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BACKGROUND: Cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1ß play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL. METHODS: In this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA. RESULTS: The cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29. CONCLUSION: rSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov under NCT06000514.
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Administração Tópica , Antiprotozoários , Quimioterapia Combinada , Leishmaniose Cutânea , Antimoniato de Meglumina , Compostos Organometálicos , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/administração & dosagem , Masculino , Feminino , Adulto , Antiprotozoários/uso terapêutico , Antiprotozoários/administração & dosagem , Pessoa de Meia-Idade , Adulto Jovem , Compostos Organometálicos/uso terapêutico , Compostos Organometálicos/administração & dosagem , Resultado do Tratamento , Meglumina/administração & dosagem , Meglumina/uso terapêutico , Adolescente , Animais , Leishmania braziliensis/efeitos dos fármacos , Administração Intravenosa , Granzimas/metabolismoRESUMO
Bacillus Calmette-Guérin (BCG) is the first line treatment for bladder cancer and it is also proposed for melanoma immunotherapy. BCG modulates the tumor microenvironment (TME) inducing an antitumor effective response, but the immune mechanisms involved still poorly understood. The immune profile of B16-F10 murine melanoma cells was assessed by infecting these cells with BCG or stimulating them with agonists for different innate immune pathways such as TLRs, inflammasome, cGAS-STING and type I IFN. B16-F10 did not respond to any of those stimuli, except for type I IFN agonists, contrasting with bone marrow-derived macrophages (BMDMs) that showed high production of proinflammatory cytokines. Additionally, we confirmed that BCG is able to infect B16-F10, which in turn can activate macrophages and spleen cells from mice in co-culture experiments. Furthermore, we established a subcutaneous B16-F10 melanoma model for intratumoral BCG treatment and compared wild type mice to TLR2-/-, TLR3-/-, TLR4-/-, TLR7-/-, TLR3/7/9-/-, caspase 1-/-, caspase 11-/-, IL-1R-/-, cGAS-/-, STING-/-, IFNAR-/-, MyD88-/-deficient animals. These results in vivo demonstrate that MyD88 signaling is important for BCG immunotherapy to control melanoma in mice. Also, BCG fails to induce cytokine production in the co-culture experiments using B16-F10 and BMDMs or spleen cells derived from MyD88-/- compared to wild-type (WT) animals. Immunotherapy with BCG was not able to induce the recruitment of inflammatory cells in the TME from MyD88-/- mice, impairing tumor control and IFN-γ production by T cells. In conclusion, MyD88 impacts on both innate and adaptive responses to BCG leading to an efficient antitumor response against melanoma.
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Vacina BCG , Imunoterapia , Melanoma Experimental , Fator 88 de Diferenciação Mieloide , Transdução de Sinais , Animais , Camundongos , Vacina BCG/imunologia , Vacina BCG/uso terapêutico , Linhagem Celular Tumoral , Citocinas/metabolismo , Imunoterapia/métodos , Macrófagos/imunologia , Macrófagos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Microambiente Tumoral/imunologiaRESUMO
Introdução: A população idosavem aumentando e consequentemente maiores riscos de doenças cardiovasculares que podem acarretar com comorbidades como a insuficiência renal. A equipe multiprofissional enfrenta o desafio de trabalhar articulada e promover da melhor forma a comunicação em um plano terapêutico de cuidados paliativos do paciente juntamente à família. Método: Atendimentos individuais com os profissionais que compõem a equipe multiprofissional de cuidados paliativos para ação de um plano terapêutico. Relato de caso: MTS de 76 anos, sexo feminino com hipertensão arterial, diabete mellitus e infarto agudo do miocárdio. No período de internação hospitalar que aguardava a clínica da hemodiálise passou por fases devido aos diagnósticos de Síndrome Coronariana Aguda, Insuficiência Cardíaca e Doença Renal Crônica Agudizada. No início a expectativa era enorme de ir para casa. A família é bem unida, apoia e tem rede de sustentação e reveza nos cuidados com a paciente. Ao ser chamada na clínica foi recusada porque estava acamada e não conseguia sentar. Assim, desse modo, ocorreu frustração e um luto da sua autonomia, independência e das atividades cotidianas que não podia realizar. A família entrou com um processo e o juiz referiu que MTS já estava sendo assistida na necessidade da hemodiálise. Ela parou de se alimentar, ficou triste e a equipe fortaleceu a rede de cuidados e trabalhou os recursos da paciente bem como sua autonomia e independência no hospital no dia a dia. Devido à fragilidade do caso, necessitou de sonda de alimentação enteral (SNE), sendo avaliada pela fonoaudiologia com diagnóstico de disfagia orofaríngea de grau moderado. Durante o processo terapêutico a paciente negava os testes com dieta oral. Através da atuação integrada com a psicologia e a assistência social, foi possível evolução no processo terapêutico, MTS a partir de então voltou a sorrir, a ficar alegre, reabilitou para deglutição funcional e aceitação das dietas. Resultado: Com o atendimento integrado notou-se a criação de um espaço seguro e efetivo da paciente para manifestar os desejos e expressar as emoções. Apesar de MTS ter ido a óbito após 06 meses, ela pôde ficar ao lado da família, realizar seus desejos e ter uma rede de suporte mais fortalecida. Conclusão: O trabalho da equipe multiprofissional é fundamental nos atendimentos de casos como este, promovendo melhor comunicação e cuidados de modo integral ao paciente dentro de um plano de cuidados paliativos.
