Farmacodermia induzida por Voriconazol em um paciente com Aspergilose Angioinvasiva e Leucemia Mieloide Aguda: relato de caso e revisão de literatura

As farmacodermias ou reações cutâneas adversas a medicamentos (RCAM), representam um espectro de condições que afetam a pele, seus anexos e as mucosas, desencadeadas ou agravadas pelo uso de medicamentos. Estudos mostram que reações cutâneas estão presentes em 5 a 15% dos pacientes tratados com medicamentos. Destes 0,1% apresentarão reações cutâneas graves, podendo necessitar de hospitalização, resultar em incapacidade persistente e significativa ou óbito. Este artigo, trata de um estudo observacional e descritivo, do tipo relato de caso de uma criança em tratamento para leucemia mieloide aguda, diagnosticada com aspergilose angioinvasiva, que desenvolveu farmacodermia após uso de voriconazol. Além disso, foi realizada uma revisão da literatura que aborda a complexidade do tratamento de infecções fúngicas invasivas, com foco especial no uso do voriconazol em pacientes imunossuprimidos. Destaca-se a importância do voriconazol como agente antifúngico de escolha, devido à sua ampla atividade antifúngica e mecanismo de ação. No entanto, são discutidas as dificuldades associadas à farmacocinética, incluindo a notável variabilidade nos níveis plasmáticos, influenciada por fatores genéticos e outros fatores multifacetados. Ainda, foram reportados os desafios específicos relacionados à administração pediátrica, levando em consideração a menor biodisponibilidade oral e a necessidade de dosagens superiores. Por fim, foram exploradas as possíveis reações adversas ao voriconazol, com ênfase nas farmacodermias

Protective Effect of Galectin-1 during Histoplasma capsulatum Infection Is Associated with Prostaglandin E2 and Nitric Oxide Modulation

Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1−/− mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1−/− mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1−/− mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Evaluation of prostaglandin and leukotrienes in lung infection induced by Achromobacter xylosoxidans.

Achromobacter xylosoxidans (A. xylosoxidans) é um bacilo gram negativo, aeróbio, móvel, não fermentador de glicose e oxidase positivo, que coloniza habitualmente o trato digestivo e auditivo de humanos. Este bacilo tem sido associado a infecções oportunistas graves, especialmente pneumonia, em indivíduos imunossuprimidos, que em geral, são de difícil controle devido principalmente a fatores de virulência, mecanismos de escape e mutirresistência a antibióticoterapia. Dentre as condições que predispõem o desenvolvimento de infecção pulmonar por A. xylosoxidans, o câncer, a fibrose cística (FC) e a doença pulmonar obstrutiva crônica (DPOC) são as mais comuns. Essas doenças apresentam produção aumentada de vários mediadores lipídicos, como LTB4 e PGE2. A PGE2 é um lipídeo imunossupressor atuante no sistema imune inato e adaptativo que regula, por exemplo, a liberação de citocinas e quimiocinas, a ativação de células T, além de inibir as funções efetoras dos macrófagos. O LTB4, por outro lado, está associado ao recrutamento de células para o foco infeccioso, a ativação dos mecanismos efetores dos macrófagos, e aumento de mediadores inflamatórios. Neste trabalho, nosso objetivo foi investigar se, esses mediadores são liberados durante a infecção pulmonar por A. xylosoxidans e o possível papel dos mesmos. Nossos resultados demonstram que os tratamentos com celecoxibe, inibidor da síntese de prostaglandinas (PGs), nas doses de 1mg/kg ou 5mg/kg, não alteram a sobrevida dos animais infectados com inóculo letal ou subletal de A. xylosoxidans. No entanto, o tratamento com MK886, um inibidor da produção de leucotrienos (LTs), resultou em aumento da mortalidade dos animais infectados com inóculos letal ou subletal, redução do recrutamento de neutrófilos no dia 1 após infecção, redução de IL-6 do dia 14 e aumento de TNF-, IL-1 e MIP-1 no dia 7, KC no dia 14 e PGE2, em todos os períodos estudados. Este tratamento também induziu no lavado broncoalveolar, a diminuição não significativa do extravasamento de proteínas no dia 1, mas aumento significativo no dia 3. Com base nesses dados, podemos sugerimos que o tratamento com MK886 aumenta a mortalidade dos animais, devido ao aumento da permeabilidade vascular, com consequente edema, que leva os animais a insuficiência respiratória. Outros experimentos serão realizados para determinar o papel das prostaglandinas (PGs) e/ou metabolitos do ácido araquidônico neste fenômeno.Achromobacter xylosoxidans (A. xylosoxidans) is a gram negative bacilli, aerobic, mobile, glucose non fermenter and oxidase positive, which normally colonizes the digestive and auditory tract of humans. This bacillus has been associated with severe opportunistic infections, especially pneumonia, in immunocompromised individuals, which are generally difficult to control mainly due to virulence factors, mechanisms and exhaust multidrug resistance to antibiotic therapy. Among the conditions that predispose the development of pulmonary infection by A. xylosoxidans, cancer, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are the most common. These diseases have increased production of various lipid mediators, such as LTB4 and PGE2. PGE2 is an immunosuppressive lipid active in the innate and adaptive immune system that regulates, for example, the release of cytokines and chemokines, activation of T cells and inhibits the effector functions of macrophages. LTB4, on the other hand, is associated with the recruitment of cells to the infection, and the activation of effector mechanisms of macrophages, and increased production of inflammatory mediators. In this study, our aim was to investigate whether these mediators are released during pulmonary infection by A. xylosoxidans and the possible role of the same. Our results demonstrate that treatment with celecoxib, prostaglandin synthesis inhibitor (PGs), at doses of 1mg/kg or 5mg/kg not alter the survival of animals infected with lethal or sublethal inoculum of A. xylosoxidans. However, treatment with MK886, an inhibitor of the production of leukotrienes (LTs) resulted in an increased mortality of the animals infected with lethal or sublethal inoculum, reduce the recruitment of neutrophils on day 1 after infection, reduction in IL-6 day 14 and increased TNF-, IL-1 and MIP-1 at day 7, KC in day 14 and PGE2 in all periods. This treatment also induced in the bronchoalveolar lavage, no significant decrease protein extravasation in the day 1, but significantly increased on day 3. Based on these data, we suggest that treatment with MK886 increases the mortality of animals due to increased vascular permeability, with consequent edema, which leads the animals to respiratory failure. Other experiments will be conducted to determine the role of prostaglandins (PGs) and/or metabolites of arachidonic acid in this phenomenon

