Míriam Paula Alonso Toldo

Universidade de Franca, Franca, São Paulo, Brazil

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Publications (36)102.71 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Reduction in the parasitemic levels of the Y strain of Trypanosoma cruzi in mice treated with oral or intraperitoneal ursolic (UA) and oleanolic (OA) acids was evaluated during the acute phase of Chagas' disease. Oral administration of UA and OA (50 mg/Kg/day) provided the most significant reduction in the parasitemic peak, while intraperitoneal administration of UA and OA did not significantly affect the biological activity of the Y strain of T. cruzi. Interleukin levels in mice treated by the intraperitoneal route were compared to untreated chagasic mice. Reduced γ-IFN levels and enhanced IL-10 concentrations potentially explain the exacerbated parasitemia. Our data suggests an immunosuppressive effect for UA and OA, which could interfere with host control of parasitemia. Optimal results were achieved with oral administration. This observation may be explained by the low intestinal absorption of UA and OA, could cause a reduced immune response and promote parasite control. Taken together, these data demonstrate that triterpenes could be interesting compounds to develop therapeutically for the treatment of Chagas' disease.
    Experimental Parasitology 05/2013; · 2.15 Impact Factor
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    ABSTRACT: Melatonin has been reported to play a fundamental role in T-cell immunoregulation. Control of Trypanosoma cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. The aim of this work was to evaluate the influence of exogenous melatonin treatment and the influences exerted by sexual hormones during the acute phase of the experimental Chagas' disease in rats. With melatonin treatment, orchiectomized animals (CMOR and IMOR) displayed the highest concentrations of IFN-γ and TNF-α. On the 7th day post-infection, untreated and treated orchiectomized animals (IOR and IMOR) showed an enhanced number of peritoneal macrophages. Nitric oxide levels were also increased in untreated and treated orchiectomized (IOR and IMOR) when compared to the other groups, with or without LPS. Our data suggest that melatonin therapy associated with orchiectomy induced a stimulating effect on the immune response to the parasite.
    Research in Veterinary Science 12/2011; 93(2):819-25. · 1.77 Impact Factor
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    ABSTRACT: Melatonin by exhibiting antioxidant, anti-aging, and immunomodulatory properties favorably modulate the immune function, protecting the hosts from several infectious diseases. Zinc is an essential trace element important for the efficiency of the immune system in reason of its widespread role in the activity of enzymes, transcription factors and cytokines. The etiology of Chagas' disease, caused by a protozoan parasite Trypanosoma cruzi, has been the focus of considerable discussion, although chronic phase still remains not fully understood. This study showed that zinc and melatonin treatment did not affect the percentage of both CD4+ and CD8+ T lymphocytes subsets in chronically infected animals. Increased levels of IL-2 and IL-10, as well as, enhanced thymocyte proliferation in T. cruzi infected groups under zinc and melatonin therapy was observed as compared to untreated group. Conversely, during the chronic phase of infection, macrophages counts were reduced in melatonin and zinc-melatonin treated animals. The combined actions of zinc and melatonin have beneficial effects in counteracting parasite-induced immune dysregulation, protecting animals against the harmful actions of chronic T. cruzi infection. Furthermore, our results provide an experimental basis for further studies on the role of immunomodulatory therapies.