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Humanos , Feminino , Idoso de 80 Anos ou mais , Equipe de Assistência ao PacienteRESUMO
INTRODUÇÃO: Cuidado Paliativo define se como medidas que promovem a qualidade de vida de pacientes e seus familiares que enfrentam uma doença sem perspectiva de cura, através da prevenção e alívio do sofrimento por meio de identificação precoce da doença, avaliação correta e controle adequado dos sintomas físicos, psicossociais e espirituais". OBJETIVO: Indicar o conhecimento teórico e prático da equipe interdisciplinar relacionados na abordagem dos Cuidados Paliativos na Cardiologia. METODO: Relato de experiência das rodas de conversas, realizadas na Unidade de Cardiologia Geral, de um hospital especializado em cardiologia de São Paulo. A equipe de Cuidados Paliativos (médico, psicólogo, enfermeiro, assistente social, nutrição, fisioterapeuta e odontologia) e graduandos de medicina e enfermagem. A equipe do hospital propiciava um ambiente acolhedor e com liberdade para que tanto os graduando e a equipe trouxessem casos, dúvidas, inquietações que eram disparadas do encontro com os pacientes, familiares e com membros das equipes sobre o que fizesse sentido aprimorar, aprender e esclarecer no cuidado paliativo com o foco de constante progresso na assistência do núcleo de cuidado com ênfase na atenção biopsicossocial e espiritual. RESULTADOS: A partir das rodas de conversas apareceram nas equipes; identificar no encontro com o paciente e familiares o sofrimento no cuidado, como se posicionavam, o que sentiram e como agiram. A identificação da história pessoal ou da doença do paciente com a vida no cuidado do cuidador também foi marcante. A questão do Burnout e de como cada um se cuida. Outro aspecto é frente à finitude dos pacientes o intenso sofrimento espiritual e moral por pouco ou nenhum conhecimento. As propostas de intervenções elencadas frente ao diagnóstico foram: ampliar os espaços de autocuidado, conversar e buscar ajuda e apoio psicológico para o enfrentamento do luto, ampliar as aulas e os grupos de discussões de casos e grupos de estudos. Outro foco fundamental é no cuidado com o paciente identificar a fase que o paciente se encontra para propor o plano de cuidado e a adequação terapêutica. CONCLUSÃO: Nota-se a extrema importância da continuidade de treinamento institucional constante para o pouco conhecimento relacionado à temática e aos desafios de cuidar dos pacientes e familiares na fase final e últimos dias.
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Introduction: Guanylate-binding proteins (GBPs) are produced in response to pro-inflammatory signals, mainly interferons. The most studied cluster of GBPs in mice is on chromosome 3. It comprises the genes for GBP1-to-3, GBP5 and GBP7. In humans, all GBPs are present in a single cluster on chromosome 1. Brucella abortus is a Gram-negative bacterium known to cause brucellosis, a debilitating disease that affects both humans and animals. Our group demonstrated previously that GBPs present on murine chromosome 3 (GBPchr3) is important to disrupt Brucella-containing vacuole and GBP5 itself is important to Brucella intracellular LPS recognition. In this work, we investigated further the role of GBPs during B. abortus infection. Methods and results: We observed that all GBPs from murine chromosome 3 are significantly upregulated in response to B. abortus infection in mouse bone marrow-derived macrophages. Of note, GBP5 presents the highest expression level in all time points evaluated. However, only GBPchr3-/- cells presented increased bacterial burden compared to wild-type macrophages. Brucella DNA is an important Pathogen-Associated Molecular Pattern that could be available for inflammasome activation after BCV disruption mediated by GBPs. In this regard, we observed reduced IL-1ß production in the absence of GBP2 or GBP5, as well as in GBPchr3-/- murine macrophages. Similar result was showed by THP-1 macrophages with downregulation of GBP2 and GBP5 mediated by siRNA. Furthermore, significant reduction on caspase-1 p20 levels, LDH release and Gasdermin-D conversion into its mature form (p30 N-terminal subunit) was observed only in GBPchr3-/- macrophages. In an in vivo perspective, we found that GBPchr3-/- mice had increased B. abortus burden and higher number of granulomas per area of liver tissue, indicating increased disease severity. Discussion/conclusion: Altogether, these results demonstrate that although GBP5 presents a high expression pattern and is involved in inflammasome activation by bacterial DNA in macrophages, the cooperation of multiple GBPs from murine chromosome 3 is necessary for full control of Brucella abortus infection.
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Brucelose , Proteínas de Ligação ao GTP , Animais , Camundongos , Brucella abortus/genética , Brucelose/microbiologia , Proteínas de Transporte/metabolismo , DNA Bacteriano , Inflamassomos/genética , Inflamassomos/metabolismo , Proteínas de Ligação ao GTP/genéticaRESUMO
The bacillus Calmette-Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines.
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Exosomes, organelles measuring 30-200nm, are secreted by various cell types. Leishmania exosomes consist of many proteins, including heat shock proteins, annexins, Glycoprotein 63, proteins exerting signaling activity and those containing mRNA and miRNA. Studies have demonstrated that Leishmania donovani exosomes downregulate IFN-γ and inhibit the expression of microbicidal molecules, such as TNF and nitric oxide, thus creating a microenvironment favoring parasite proliferation. Despite lacking immunological memory, data in the literature suggest that, following initial stimulation, mononuclear phagocytes may become "trained" to respond more effectively to subsequent stimuli. Here we characterized the effects of macrophage sensitization using L. braziliensis exosomes prior to infection by the same pathogen. Human macrophages were stimulated with L. braziliensis exosomes and then infected with L. braziliensis. Higher levels of IL-1ß and IL-6 were detected in cultures sensitized prior to infection compared to unstimulated infected cells. Moreover, stimulation with L. braziliensis exosomes induced macrophage production of IL-1ß, IL-6, IL-10 and TNF. Inhibition of exosome secretion by L. braziliensis prior to macrophage infection reduced cytokine production and produced lower infection rates than untreated infected cells. Exosome stimulation also induced the consumption/regulation of NLRP3 inflammasome components in macrophages, while the blockade of NLRP3 resulted in lower levels of IL-6 and IL-1ß. Our results suggest that L. braziliensis exosomes stimulate macrophages, leading to an exacerbated inflammatory state that may be NLRP3-dependent.
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Exossomos , Leishmania braziliensis , Leishmania donovani , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Interleucina-6/farmacologia , MacrófagosRESUMO
The bacillus Calmette-Guérin (BCG) can elicit enhanced innate immune responses against a wide range of infections, known as trained immunity. Brucella abortus is the causative agent of brucellosis, a debilitating disease that affects humans and animals. In this study, we demonstrate that C57BL/6 mouse bone marrow-derived macrophages under BCG training enhance inflammatory responses against B. abortus. BCG-trained macrophages showed increased MHC class II and CD40 expression on the cell surface and higher IL-6, IL-12, and IL-1ß production. The increase in IL-1ß secretion was accompanied by enhanced activation of canonical and noncanonical inflammasome platforms. We observed elevated caspase-11 expression and caspase-1 processing in BCG-trained macrophages in response to B. abortus compared with untrained cells. In addition, these BCG-trained cells showed higher NLRP3 expression after B. abortus infection. From a metabolic point of view, signaling through the Akt/mammalian target of rapamycin/S6 kinase pathway was also enhanced. In addition, BCG training resulted in higher inducible NO synthase expression and nitrite production, culminating in an improved macrophage-killing capacity against intracellular B. abortus. In vivo, we monitored a significant reduction in the bacterial burden in organs from BCG-trained C57BL/6 mice when compared with the untrained group. In addition, previous BCG immunization of RAG-1-deficient mice partially protects against Brucella infection, suggesting the important role of the innate immune compartment in this scenario. Furthermore, naive recipient mice that received BM transfer from BCG-trained donors showed greater resistance to B. abortus when compared with their untrained counterparts. These results demonstrate that BCG-induced trained immunity in mice results in better control of intracellular B. abortus in vivo and in vitro.
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Brucella abortus , Brucelose , Humanos , Animais , Camundongos , Vacina BCG , Camundongos Endogâmicos C57BL , Macrófagos , Brucelose/metabolismo , Caspases/metabolismo , MamíferosRESUMO
The objective of this research was to produce an activated carbon (AC) from exhausted coffee grounds (ECG) and chemically activate it with natural lye from eucalyptus ash to subsequently evaluate the fluoride adsorption process in an aqueous medium. The thermal analysis of ECG was determined as well as solubilized extraction, alkalinity and calcium content of eucalyptus ashes. AC was characterized by elemental analysis, scanning electron microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), analysis of textural properties, pH and point of zero charge (PZC). The AC presented macroporosity and XRD confirmed the amorphous characteristic of cellulose-containing materials. Carboxylic acid functional group was identified in the AC surface, which can contribute to the adsorption of fluoride. The specific surface area of ECG and AC were 189.01 and 21.74 m2/g. The adsorption kinetics of fluoride revealed that equilibrium is reached around 800 min and the data followed the pseudo-second order model. The Freundlich model fitted the experimental data with the best quality and Freundlich's constant n allowed inferring that the adsorption is favorable and the isotherm appears to be L-type, with an initial downward curvature, which suggests less availability of active sites when increasing the adsorbent concentration.
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Eucalyptus , Lixívia , Poluentes Químicos da Água , Fluoretos , Café , Carvão Vegetal/química , Adsorção , Cinética , Espectroscopia de Infravermelho com Transformada de Fourier , Concentração de Íons de Hidrogênio , Poluentes Químicos da Água/químicaRESUMO
Despite the importance of the respiratory route for Brucella transmission, the lung immune response to this pathogen is scarcely characterized. We investigated the role of the cGAS/STING pathway of microbial DNA recognition in the control of respiratory Brucella infection. After in vitro B. abortus infection, CFU numbers were significantly higher in alveolar macrophages (AM) and lung explants from STING KO mice than in samples from wild type (WT) mice, but no difference was observed for cGAS KO samples. CFU were also increased in WT AM and lung epithelial cells preincubated with the STING inhibitor H151. Several proinflammatory cytokines (TNF-α, IL-1ß, IL-6, IP-10/CXCL10) were diminished in Brucella-infected lung explants and/or AM from STING KO mice and cGAS KO mice. These cytokines were also reduced in infected AM and lung epithelial cells pretreated with H151. After intratracheal infection with B. abortus, STING KO mice exhibited increased CFU in lungs, spleen and liver, a reduced expression of IFN-ß mRNA in lungs and spleen, and reduced levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and lung homogenates. Increased lung CFU and reduced BALF cytokines were also observed in cGAS KO mice. In summary, the cGAS/STING pathway induces the production of proinflammatory cytokines after respiratory Brucella infection, which may contribute to the STING-dependent control of airborne brucellosis.
