Mortality due to systemic mycoses as a primary cause of death or in association with AIDS in Brazil: a review from 1996 to 2006

Deaths caused by systemic mycoses such as paracoccidioidomycosis, cryptococcosis, histoplasmosis, candidiasis, aspergillosis, coccidioidomycosis and zygomycosis amounted to 3,583 between 1996-2006 in Brazil. When analysed as the underlying cause of death, paracoccidioidomycosis represented the most important cause of deaths among systemic mycoses (~ 51.2%). When considering AIDS as the underlying cause of death and the systemic mycoses as associated conditions, cryptococcosis (50.9%) appeared at the top of the list, followed by candidiasis (30.2%), histoplasmosis (10.1%) and others. This mortality analysis is useful in understanding the real situation of systemic mycoses in Brazil, since there is no mandatory notification of patients diagnosed with systemic mycoses in the official health system.FAPESPCNP

The role of adjuvants in therapeutic protection against paracoccidioidomycosis after immunization with the P10 peptide

Paracoccidioidomycosis (PCM), a common chronic mycosis in Latin America, is a granulomatous systemic disease caused by the thermo-dimorphic fungus Paracoccidioides brasiliensis. The glycoprotein gp43 is the main antigen target of P. brasiliensis and a 15-mer internal peptide (QTLIAIHTLAIRYAN), known as P10, defines a major CD4+-specific T cell epitope. Previous results have indicated that, besides having a preventive role in conventional immunizations prior to challenge with the fungus, protective anti-fungal effects can be induced in P. brasiliensis-infected mice treated with P10 administered with complete Freund’s adjuvant (CFA). The peptide elicits an IFN-γ-dependent Th1 immune response and is the main candidate for effective immunotherapy of patients with PCM, as an adjunctive approach to conventional chemotherapy. In the present study we tested the therapeutic effects of P10 combined with different adjuvants [aluminum hydroxide, CFA, flagellin, and the cationic lipid dioctadecyl-dimethylammonium bromide (DODAB)] in BALB/c mice previously infected with the P. brasiliensis Pb18 strain. Significant reductions in the number of colony forming units of the fungus were detected in lungs of mice immunized with P10 associated with the different adjuvants 52 days after infection. Mice treated with DODAB and P10, followed by mice treated with P10 and flagellin, showed the most prominent effects as demonstrated by the lowest numbers of viable yeast cells as well as reductions in granuloma formation and fibrosis. Concomitantly, secretion of IFN-γ and TNF-α, in contrast to interleukin (IL)-4 and IL-10, was enhanced in the lungs of mice immunized with P10 in combination with the tested adjuvants, with the best results observed in mice treated with P10 and DODAB. In conclusion, the present results demonstrate that the co-administration of the synthetic P10 peptide with several adjuvants, particularly DODAB, have significant therapeutic effects in experimental PCM

Therapeutic use of a cationic antimicrobial peptide from the spider Acanthoscurria gomesiana in the control of experimental candidiasis

<p>Abstract</p> <p>Background</p> <p>Antimicrobial peptides are present in animals, plants and microorganisms and play a fundamental role in the innate immune response. Gomesin is a cationic antimicrobial peptide purified from haemocytes of the spider <it>Acanthoscurria gomesiana</it>. It has a broad-spectrum of activity against bacteria, fungi, protozoa and tumour cells. <it>Candida albicans</it> is a commensal yeast that is part of the human microbiota. However, in immunocompromised patients, this fungus may cause skin, mucosal or systemic infections. The typical treatment for this mycosis comprises three major categories of antifungal drugs: polyenes, azoles and echinocandins; however cases of resistance to these drugs are frequently reported. With the emergence of microorganisms that are resistant to conventional antibiotics, the development of alternative treatments for candidiasis is important. In this study, we evaluate the efficacy of gomesin treatment on disseminated and vaginal candidiasis as well as its toxicity and biodistribution.</p> <p>Results</p> <p>Treatment with gomesin effectively reduced <it>Candida albicans </it>in the kidneys, spleen, liver and vagina of infected mice. The biodistribution of gomesin labelled with technetium-99 m showed that the peptide is captured in the kidneys, spleen and liver. Enhanced production of TNF-α, IFN-γ and IL-6 was detected in infected mice treated with gomesin, suggesting an immunomodulatory activity. Moreover, immunosuppressed and <it>C. albicans</it>-infected mice showed an increase in survival after treatment with gomesin and fluconazole. Systemic administration of gomesin was also not toxic to the mic</p> <p>Conclusions</p> <p>Gomesin proved to be effective against experimental <it>Candida albicans</it> infection. It can be used as an alternative therapy for candidiasis, either alone or in combination with fluconazole. Gomesin's mechanism is not fully understood, but we hypothesise that the peptide acts through the permeabilisation of the yeast membrane leading to death and/or releasing the yeast antigens that trigger the host immune response against infection. Therefore, data presented in this study reinforces the potential of gomesin as a therapeutic antifungal agent in both humans and animals.</p

Antibodies Against Glycolipids Enhance Antifungal Activity of Macrophages and Reduce Fungal Burden After Infection with Paracoccidioides brasiliensis