    Cytokine 09/2011; 56(3):627-32. · 2.52 Impact Factor
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    ABSTRACT: During the course of infection by Trypanosoma cruzi, the host immune system is involved in distinct, complex interactions with the endocrine system, and prolactin (PRL) is one of several hormones involved in immunoregulation. Although intensive studies attempting to understand the mechanisms that underlie Chagas' disease have been undertaken, there are still some pieces missing from this complex puzzle. Because data are scarce concerning the role of PRL involvement in Chagas' disease and taking into account the existence of crosstalk between neuroendocrine hormones and the immune system, the current study evaluates a possible up-regulation of the cellular immune response triggered by PRL in T. cruzi-infected rats and the role of PRL in reversing immunosuppression caused by the parasitic infection. The data shown herein demonstrate that PRL induces the proliferation of T lymphocytes, coupled with an activation of macrophages and the production of nitric oxide (NO), leading to a reduction in the number of blood trypomastigotes during the peak of parasitemia. During the acute phase of T. cruzi infection, an enhancement of both CD3+CD4+ and CD3+CD8+ T cell populations were observed in infected groups, with the highest numbers of these T cell subsets found in the infected group treated with PRL. Because NO is a signaling molecule involved in a number of cellular interactions with components of the immune system and the neuroendocrine system, PRL can be considered an alternative hormone able to up-regulate the host's immune system, consequently lowering the pathological effects of a T. cruzi infection.
    Veterinary Parasitology 04/2011; 181(2-4):139-45. · 2.38 Impact Factor
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    ABSTRACT: Zinc is an essential micronutrient and has significant effects on human growth, development, and immune function. Zinc supplementation or deficiency may affect the course of infection. Zinc enhances immune response against a wide range of viral, bacterial, and parasitic pathogens. In the present study, we investigated the effects of zinc sulphate (ZnSO(4)) supplementation (20mg/kg/day) during pregnancy in mice, Swiss Webster strain infected by the Y strain of Trypanosoma cruzi. Oral supplementation of zinc sulphate in pregnant and non-pregnant infected animals did not affect the count of blood parasites as well as tissue parasitism in the heart, liver, and spleen. Zinc supplementation did not alter female body weight, the length of fetuses and neonates, placental size/weight and mortality rate. Among zinc supplied animals, no significant plasmatic zinc concentrations were observed. Concerning to tissue zinc concentrations, only the liver displayed enhanced values as compared to other organs. For placental parasitism, zinc supplied group displayed a significant decrease in amastigote burdens (P<0.05). However due to the reduced number of parasite burdens in placenta of animals supplied with zinc, these data suggest that zinc was partially effective in up-regulating the host's immune response against parasite, probably attenuating the infection in fetuses.
    Research in Veterinary Science 04/2011; 90(2):269-74. · 1.77 Impact Factor
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    ABSTRACT: DHEA, a steroid hormone synthesized from cholesterol by cells of the adrenal cortex, plays an essential role in enhancing the host's resistance to different experimental infections. Receptors for this hormone can be found in distinct immune cells (especially macrophages) that are known to be the first line defense against Trypanosoma cruzi infection. These cells operate through an indirect pathway releasing nitric oxide (NO) and cytokines such TNF-α and IL-12 which in turn trigger an enhancement of natural killer cells and lymphocytes which finally secrete pro and anti-inflammatory cytokines. The effects of pre- and post-infection DHEA treatment on production of IL-12, TNFα and NO were evaluated. T. cruzi infected macrophages post treated with DHEA displayed enhanced concentrations of TNF-α, IL-12 and NO. Probably, the mechanisms that induced the production of cytokines by infected cells are more efficient when the immune system has been stimulated first by parasite invasion, suggesting that the protective role of DHEA is greater when administered post infection.
    Veterinary Parasitology 12/2010; 177(3-4):242-6. · 2.38 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate a possible synergism between melatonin and meloxicam in up-regulating the immune response in male Wistar rats infected with Trypanosoma cruzi during immunosuppression phenomenon, which characterizes the acute phase of the Chagas' disease. Male Wistar rats were infected with the Y strain of T. cruzi. Experiments were performed on 7, 14 and 21 days post-infection. Several immunological parameters were evaluated including gamma-interferon (IFN-gamma), interleukin-2 (IL-2), nitric oxide (NO) and prostaglandin E(2) (PGE(2)). The combined treatment with melatonin and meloxicam significantly enhanced the release of IL-2 and INF-gamma into animals' serum, when compared with the infected control groups during the course of infection. Furthermore, the blockade of PGE(2) synthesis and the increased release of NO by macrophage cells from T. cruzi-infected animals contributed to regulate the production of Th1 subset cytokines significantly reducing the parasitaemia in animals treated with the combination of both substances. Therefore, our results suggest that the association of melatonin and meloxicam was more effective in protecting animals against the harmful actions of T. cruzi infection as compared with the treatments of meloxicam or melatonin alone.
