, as it may reveal targets for disease control. The initiation of the immune response relies on the activation of pattern recognition receptors, among which are TLRs. Both TLR2 and TLR4 have been implicated in the recognition of P. brasiliensis and regulation of the immune response. However, the role of TLR9 during the infection by this fungus remains unclear.J.F. Menino was supported by a grant from Fundacao para a Ciencia e Tecnologia (FCT), Portugal (SFRH/BD/33446/2008). This work was supported by a grant from FCT (PTDC/BIA-MIC/108309/2008). M. Saraiva is a Ciencia 2007 fellow and M. Sturme is a Ciencia 2008 fellow. We would also like to thank FAPESP (Fundacao para Amparo a Pesquisa do Estado de Sao Paulo) and CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors

Immunotherapy has become an important ally in the fight against distinct types of cancer. However, the metabolic plasticity of the tumor environment frequently influences the efficacy of therapeutic procedures, including those based on immunological tools. In this scenario, immunometabolic adjuvants arise as an alternative toward the development of more efficient cancer therapies. Here we demonstrated that the combination of melatonin, a neuroimmunomodulator molecule, and an indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-DL-tryptophan, DL-1MT) improves the efficacy of an immunotherapy (gDE7) targeting human papillomavirus (HPV)-associated tumors. Melatonin or IDO inhibitors (D-1MT and DL-1MT) directly reduced proliferation, migration, adhesion and viability of a tumor cell line (TC-1), capable to express the HPV-16 E6 and E7 oncoproteins, but could not confer in vivo antitumor protection effects. Nonetheless, combination of gDE7 with melatonin or D-1MT or DL-1MT enhanced the antitumor protective immunity of gDE7-based vaccine in mice. Notably, expression of IDO1 in stromal cells and/or immune cells, but not in tumor cells, inhibited the antitumor effects of the gDE7, as demonstrated in IDO1-deficient mice. Finally, co-administration of gDE7, melatonin and DL-1MT further improved the protective antitumor effects and the numbers of circulating E7-specific CD8+ T cells in mice previously transplanted with TC-1 cells. The unprecedented combination of melatonin and IDO inhibitors, as immunometabolic adjuvants, thus, represents a new and promising alternative for improving the efficacy of immunotherapeutic treatments of HPV-associated tumors