Paracoccidioidomycosis is a fungal disease endemic in Latin America. Polyclonal antibodies to acidic glycosphingolipids (GSLs) from Paracoccidioides brasiliensis opsonized yeast forms in vitro increasing phagocytosis and reduced the fungal burden of infected animals. Antibodies to GSL were active in both prophylactic and therapeutic protocols using a murine intratracheal infection model. Pathological examination of the lungs of animals treated with antibodies to GSL showed well-organized granulomas and minimally damaged parenchyma compared to the untreated control. Murine peritoneal macrophages activated by IFN-gamma and incubated with antibodies against acidic GSLs more effectively phagocytosed and killed P brasiliensis yeast cells as well as produced more nitric oxide compared to controls. The present work discloses a novel target of protective antibodies against P brasiliensis adding to other well-studied mediators of the immune response to this fungus.CapesFAPESPUniv Sao Paulo, Dept Microbiol, Inst Biomed Sci, Sao Paulo, BrazilUniv Sao Paulo, Lab Med Mycol IMTSP LIM53, Sao Paulo, BrazilAlbert Einstein Coll Med, Dept Med, New York, NY USAAlbert Einstein Coll Med, Dept Microbiol & Immunol, New York, NY USAUniv Fed Fluminense, Niteroi, RJ, BrazilUniv Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilFAPESP: 2011/17267-4FAPESP: 2013/18655-3Web of Scienc

DETERMINATION OF THE THINNING PERIOD BY DENDROCHRONOLOGICAL AND MORPHOMETRIC ANALYSIS IN UNMANAGED STAND OF Ocotea porosa

Plantios comerciais de Ocotea porosa dispon\uedveis para estudo s\ue3o raros e por esse motivo devem ser usados como fonte de informa\ue7\ue3o para se estabelecer o potencial de manejo da esp\ue9cie. A recupera\ue7\ue3o do hist\uf3rico do crescimento desses povoamentos para estrutura\ue7\ue3o dos planos de manejo \ue9 poss\uedvel com o uso da t\ue9cnica da dendrocronologia e a an\ue1lise de dados dendrom\ue9tricos e morfom\ue9tricos. O objetivo desse trabalho foi utilizar ferramentas de an\ue1lise de povoamentos florestais aliadas aos estudos dendrocronol\uf3gicos, para recuperar e sistematizar o desenvolvimento de povoamento n\ue3o manejado. O trabalho foi conduzido em um povoamento n\ue3o manejado de imbuia, com 44 anos, em Rio Negro - PR, na Esta\ue7\ue3o Experimental da UFPR. Infer\ueancias do crescimento recuperado por dendrocronologia, e competi\ue7\ue3o pela aplica\ue7\ue3o de metodologias como \uedndice de abrang\ueancia e de proje\ue7\ue3o de copa mostraram resultados compat\uedveis na an\ue1lise do povoamento, indicando necessidade de primeiro desbaste pr\uf3ximo aos 12 anos. Em fun\ue7\ue3o do pequeno n\ufamero de \ue1rvores amostradas, os resultados n\ue3o permitem generaliza\ue7\uf5es definitivas, entretanto, s\ue3o consistentes para estabelecer um protocolo para an\ue1lise de povoamentos n\ue3o manejados de Ocotea porosa, assim como de outras esp\ue9cies.Commercial plantations of Ocotea porosa available for studying are scarce and therefore should be used as a source of information to establish the potential for management of the species in plantations, even if these evaluations were not been held along the stand development. The recovery of the historical growth of these stands to optimize the management plans is possible by dendrochronology and by the analysis of morphometric and dendrometric data. The aim of this study was to use stand analysis tools, combined with the dendrochronological studies, to recover and to systematize the development of unmanaged stands. The study was conducted in an unmanaged stand of Ocotea porosa, with with 44 years of age in Rio Negro, PR state, in a UFPR research station. Growth inferences recovered by dendrochronology and the competition by the application of methodologies such as rate of coverage and crown cover rate showed consistent results in the analysis of population, indicating the need for a first thinning near 12 years old. Due to the small number of sampled trees, the results do not allow any definitive generalization. However, they are consistent to establish an analysis protocol for unmanaged stands of Ocotea porosa or other species

Therapeutic DNA Vaccine Encoding Peptide P10 against Experimental Paracoccidioidomycosis

Paracoccidioidomycosis (PCM), caused by Paracoccidioides brasiliensis, is the most prevalent invasive fungal disease in South America. Systemic mycoses are the 10th most common cause of death among infectious diseases in Brazil and PCM is responsible for more than 50% of deaths due to fungal infections. PCM is typically treated with sulfonamides, amphotericin B or azoles, although complete eradication of the fungus may not occur and relapsing disease is frequently reported. A 15-mer peptide from the major diagnostic antigen gp43, named P10, can induce a strong T-CD4+ helper-1 immune response in mice. The TEPITOPE algorithm and experimental data have confirmed that most HLA-DR molecules can present P10, which suggests that P10 is a candidate antigen for a PCM vaccine. In the current work, the therapeutic efficacy of plasmid immunization with P10 and/or IL-12 inserts was tested in murine models of PCM. When given prior to or after infection with P. brasiliensis virulent Pb 18 isolate, plasmid-vaccination with P10 and/or IL-12 inserts successfully reduced the fungal burden in lungs of infected mice. In fact, intramuscular administration of a combination of plasmids expressing P10 and IL-12 given weekly for one month, followed by single injections every month for 3 months restored normal lung architecture and eradicated the fungus in mice that were infected one month prior to treatment. The data indicate that immunization with these plasmids is a powerful procedure for prevention and treatment of experimental PCM, with the perspective of being also effective in human patients

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO