LEVANTAMENTO EPIDEMIOLÓGICO DA MALÁRIA NO ESTADO DO MARANHÃO, BRASIL NOS ANOS DE 2007 A 2012

A malária é um problema global e signifcativo para a saúde pública, atingindo entre 300 e 500 milhões de pessoas e ocasionando aproximadamente dois milhões de óbitos anualmente. A malária é endêmica no Brasil, especifcamente na região da Amazônia Legal, com média de 500 mil casos ao ano.  Das 156 espécies de plasmódio, somente cinco estão associadas à etiologia em humanos: Plasmodium vivax, P. falciparum, P. malariae, P. ovale e P. knowlesi. O presente estudo teve por objetivo  realizar um  levantamento epidemiológico dos casos de malária no Estado do Maranhão entre os anos de 2007 e 2012, através da análise de dados de  indivíduos  infectados disponível no Sistema de Vigilância Epidemiológica - SIVEP/MALÁRIA. Foram avaliados os seguintes parâmetros: número total de casos por ano, índice parasitário anual (IPA), origem da contaminação (casos autóctones ou importados), distribuição dos indivíduos acometidos por idade e sexo além da espécie de parasito causador. De 2007 a 2012 houve uma redução progressiva do número casos notifcados de malária no Estado do Maranhão, com consequente redução do IPA, exceto no ano de 2009. Verifcou-se a prevalência de casos de malária em indivíduos do sexo masculino, em idade adulta (de 20 a 39 anos), sendo a maioria dos casos por transmissão autóctone. No Maranhão, bem como na Amazônia Legal, a grande maioria de casos de malária foi causada por Plasmodium vivax.Descritores: Malária. Plasmodium sp. SIVEP. Maranhão.AbstractEpidemiological survey of malaria cases  in the state of Maranhão, Brazil from 2007 to 2012. Malaria is a global problem with great  impact  in public health, affecting between 300 and 500 million people and causing nearly  two million deaths annually. Malaria is endemic in Brazil, specifcally in the Amazon region, with the average of 500.000 cases per year. Over 156  species of Plasmodium are known, but only fve are associated with disease  in humans: Plasmodium vivax, P. falciparum, P. malariae, P. ovale and P. knowlesi. The aim of this study was to perform an epidemiological survey of malaria cases in the state of Maranhão, during the years of 2007 to 2012, by analyzing the data of infected individuals available at  the Epidemiological Surveillance System- SIVEP/MALARIA. The following parameters were analyzed: total number of cases per year, the annual parasite incidence (API), source of contamination (indigenous or imported cases) and distribution of affected individuals by age, sex and species of infecting parasite. From 2007 to 2012 there was a progressive reduction of notifed malaria cases in Maranhão, as well as the API, except in the year of 2009. The cases of malaria were prevalent in males, aged mostly from 20 to 39 year old, and were due to indigenous contamination. In Maranhão, as well as in the Amazon region, the vast majority of the malaria infections were caused by Plasmodium vivax.Descriptors: Malaria. Plasmodium sp. SIVEP. Maranhao

AVALIAÇÃO DE MARCADORES DE ATIVAÇÃO E REGULAÇÃO EM LEUCÓCITOS DE PACIENTES INFECTADOS POR Plasmodium vivax

A malária é uma doença infecciosa aguda causada por protozoários do gênero Plasmodium e é transmitida ao homem pela picada da fêmea do mosquito Anopheles. Dentre as cinco espécies de Plasmodium que infectam seres humanos o P. falciparum e P. vivax são as mais prevalentes na região Amazônica. Dentre os mecanismos imunológicos associados a essa doença, muitos fatores ainda não são totalmente compreendidos, como relação entre ativação de células do sistema imunes e a função das células regulatórias no controle da parasitemia. Este trabalho analisou marcadores de ativação, regulação e moléculas coestimulatórias de células do sistema imune durante a infecção pelo Plasmodium vivax em pacientes infectados residentes na cidade de Cruzeiro do Sul (AC). O sangue periférico dos pacientes infectados foi coletado para realização de imunofenotipagem por citometria de fluxo. Indivíduos sadios nunca infectados com malária serviram como controle. Resultados: A infecção pelo Plasmodium vivax induziu o aumento de CD69 por células T CD4+, CD8+ e linfócitos B e de HLA-DR por linfócitos T CD4+. A expressão aumentada das moléculas coestimulatórias OX40 e ICOS mas não GITR também foi observada em células T CD4+ e CD8+ dos indivíduos acometidos pelo Plasmodium vivax em comparação com controles sadios. Por outro lado, um percentual significantemente maior de células T reguladoras foi observado no grupo de pacientes. Em conjunto, esses dados sugerem que a infecção pelo P. vivax promove aumento de marcadores de ativação e moléculas coestimulatórias em indivíduos infectados bem como condiciona um aumento no compartimento de células T reguladoras.Descritores: Plasmodium vivax. Células reguladoras. Co-estimulação.AbstractMalaria is an acute infectious disease caused by a protozoa of the genus Plasmodium being transmitted by the bite of the female Anopheles´ mosquito. Considering the five species of Plasmodium that infect humans, P. falciparum and P. vivax are the most prevalent in the Amazon region. Among the immunological mechanisms associated with this disease, many factors are still not fully understood, as the relationship between the immune system cell activation and function of regulatory T cells in the control of parasitaemia. This study examined activation markers, regulation and co-stimulatory molecules of the immune system cells during infection by Plasmodium vivax-infected patients living in the city of Cruzeiro do Sul (AC). The peripheral blood cells of infected patients ware collected to perform Immunophenotyping by flow cytometry. Healthy individuals never infected with malaria served as controls. Results: Infection with Plasmodium vivax induced increase of CD69 on CD4+, CD8+ T and B cells and HLA-DR on CD4 + T cells. The increased expression of co-stimulatory molecules OX40 and ICOS but not GITR was also observed in CD4+ and CD8+ T cells of individuals affected by Plasmodium vivax, compared to healthy controls. On the other hand, a significantly greater percentage of T regulatory cells was observed in the group of patients. Altogether, these data suggest that the P. vivax infection promotes an increase in activation markers and co-stimulatory molecules in infected individuals as well as an increase in the regulatory T cell compartment.Descriptors: Plasmodium vivax. Regulatory T cells. Co-stimulation

Association of Malaria Infection During Pregnancy With Head Circumference of Newborns in the Brazilian Amazon.