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Brucelose Bovina , Brucelose , Animais , Camundongos , Bovinos , Brucella abortus , Citocinas/metabolismo , Nucleotidiltransferases/genéticaRESUMO
COVID-19 has accounted for more than 6 million deaths worldwide. Bacillus Calmette-Guérin (BCG), the existing tuberculosis vaccine, is known to induce heterologous effects over other infections due to trained immunity and has been proposed to be a potential strategy against SARS-CoV-2 infection. In this report, we constructed a recombinant BCG (rBCG) expressing domains of the SARS-CoV-2 nucleocapsid and spike proteins (termed rBCG-ChD6), recognized as major candidates for vaccine development. We investigated whether rBCG-ChD6 immunization followed by a boost with the recombinant nucleocapsid and spike chimera (rChimera), together with alum, provided protection against SARS-CoV-2 infection in K18-hACE2 mice. A single dose of rBCG-ChD6 boosted with rChimera associated with alum elicited the highest anti-Chimera total IgG and IgG2c Ab titers with neutralizing activity against SARS-CoV-2 Wuhan strain when compared with control groups. Importantly, following SARS-CoV-2 challenge, this vaccination regimen induced IFN-γ and IL-6 production in spleen cells and reduced viral load in the lungs. In addition, no viable virus was detected in mice immunized with rBCG-ChD6 boosted with rChimera, which was associated with decreased lung pathology when compared with BCG WT-rChimera/alum or rChimera/alum control groups. Overall, our study demonstrates the potential of a prime-boost immunization system based on an rBCG expressing a chimeric protein derived from SARS-CoV-2 to protect mice against viral challenge.
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COVID-19 , Mycobacterium bovis , Animais , Camundongos , Vacina BCG/genética , Proteínas Recombinantes de Fusão/genética , SARS-CoV-2 , Vacinas Sintéticas , COVID-19/prevenção & controle , Mycobacterium bovis/genéticaRESUMO
Production of nitric oxide (NO) by LPS-activated macrophages is due to a complex cellular signaling initiated by TLR4 that leads to the transcription of IFN-ß, which activates IRF-1 and STAT-1, as well as to the activation of NF-κB, required for iNOS transcription. High concentrations of LPS can also be uptaken by scavenger receptors (SRs), which, in concert with TLR4, leads to inflammatory responses. The mechanisms by which TLR4 and SRs interact, and the pathways activated by this interaction in macrophages are not elucidated. Therefore, our main goal was to evaluate the role of SRs, particularly SR-A, in LPS-stimulated macrophages for NO production. We first showed that, surprisingly, LPS can induce the expression of iNOS and the production of NO in TLR4-/- mice, provided exogenous IFN-ß is supplied. These results indicate that LPS stimulate receptors other than TLR4. The inhibition of SR-A using DSS or neutralizing antibody to SR-AI showed that SR-A is essential for the expression of iNOS and NO production in stimulation of TLR4 by LPS. The restoration of the ability to express iNOS and produce NO by addition of rIFN-ß to inhibited SR-A cells indicated that the role of SR-AI in LPS-induced NO production is to provide IFN-ß, probably by mediating the internalization of LPS/TLR4, and the differential inhibition by DSS and neutralizing antibody to SR-AI suggested that other SRs are also involved. Our results reinforce that TLR4 and SR-A act in concert in LPS activation and demonstrated that, for the production of NO, it does mainly by synthesizing IRF-3 and also by activating the TRIF/IRF-3 pathway for IFN-ß production, essential for LPS-mediated transcription of iNOS. Consequently STAT-1 is activated, and IRF-1 is expressed, which together with NF-κB from TLR4/MyD88/TIRAP, induce iNOS synthesis and NO production. SUMMARY SENTENCE: TLR4 and SRs act in concert activating IRF-3 to transcribe IFN-ß and activate STAT-1 to produce NO by LPS-activated macrophages.
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NF-kappa B , Óxido Nítrico , Camundongos , Animais , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Receptores Depuradores/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismoRESUMO
BACKGROUND: The continuous proliferation of intestinal stem cells followed by their tightly regulated differentiation to epithelial cells is essential for the maintenance of the gut epithelial barrier and its functions. How these processes are tuned by diet and gut microbiome is an important, but poorly understood question. Dietary soluble fibers, such as inulin, are known for their ability to impact the gut bacterial community and gut epithelium, and their consumption has been usually associated with health improvement in mice and humans. In this study, we tested the hypothesis that inulin consumption modifies the composition of colonic bacteria and this impacts intestinal stem cells functions, thus affecting the epithelial structure. METHODS: Mice were fed with a diet containing 5% of the insoluble fiber cellulose or the same diet enriched with an additional 10% of inulin. Using a combination of histochemistry, host cell transcriptomics, 16S microbiome analysis, germ-free, gnotobiotic, and genetically modified mouse models, we analyzed the impact of inulin intake on the colonic epithelium, intestinal bacteria, and the local immune compartment. RESULTS: We show that the consumption of inulin diet alters the colon epithelium by increasing the proliferation of intestinal stem cells, leading to deeper crypts and longer colons. This effect was dependent on the inulin-altered gut microbiota, as no modulations were observed in animals deprived of microbiota, nor in mice fed cellulose-enriched diets. We also describe the pivotal role of γδ T lymphocytes and IL-22 in this microenvironment, as the inulin diet failed to induce epithelium remodeling in mice lacking this T cell population or cytokine, highlighting their importance in the diet-microbiota-epithelium-immune system crosstalk. CONCLUSION: This study indicates that the intake of inulin affects the activity of intestinal stem cells and drives a homeostatic remodeling of the colon epithelium, an effect that requires the gut microbiota, γδ T cells, and the presence of IL-22. Our study indicates complex cross kingdom and cross cell type interactions involved in the adaptation of the colon epithelium to the luminal environment in steady state. Video Abstract.