    Parasite Immunology 04/2010; 32(4):245-51. · 2.21 Impact Factor
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    ABSTRACT: The ability of the gonadal hormones to influence diverse immunological functions during the course of several infections has been extensively studied in the latest decades. Testosterone has a suppressive effect on immune response of vertebrates and increases susceptibility toward numerous parasitic diseases. Dehydroepiandrosterone is an abundant steroid hormone secreted by the human adrenal cortex and it is considered potent immune-activator. In this paper, it was examined the effects of DHEA and testosterone supplementation in the thymic atrophy in rats infected with Trypanosoma cruzi, by comparing blood parasitism, thymocyte proliferation, TNF-alpha and IL-12 levels. Our data point in the direction that DHEA treatment triggered enhanced thymocyte proliferation as compared to its infected counterparts and reduced production of TNF-alpha during the acute phase of infection. Oppositely, the lowest values for cells proliferation and IL-12 concentrations were reached in testosterone-supplied animals. The combined treatment testosterone and DHEA improves the effectiveness of the host's immune response, reducing blood parasites and the immunosuppressive effects of male androgens besides increasing IL-12 concentrations and decreasing TNF-alpha levels.
    Research in Veterinary Science 03/2010; 89(1):98-103. · 1.77 Impact Factor
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    ABSTRACT: The present study evaluates the in vitro and in vivo trypanocidal activity of ursolic acid and oleanolic acid against the Bolivia strain of Trypanosoma cruzi. Their acute toxicity is also assessed on the basis of median lethal dose (DL50) determination and quantification of biochemical parameters. Ursolic acid is the most active compound in vitro, furnishing IC50 of 25.5 microM and displaying 77% of trypomastigote lysis at a concentration of 128 microM. In agreement with in vitro assays, the results obtained for the in vivo assay reveals that ursolic acid (at a dose of 20 mg/Kg/day) provides the most significant reduction in the number of parasites at the parasitemic peak. Results concerning the LD50 assay and the biochemical parameters evaluated in the present study demonstrate that these substances can be safely used on an experimental basis.
    Parasitology Research 02/2010; 106(4):985-9. · 2.85 Impact Factor
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    ABSTRACT: A significant role for hormones in regulating the balance of Th1- and Th2-associated cytokines with a role in modulating diseases has been accumulating. Previously, we reported that dehydroepiandrosterone (DHEA), the most abundant steroid hormone synthesized by the adrenal cortex, markedly reduced the blood and tissue parasites in experimentally Trypanosoma cruzi-infected rats. Based on these findings, the main purpose of this study was to investigate the effect of dehydroepiandrosterone-sulfate ester (DHEA-S) therapy alone or in combination with benznidazole (BNZ) (recommended in Brazil for the treatment of T. cruzi infection) will be effective during the acute phase of two different lineages of T. cruzi strains: type I (Y strain) and type II (Bolivia strain) of T. cruzi. Administration of either DHEA-S or BNZ alone or in combination significantly reduced the Y strain parasite load as compared with untreated. Furthermore treatment with DHEA-S resulted in Bolivia strain clearance. This protective effect of DHEA-S was associated with the host's immune response, as evidence by enhanced levels of interferon-gamma and interleukin-2. DHEA-S treatment also increased peritoneal macrophages levels and nitrite production. DHEA-S treatment was effective in reducing the mortality rate as compared to BNZ alone or to combiner DHEA-S+BNZ treatment of T. cruzi Bolivia strain infected animals. These findings suggest that hormonal therapy may have a protective effect in the treatment of T. cruzi infection.
