Role of ErbB and IL-1 signaling pathways in the dermonecrotic lesion induced by Loxosceles sphingomyelinases D.

Sphingomyelinase D (SMase D), the main toxic component of Loxosceles venom, has a well-documented role on dermonecrotic lesion triggered by envenomation with these species; however, the intracellular mechanisms involved in this event are still poorly known. Through differential transcriptomics of human keratinocytes treated with L. laeta or L. intermedia SMases D, we identified 323 DEGs, common to both treatments, as well as upregulation of molecules involved in the IL-1 and ErbB signaling. Since these pathways are related to inflammation and wound healing, respectively, we investigated the relative expression of some molecules related to these pathways by RT-qPCR and observed different expression profiles over time. Although, after 24 h of treatment, both SMases D induced similar modulation of these pathways in keratinocytes, L. intermedia SMase D induced earlier modulation compared to L. laeta SMase D treatment. Positive expression correlations of the molecules involved in the IL-1 signaling were also observed after SMases D treatment, confirming their inflammatory action. In addition, we detected higher relative expression of the inhibitor of the ErbB signaling pathway, ERRFI1, and positive correlations between this molecule and pro-inflammatory mediators after SMases D treatment. Thus, herein, we describe the cell pathways related to the exacerbation of inflammation and to the failure of the wound healing, highlighting the contribution of the IL-1 signaling pathway and the ERRFI1 for the development of cutaneous loxoscelism.

Role of ErbB and IL-1 signaling pathways in the dermonecrotic lesion induced by Loxosceles sphingomyelinases D

Sphingomyelinase D (SMase D), the main toxic component of Loxosceles venom, has a well-documented role on dermonecrotic lesion triggered by envenomation with these species; however, the intracellular mechanisms involved in this event are still poorly known. Through differential transcriptomics of human keratinocytes treated with L. laeta or L. intermedia SMases D, we identified 323 DEGs, common to both treatments, as well as upregulation of molecules involved in the IL-1 and ErbB signaling. Since these pathways are related to inflammation and wound healing, respectively, we investigated the relative expression of some molecules related to these pathways by RT-qPCR and observed different expression profiles over time. Although, after 24 h of treatment, both SMases D induced similar modulation of these pathways in keratinocytes, L. intermedia SMase D induced earlier modulation compared to L. laeta SMase D treatment. Positive expression correlations of the molecules involved in the IL-1 signaling were also observed after SMases D treatment, confirming their inflammatory action. In addition, we detected higher relative expression of the inhibitor of the ErbB signaling pathway, ERRFI1, and positive correlations between this molecule and pro-inflammatory mediators after SMases D treatment. Thus, herein, we describe the cell pathways related to the exacerbation of inflammation and to the failure of the wound healing, highlighting the contribution of the IL-1 signaling pathway and the ERRFI1 for the development of cutaneous loxoscelism.

Exploring prognosis in chronic relapsing visceral leishmaniasis among HIV-infected patients: Circulating Leishmania DNA.

BACKGROUND: Visceral leishmaniasis (VL) affecting HIV-infected patients is considered a challenging condition because of its high mortality and relapse rates. The approach of this condition is still surrounded by many uncertainties, especially regarding the criteria to institute and discontinue secondary prophylaxis for VL. The aim of this study was to evaluate the Leishmania parasitism kinetic assessed by polymerase chain reaction (PCR) as a possible tool in the prognostic assessment in a context in which patients are receiving highly active antiretroviral therapy and secondary prophylaxis. METHODS: A prospective observation of Leishmania-HIV-co infected patients was performed and two groups with distinct clinical prognosis unpredicted by their CD4 count at the moment of VL diagnosis and not related to their HIV load control were confirmed. RESULTS: Relapsing (R) and non-relapsing (NR) patients had similar antiviral therapy use rates, CD4 lymphocyte count medians and HIV load levels at VL-diagnosis. At the 12-month follow-up, R-patients presented a significantly lower CD4 lymphocyte count than NR-patients, without difference in HIV load control. The time between HIV and VL diagnoses was longer in the R than NR-group. Comparison between Kaplan-Meier relapse-free survival curves (time to relapse) using a log rank test showed that patients presenting circulating Leishmania DNA had a significantly higher risk of clinical VL relapse within 4 months after a positive test (p=0.001). CONCLUSIONS: These results reinforce that a negative PCR could be a useful tool to support prophylaxis interruption among patients with CD4 counts above 200cells/mm3 and that a positive PCR suggests imminent VL relapse.