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Microbioma Gastrointestinal , Inulina , Humanos , Animais , Camundongos , Inulina/farmacologia , Dieta , Fibras na Dieta , Celulose , Epitélio , Comunicação CelularRESUMO
APRESENTAÇÃO DO CASO: Com a ampliação da expectativa de vida e o aumento das doenças crônicas, cada vez mais familiares e pacientes são atendidos nos cuidados paliativos. Nessa nova configuração o desafio é a atenção na vontade do paciente que contribua na melhora da qualidade na fase final de vida com foco em alinhar a comunicação e o plano de cuidado. Relatar o trabalho da equipe multidisciplinar e as dificuldades na ida do paciente para casa. DISCUSSÃO: Ele tinha 89 anos, residia com a esposa e tinha quatro filhos independentes financeiramente. Apresentava hipertensão, insuficiência cardíaca descompensada e lesão renal aguda sendo internado para compensação clínica devido a gravidade das comorbidades e curso inexorável da doença cardíaca. Foi agendada uma reunião familiar com a equipe médica e multiprofissional (assistente social, psicólogo e enfermagem) em que a família consenso ou com a equipe por realizar as medidas de conforto clinico em detrimento de medidas invasivas que não prolongassem a sobrevida e aumentasse o sofrimento do paciente. Durante as visitas ele manifestou o desejo de ir para casa e ficar com a esposa. Solicitava alta a equipe até que num dado momento ao apresentar as condições clínicas favoráveis para a alta os filhos não quiseram levá-lo para casa. Frente ao desejo a equipe buscou entender a manifestação contrária da família e era devido ao medo da mãe do marido morrer com ela sozinho. "Sou desprezado pela minha família. Porque vocês não me dão alta? Eu posso me virar muito bem na minha casa." A equipe trabalhou e buscou oferecer um espaço de apoio e escuta ativa, para gerenciar possíveis dificuldades e desconfortos físicos, e permitir que o impacto emocional fosse expresso e o luto por não ir para casa. Naquele momento, os filhos do paciente acrescentaram uma reflexão sobre os desejos do pai, referindo-se ao arrependimento de tê-lo internado, mas reconhecendo a complexidade de suas escolhas e a impossibilidade dele retornar para casa naquele momento. É importante salientar que após duas semanas em Cuidados Paliativos o paciente foi a óbito na Unidade Hospitalar. CONSIDERAÇÕES FINAIS: Notou-se a impotência na equipe em alinhar o desejo do paciente com as expectativas da família embora o desejo foi acolhido e trabalhada as emoções, as perdas e dores por não retornar ao lar antes de falecer.
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Alta do Paciente , MorteRESUMO
In recent years the concern with emerging pollutants in water has become more prominent, especially pharmaceutical residues, such as antibiotics due to the influence to increase antibacterial resistance. Further, conventional wastewater treatment methods have not demonstrated efficiency for the complete degradation of these compounds, or they have limitations to treat a large volume of waste. In this sense, this study aims to investigate the degradation of amoxicillin, one of the most prescribed antibiotics, in wastewater via supercritical water gasification (SCWG) using a continuous flow reactor. For this purpose, the process operating conditions of temperature, feed flow rate, and concentration of H2O2 was evaluated using Experimental Design and Response Surface Methodology techniques and optimized by Differential Evolution methodology. Total organic carbon (TOC) removal, chemical oxygen demand (COD) degradability, reaction time, amoxicillin degradation rate, toxicity of degradation by-products, and gaseous products were evaluated. The use of SCWG for treatment achieved 78.4% of the TOC removal for the industrial wastewater. In the gaseous products, hydrogen was the majority component. Furthermore, high-performance liquid chromatography analyses demonstrated that the antibiotic amoxicillin was degraded. For a mass flow rate of 15 mg/min of amoxicillin fed into the reaction system, 14.4 mg/min was degraded. Toxicity tests with microcrustacean Artemia salina showed slight toxicity to treated wastewater. Despite that, the outcomes reveal the SCWG has great potential to degrade amoxicillin and may be applied to treat several pharmaceutical pollutants. Aside from this, carbon-rich effluents may lead to a significant energy gaseous product, especially, hydrogen and syngas.