    Immunobiology 02/2010; 215(12):980-6. · 2.81 Impact Factor
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    ABSTRACT: We developed a new method for the quantification of parasites in tissue. Trypanosoma cruzi strain CL parasites were genetically engineered to express the Escherichia coli beta-galactosidase gene, lacZ and this enzyme is able to catalyze a colorimetric reaction with chlorophenol red beta-D: galactopyranoside (CPRG) as the substrate. The animals were infected with clone CL Brener strain B5 of T. cruzi and treated with benznidazole in order to verify the reduction in the number of parasites in tissue study by quantifying the enzyme beta-galactosidase. The assay demonstrates a reduction in the number of parasites in the groups treated. Thus, this test can be used to test other substances with the aim of verifying the effectiveness in the chronic phase of experimental Chagas' disease.
    Parasitology Research 02/2010; 106(6):1471-3. · 2.85 Impact Factor
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    ABSTRACT: Previous studies showed that melatonin or dehydroepiandrosterone (DHEA) enhances the immune response against parasitic pathogens. The present study investigated the in vitro activity of melatonin combined with DHEA in a period of 24 hr during the course of in vivo T. cruzi infection. The in vitro activity of melatonin or DHEA alone, as well as together, were tested for the trypomastigote forms (doses ranging from 0.5 to 128 microm). In vitro, neither melatonin nor DHEA alone had any activity against trypomastigote forms, although when the highest concentration of combined melatonin and DHEA was used, it was active against the trypomastigote forms of the parasite. However, for this concentration, a quite toxicity on peritoneal macrophages was observed. For in vivo evaluation, male Wistar rats were infected with the Y strain of T. cruzi. They were orally treated with 10 mg/kg body weight/day of melatonin and subcutaneously with 40 mg/kg body weight/day of DHEA. Treatment with melatonin, DHEA and the association showed a significant reduction in the number of blood trypomastigotes during the acute phase of infection as compared to untreated animals (P < 0.05). A significant increase in the number of macrophages and nitric oxide (NO) concentrations were observed during the peak of parasitaemia with melatonin alone or combined with DHEA. However, with DHEA alone the highest concentration of NO was observed (P < 0.05). Moreover, DHEA treatment increased TNF-alpha levels during the infection (P < 0.05). These results show that melatonin, DHEA or the combination of both reduces parasitemia during the acute phase of infection. The combined action of both molecules did not exert a synergic action on the host's ability to fight infection, and it seems that among all treatments DHEA induces a more efficient immune response.
    Journal of Pineal Research 11/2009; 47(3):253-9. · 7.30 Impact Factor
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    ABSTRACT: Growth hormone (GH) is an important hypophyseal hormone that is primarily involved in body growth and metabolism. In mammals, control of Trypanosoma cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. To explore the possibility that GH might be effective in the treatment of Chagas' disease, we investigated its effects on the course of T. cruzi infection in rats, focusing our analyses on its influences on parasitemia, NO, TNF-alpha and IFN-gamma concentration and on histopathological alterations and parasite burden in heart tissue. T. cruzi-infected male Wistar rats were intraperitoneally treated with 5 ng/10 g body weight/day of GH. Animals treated with GH showed a significant reduction in the number of blood trypomastigotes during the acute phase of infection compared with untreated animals (P<0.05). For all experimental days (7, 14 and 21 post infection) of the acute phase, infected and GH treated animals reached higher concentrations of TNF-alpha, IFN-gamma and nitric oxide as compared to untreated and infected counterparts (P<0.05) Histopathological observations of heart tissue revealed that GH administration also resulted in fewer and smaller amastigote burdens, and less inflammatory infiltrate and tissue disorganization, indicating a reduced parasitism of this tissue. These results show that GH can be considered as an immunomodulator substance for controlling parasite replication and combined with the current drug used may represent in the future a new therapeutic tool to reduce the harmful effects of Chagas' disease.