The influence of dehydroepiandrosterone on effector functions of neutrophils

Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands, gonads and brain. It is a precursor to sex hormones and also is known to have immune modulatory activity. However, little is known about the relationship between DHEA and neutrophils and thus our study evaluates the influence of DHEA in the effector functions of neutrophils. Human neutrophils were treated in vitro with DHEA and further infected with Salmonella enterica serovar Typhimurium. The treatment of neutrophils with 0.01 μM of DHEA increased the phagocytosis of Salmonella independent of TLR4 as the treatment did not modulate the TLR4 expression. Additionally, DHEA caused a decrease in ROS (reactive oxygen species) production and did not influence the formation of the neutrophil extracellular trap (NET). Steroid treated neutrophils, infected or stimulated with LPS (lipopolysaccharide), showed reduced production of IL-8, compared to untreated cells. Also, the protein levels of p-NFκB were decreased in neutrophils treated with DHEA, and this reduction could explain the reduced levels of IL-8. These results led us to conclude that the steroid hormone DHEA has important modulatory functions in neutrophils

Erythropoietin Exacerbates Inflammation and Increases the Mortality of Histoplasma capsulatum-Infected Mice

Erythropoietin (EPO) is a key hormone involved in red blood cell formation, but its effects on nonerythroid cells, such as macrophages, have not been described. Macrophages are key cells in controlling histoplasmosis, a fungal infection caused by Histoplasma capsulatum (Hc). Considering that little is known about EPO’s role during fungal infections and its capacity to activate macrophages, in this study we investigated the impact of EPO pretreatment on the alveolar immune response during Hc infection. The consequence of EPO pretreatment on fungal infection was determined by evaluating animal survival, fungal burden, activation of bronchoalveolar macrophages, inflammatory mediator release, and lung inflammation. Pretreatment with EPO diminished mononuclear cell numbers, increased the recruitment of F4/80+/CD80+ and F4/80+/CD86+ cells to the bronchoalveolar space, induced higher production of IFN-γ, IL-6, MIP-1α, MCP-1, and LTB4, reduced PGE2 concentration, and did not affect fungal burden. As a consequence, we observed an increase in lung inflammation with extensive tissue damage that might account for augmented mouse mortality after infection. Our results demonstrate for the first time that EPO treatment has a deleterious impact on lung immune responses during fungal infection