Assuntos
Águas Residuárias , Poluentes Químicos da Água , Amoxicilina , Antibacterianos , Água/química , Eliminação de Resíduos Líquidos/métodos , Peróxido de Hidrogênio , Gases , Hidrogênio/química , Poluentes Químicos da Água/química , Carbono , Preparações FarmacêuticasRESUMO
Intracellular parasites from the Leishmania genus cause Leishmaniasis, a disease affecting millions of people worldwide. NLRP3 inflammasome is key for disease outcome, but the molecular mechanisms upstream of the inflammasome activation are still unclear. Here, we demonstrate that despite the absence of pyroptosis, Gasdermin-D (GSDMD) is active at the early stages of Leishmania infection in macrophages, allowing transient cell permeabilization, potassium efflux, and NLRP3 inflammasome activation. Further, GSDMD is processed into a non-canonical 25 kDa fragment. Gsdmd-/- macrophages and mice exhibit less NLRP3 inflammasome activation and are highly susceptible to infection by several Leishmania species, confirming the role of GSDMD for inflammasome-mediated host resistance. Active NLRP3 inflammasome and GSDMD are present in skin biopsies of patients, demonstrating activation of this pathway in human leishmaniasis. Altogether, our findings reveal that Leishmania subverts the normal functions of GSDMD, an important molecule to promote inflammasome activation and immunity in Leishmaniasis.
Assuntos
Leishmania , Leishmaniose , Humanos , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Gasderminas , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leishmania/metabolismo , Piroptose/fisiologiaRESUMO
Background: Post-procedure residual ischemia is associated with worse prognosis in patients with coronary artery diasease (CAD). Objective: We evaluated whether autologous bone marrow-derived cells (BMC) contribute to additional reduction in regional stress-induced myocardial ischemia (SIMI) in patients undergoing incomplete coronary artery bypass graft surgery (CABG). Methods: In a double-blind, randomized, placebo-controlled trial, we enrolled 143 patients (82% men, 58 ± 11 years) with stable CAD and not candidates for complete CABG. They received 100 million BMC (n = 77) or placebo (n = 66) injected into ischemic non-revascularized segments during CABG. The primary outcome was improvement on SIMI quantified as the area at risk in injected segments assessed by cardiovascular magnetic resonance (CMR) 1, 6, and 12 months after CABG. Results: The reduction in global SIMI after CABG was comparable (p = 0.491) in both groups indicating sustained beneficial effects of the surgical procedure over 12 month period. In contrast, we observed additional improvement in regional SIMI in BMC treated group (p = 0.047). Baseline regional SIMI values were comparable [18.5 (16.2-21.0) vs. 18.5 (16.5-20.7)] and reached the lowest values at 1 month [9.74 (8.25; 11.49) vs. 12.69 (10.84; 14.85)] for BMC and placebo groups, respectively. The ischemia's improvement from baseline represented a 50% difference in regional SIMI in favor of the BMC transplanted group at 30 days. We found no differences in clinical and LVEF% between groups during the 12 month follow-up period. The 1 month rate of major adverse cerebral and cardiovascular events (MACCE) (p = 0.34) and all-cause mortality (p = 0.08) did not differ between groups 1 month post intervention. Conclusion: We provided evidence that BMC leads to additional reduction in regional SIMI in chronic ischemic patients when injected in segments not subjected to direct surgical revascularization. This adjuvant therapy deserves further assessment in patients with advanced CAD especially in those with microcirculation dysfunction. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT01727063.