Efeitos sistêmicos da mobilização precoce em pacientes adultos internados na unidade de terapia intensiva: revisão atualizada / Systemic effects of early mobilization in adult patients admitted to the intensive care unit: updated review

Introdução: Nos últimos anos, com o avanço tecnológico e da medicina, a sobrevida dos pacientes internados nas unidades de terapia intensiva (UTI) tem aumentado consideravelmente. No entanto, muitos desses pacientes permanecem imóveis e restritos ao leito causando diversas consequências deletérias associadas à imobilidade prolongada. Objetivo: Elucidar os efeitos sistêmicos da mobilização precoce em pacientes adultos internados na UTI. Métodos: Trata-se de uma revisão realizada nas bases de dados eletrônica: Pubmed, Scielo e Web of Science. Foram selecionados artigos indexados publicados entre o período de 2012 a 2017. Foram encontrados 9 estudos relevantes a essa revisão. Resultados: De forma geral, essa prática proporcionou aumento da força muscular, aumento da pressão inspiratória máxima, redução na produção de citocinas pró-inflamatórias e do estresse oxidativo, menor permanência na ventilação mecânica (VM), menor tempo de internação hospitalar e maior qualidade de vida. Conclusão: A fisioterapia torna-se essencial no desenvolvimento da mobilização precoce, contribuindo para a melhora da funcionalidade e da qualidade de vida do paciente tanto no meio hospitalar quanto pós-alta.

Introduction: In recent years, with advances in technology and medicine, the survival of patients admitted to intensive care units (ICU) has increased considerably. However, many of these patients remain immobile and restricted in the beds causing several deleterious consequences associated with prolonged immobility. Objective: To elucidate the systemic effects of early mobilization in adult patients hospitalized in the ICU. Methods: This is a review carried out in the electronic databases: PubMed, Scielo and Web of Science. We selected indexed articles between 2012 and 2017. We found 9 studies relevant to this review. Results: In general, this practice increased muscle strength, increased maximal inspiratory pressure, reduced production of proinflammatory cytokines and oxidative stress, shorter mechanical ventilation (MV), shorter hospital stay and higher quality of life. Conclusion: Physical therapy becomes essential in the development of early mobilization, contributing to improve the functionality and quality of life of the patient both in hospital and post-discharge.

Comparison of parasitological, serological, and molecular tests for visceral leishmaniasis in HIV-infected patients: a cross-sectional delayed-type study.

The aim of this study was to evaluate the accuracy of invasive and non-invasive tests for diagnosis of visceral leishmaniasis (VL) in a large series of human immunodeficiency virus (HIV)-infected patients. In this delayed-type cross-sectional study, 113 HIV-infected symptomatic patients were evaluated by an adjudication committee after clinical follow-up to establish the presence or absence of VL as the target condition (reference test). The index tests were recombinant K39 antigen-based immunochromatographic test (rK39), indirect fluorescent antibody test (IFAT), prototype kit of direct agglutination test (DAT-LPC), and real-time polymerase chain reaction (qPCR) in peripheral blood. Compared with parasitological test and adjudication committee diagnosis or latent class model analyses, IFAT and rk39 dipstick test presented the lowest sensitivity. DAT-LPC exhibited good overall performance, and there was no statistical difference between DAT-LPC and qPCR diagnosis accuracy. Real-time PCR emerges as a less invasive alternative to parasitological examination for confirmation of cases not identified by DAT.

Dyarrheal Syndrome in a Patient Co-Infected with Leishmania infantum and Schistosoma mansoni.

This case report describes an atypical clinical presentation of visceral leishmaniasis affecting the digestive tract and causing malabsorption syndrome in a patient without recognized immunosuppressive condition. After appropriate treatment for the classical visceral form of the disease, diarrhea persisted as the main symptom and massive infection by Leishmania was detected by histopathology analysis of the duodenal mucosa. Schistosoma mansoni coinfection was also confirmed and treated without impact on diarrhea. New course of amphotericin B finally led to complete improvement of diarrhea. Atypical visceral leishmaniasis involving the gastrointestinal tract is well recognized in HIV coinfection but very rare in immunocompetent patients. The factors determining the control or evolution of the Leishmania infection have not been completely identified. This case stresses the importance of atypical symptoms and the unusual location of visceral leishmaniasis, not only in immunodepressed patients, and raises the possible influence of chronic infection by S. mansoni reducing the immune response to Leishmania.