    Research in Veterinary Science 10/2009; 88(2):273-8. · 1.77 Impact Factor
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    ABSTRACT: Strains of Trypanosoma cruzi are multiclonal populations that can be classified in groups or genotypes, differing in pathogenicity, virulence, and histotropism. In this experiment the distinct behavior of two strains of T. cruzi, MORC-1 and MORC-2, was documented. Blood parasitemia, spleen proliferation, nitric oxide, histopathology of the spleen and heart were used as tools to evaluate parasite persistence. Groups of male mice were separated and divided in three groups: Control (C), Infected (IM-1) and Infected (IM-2). The peak of parasitemia occurred on 10days post infection for both strains. LPS stimulated animals, infected MORC-2 group displayed significant higher concentrations of NO when compared to infected MORC-1 group (P<0.05). For ConA stimulated lymphoproliferation, infected MORC-1 group displayed higher proliferation index as compared to infected MORC-2 group. An opposite behavior for IL-4 and TNF-alpha was observed according to the strain. For MORC-1 enhanced concentrations of IL-4 were present with concomitant reduced levels of TNF-alpha, while for MORC-2 enhanced concentrations of TNF-alpha and reduced levels of IL-4 were found. The histopathology of heart and spleen showed important differences in which MORC-1 displayed statistically enhanced number of amastigote in the heart and spleen as compared to MORC-2. Concluding, each strain triggered a distinct immune response with enhanced cytokine TH-1 profile for MORC-2 and TH-2 for MORC-1.
    Experimental Parasitology 09/2009; 124(2):219-24. · 2.15 Impact Factor
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    ABSTRACT: Gonadal steroids exert an important influence on the host immune response during infection. Changes resulting from the absence or replacement of gonadal hormones may represent a distinct evolution of a particular parasite. Taking into account the greater susceptibility of males to parasites, the magnitude of the immune response seems to depend on the interaction of many hormones that will act synergistically with other immune cells. The aims of this research were to evaluate the effects of the luck of male sex hormones due to orchiectomy, and the influence of oral administration of melatonin on the immune response of male Wistar rats infected with the Y strain of Trypanosoma cruzi. The percentage of CD3(+) CD4(+) and CD3(+) CD8(+) lymphocyte T cell subsets were evaluated using flow cytometry and the measurement of IL-2 and IL-12. For all parameters examined, a synergistic action of melatonin and orchiectomy on the host's immune response was observed, promoting an effective response against the parasite during the acute phase of infection. These results offer insight into other possibilities for possibly controlling T. cruzi proliferation through melatonin therapy and also the stimulatory effects on host's immune response triggered by the absence of male gonadal steroids during the acute phase of infection.
    Journal of Pineal Research 09/2009; 47(3):271-6. · 7.30 Impact Factor
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    ABSTRACT: Chagas' disease is considered the sixth most important neglected tropical disease worldwide. Considerable knowledge has been accumulated concerning the role of zinc on cellular immunity. The steroid hormone dehydroepiandrosterone (DHEA) is also known to modulate the immune system. The aims of this paper were to investigate a possible synchronization of their effects on cytokines and NO production and the resistance to Trypanosoma cruzi during the acute phase of infection. It was found that zinc, DHEA or zinc and DHEA supplementation enhanced the immune response, as evidenced by a significant reduction in parasitemia levels. Zinc and DHEA supplementation exerted additive effects on the immune response by elevation of macrophage counts, and by increasing concentrations of IFN-gamma and NO.
    Immunobiology 08/2009; 215(5):427-34. · 2.81 Impact Factor
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    ABSTRACT: Dehydroepiandrosterone (DHEA) has long been considered as a precursor for many steroid hormones. It also enhances the immune responses against a wide range of viral, bacterial, and parasitic pathogens. The aims of this work were to evaluate the influences of exogenous DHEA treatment on Wistar rats infected with the Y strain of Trypanosoma cruzi during the acute and its influence on the chronic phase of infection. Animals were subcutaneous treated with 40 mg/kg body weight/day of DHEA. DHEA treatment promoted increased lymphoproliferative responses as well as enhanced concentrations of NO and IL-12. So, we point in the direction that our results validate the utility of the use of DHEA as an alternative therapy candidate against T. cruzi.