RESUMO
Although the baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) infects lepidopteran invertebrates as natural hosts, represents an efficient vector for vaccine development. Baculovirus surface display induces strong humoral responses against viruses and parasites. A novel strategy based on capsid display carrying foreign antigens in the AcMNPV particle further improved the immune response by eliciting CD8+ T cell activation. In this study, we analyze the intracellular mechanisms and signalling pathways involved in CD8+ T cell activation by capsid display. Our results show that baculovirus can attach to the cell surface, enter dendritic cells (DCs), transit within endocytic vesicles and escape to the cytosol for further degradation by the proteasome. We found that the availability of viral proteins, endosomal acidification, and proteasome activity are needed for efficient Major Histocompatibility Complex class-I presentation by baculovirus carrying Ovalbumin in the viral capsid. Importantly, we demonstrated with this strategy that the induction of cytotoxic T cells and IL-12 production by DCs are TLR9-dependent and STING-independent. Finally, our study shows differential intracellular processing for capsid and surface baculovirus proteins in DCs and highlights the role of different danger receptors during cytotoxic T cell priming through the capsid display delivery system, which could lead to improved baculovirus-based vaccines development.
Assuntos
Antineoplásicos , Baculoviridae , Baculoviridae/genética , Baculoviridae/metabolismo , Capsídeo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas do Capsídeo/genéticaRESUMO
A Comissão Consultiva em Avaliação Psicológica (CCAP) do Conselho Federal de Psicologia (CFP), em seu 20º aniversário, vem discutir os possíveis efeitos, ainda efetivamente desconhecidos, da Ação Direta de Inconstitucionalidade (ADI) 3481, instruída no Supremo Tribunal Federal (STF), a qual desestruturou o modo como os testes psicológicos eram comercializados no Brasil. A livre comercialização de testes psicológicos coloca em risco a segurança de avaliações psicológicas e cabe à categoria profissional pensar estratégias de enfrentamento desses riscos. Neste artigo, são discutidos possíveis efeitos da ADI 3481 para a categoria profissional da psicologia, bem como para a sociedade em geral, e são também elencadas possíveis estratégias de enfrentamento desses riscos, sem desconsiderar aspectos éticos relacionados a eles. Dessa forma, busca-se neste manuscrito, além da problematização dos efeitos derivados da ADI 3481, pensar soluções ou alternativas que venham a redirecionar a trajetória da área da avaliação psicológica no Brasil. Com isso, abre-se um espaço de discussão e encaminhamentos que a categoria profissional precisará tomar nos próximos anos.(AU)
The Advisory Commission for Psychological Assessment of the Federal Council of Psychology discusses, on its 20th anniversary, the possible and still effectively unknown effects of the Direct Action of Unconstitutionality (DAU) 3481, following the Supreme Federal Court, which interrupted how psychological tests were marketed in Brazil. The free trade of psychological tests puts the safety of psychological assessments at risk, and this professional category must think of strategies to face these risks. This study discusses the possible effects of DAU 3481 for professional psychology and for society in general, listing possible strategies for coping with these risks without disregarding its ethical aspects. Thus, this study seeks to problematize the effects derived from DAU 3481 and think of solutions or alternatives that may redirect the trajectory of the field of psychological assessment in Brazil, thus opening a space for discussion and referrals professional psychology will require in the coming years.(AU)
La Comisión Consultiva en Evaluación Psicológica (CCEP) del Consejo Federal de Psicología (CFP), en su 20.º aniversario, propone discutir los posibles efectos aún efectivamente desconocidos de la Acción Directa de Inconstitucionalidad (ADI) 3481, determinada por el Supremo Tribunal Federal (STF), por la cual trastornó la forma de comercializar las pruebas psicológicas en Brasil. La comercialización sin restricciones de las pruebas psicológicas pone en riesgo la seguridad de las evaluaciones psicológicas, y le corresponde a la categoría profesional pensar estrategias para enfrentar estos riesgos. En este artículo se discuten los posibles efectos de la ADI 3481 para la categoría profesional de la Psicología, así como para la sociedad en general, pero también se enumeran posibles estrategias para el enfrentamiento de estos riesgos, sin descuidar los aspectos éticos relacionados con ellos. Así, este manuscrito busca, además de problematizar los efectos derivados de la ADI 3481, pensar en soluciones o alternativas que puedan reconducir la trayectoria del campo de la evaluación psicológica en Brasil. Esto abre un espacio de discusión y derivaciones que la categoría profesional deberá tomar en los próximos años.(AU)