    Veterinary Parasitology 05/2009; 163(1-2):27-32. · 2.38 Impact Factor
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    ABSTRACT: Zinc is an essential nutritional component required for normal development and maintenance of immune functions. The possible effects of zinc in upregulating the host immune response during the acute and chronic phases of experimental Chagas' disease were evaluated. In young, infected and Zn-supplemented animals, higher concentrations of IFN-gamma and NO were observed. During the chronic phase, decreased concentrations of NO and IFN-gamma were found for older infected animals that received Zn supplementation. For young animals, hearts from Zn-supplemented groups displayed reduced inflammatory infiltrate, heart weight and number of amastigote burdens. For older, infected and Zn-supplemented animals amastigote nests were absent with reduced inflammatory cell infiltrate. This study identifies a potentially novel therapeutic approach that could control the parasite load during acute phase of disease, consequently preventing the deleterious, parasite-elicited responses observed during chronic phase.
    Experimental Parasitology 11/2008; 121(1):105-9. · 2.15 Impact Factor
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    ABSTRACT: The effect of repetitive stress during acute infection with Trypanosoma cruzi (T. cruzi) on the chronic phase of ensuing Chagas' disease was the focus of this investigation. The aim of this study was to evaluate in Wistar rats the influence of repetitive stress during the acute phase of infection (7 days) with the Y strain of T. cruzi on the chronic phase of the infection (at 180 days). Exposure to ether vapor for 1 min twice a day was used as a stressor. Repetitive stress enhanced the number of circulating parasites and cardiac tissue disorganization, from a moderate to a severe diffuse mononuclear inflammatory process and the presence of amastigote burden in the cardiac fibers. Immunological parameters revealed that repetitive stress triggered a reduced concanavalin A induced splenocyte proliferation in vitro with major effects on the late chronic phase. Serum interleukin-12 concentration decreased in both stressed and infected rats in the early phase of infection although it was higher on 180 days post-infection. These results suggest that repetitive stress can markedly impair the host's immune system and enhance the pathological process during the chronic phase of Chagas' disease.
    Stress (Amsterdam, Netherlands) 11/2008; 12(2):144-51. · 3.21 Impact Factor
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    ABSTRACT: In this study, we verified the possible role of cyclophosphamide (CY) in protecting or not against neuronal losses in young and aged male Calomys callosus chronically infected with the MORC-1 strain of Trypanosoma cruzi through numerical quantification of neurons from the myenteric plexus of the colon and quantification of nitric-oxide concentration (NO) during the acute and chronic phase of infection. For this purpose, groups of young C. callosus were infected with the MORC-1 strain of T. cruzi. A group of infected animals received i.p. 0.2mg/ml genuxal dissolved in distilled water treatment with CY. NO concentration in aged animals displayed reduced levels when compared to those found in young animals. No significant alterations in the number of neurons were observed in young animals, but for aged ones, a protective role of CY in reducing neuron loss was noted, in addition to enhancing the neuronal volume, area, and perimeter. These results suggest that CY administration, depending on the dose and time span, can act as a protective agent against neuronal losses.
    Digestive Diseases and Sciences 11/2008; 53(11):2929-2934. · 2.26 Impact Factor

Publication Stats

261 Citations
102.71 Total Impact Points

Institutions

  • 2013
    • Universidade de Franca
      • Núcleo de Pesquisa em Ciências Exatas e Tecnológicas
      Franca, São Paulo, Brazil
  • 2005–2013
    • University of São Paulo
      • Ribeirão Preto School of Pharmaceutical Sciences (FCFRP)
      San Paulo, São Paulo, Brazil
  • 2008–2010
    • Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
      San Paulo, São Paulo, Brazil