Importance: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear. Objective: To investigate the association of malaria during pregnancy with fetal head growth. Design, Setting, and Participants: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated. Exposure: Malaria during pregnancy. Main Outcomes and Measures: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference. Results: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference. Conclusions and Relevance: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria

Application of Omics Technologies for evaluation of antibacterial mechanisms of action of plant-derived products

In the face of increasing bacterial resistance to antibiotics currently in use, the search for new antimicrobial agents has received a boost in recent years, with natural products playing an important role in this field. In fact, several methods have been proposed to investigate the antibacterial activities of natural products. However, given that the ultimate aim is future therapeutic use as novel drugs, it is extremely necessary to elucidate their modes of action, stating the molecular effects in detail and identifying their targets in the bacterial cell. This review analyzes the application of omics technologies to understand the antibacterial mechanisms of bioactive natural products, to stimulate research interest in this area and promote scientific collaborations. Some studies have been specifically highlighted herein by examining their procedures and results (targeted proteins and metabolic pathways). These approaches have the potential to provide new insights into our comprehension of antimicrobial resistance/susceptibility, creating new perspectives for the struggle against bacteria, and leading to the development of novel products in the future

Polymorphisms in <i>Plasmodium vivax</i> Circumsporozoite Protein (CSP) Influence Parasite Burden and Cytokine Balance in a Pre-Amazon Endemic Area from Brazil

<div><p>Mechanisms involved in severe <i>P</i>. <i>vivax</i> malaria remain unclear. Parasite polymorphisms, parasite load and host cytokine profile may influence the course of infection. In this study, we investigated the influence of circumsporozoite protein (CSP) polymorphisms on parasite load and cytokine profile in patients with vivax malaria. A cross-sectional study was carried out in three cities: São Luís, Cedral and Buriticupu, Maranhão state, Brazil, areas of high prevalence of <i>P</i>. <i>vivax</i>. Interleukin (IL)-2, IL-4, IL-10, IL-6, IL-17, tumor necrosis factor alpha (TNF-α, interferon gamma (IFN-γ and transforming growth factor beta (TGF-β were quantified in blood plasma of patients and in supernatants from peripheral blood mononuclear cell (PBMC) cultures. Furthermore, the levels of cytokines and parasite load were correlated with VK210, VK247 and <i>P</i>. <i>vivax</i>-like CSP variants. Patients infected with <i>P</i>. <i>vivax</i> showed increased IL-10 and IL-6 levels, which correlated with the parasite load, however, in multiple comparisons, only IL-10 kept this association. A regulatory cytokine profile prevailed in plasma, while an inflammatory profile prevailed in PBMC culture supernatants and these patterns were related to CSP polymorphisms. VK247 infected patients showed higher parasitaemia and IL-6 concentrations, which were not associated to IL-10 anti-inflammatory effect. By contrast, in VK210 patients, these two cytokines showed a strong positive correlation and the parasite load was lower. Patients with the VK210 variant showed a regulatory cytokine profile in plasma, while those infected with the VK247 variant have a predominantly inflammatory cytokine profile and higher parasite loads, which altogether may result in more complications in infection. In conclusion, we propose that CSP polymorphisms is associated to the increase of non-regulated inflammatory immune responses, which in turn may be associated with the outcome of infection.</p></div

Correlation between parasite density and the cytokine profile.

<p>The <i>x</i> axis indicates Log Parasites/μL (A and B) or Log IL-6 (pg/mL) (C); the <i>y</i> axis indicates Log Interleukin 6 (pg/mL)(A), Log Interleukin 10 (pg/mL) (B) and (C). Each point represents the relative parasitaemia and cytokine responses of a single patient (A and B) or represents the relative IL-10 and IL-6 (C) responses of a single patient, n = 25 infected patients. The correlations were determined by Spearman’s correlation tests.</p

Cytokine profile and parasite density in <i>P</i>. <i>vivax</i> circumsporozoite protein (CSP) genotypes.

<p>Cytokines were measured by CBA and parasite density was determined by real-time PCR. A: Parasite density (Log parasites/μL); B: Interleukin 6 (pg/mL); C: Interleukin 10 (pg/mL); The bar represents the median of the group, n = 25 patients. <i>P</i> values were determined by nonparametric Mann-Whitney U tests (*<i>p</i>≤0.05). In correlations analyses, the <i>x</i> axis indicates Log IL-10 patient concentrations (pg/mL) in VK247 (D) or VK210 (E); the <i>y</i> axis indicates Log IL-6 patient concentrations (pg/mL) in VK247 (D) or VK210 (E). Each point represents the relative IL-10 and IL-6 responses of a single patient. Correlations were determined by Spearman’s correlation tests.</p

Multivariable analysis of correlation among cytokines and parasite load.

<p>Multivariable analysis of correlation among cytokines and parasite load.</p

Sulforaphane Modulates Joint Inflammation in a Murine Model of Complete Freund’s Adjuvant-Induced Mono-Arthritis

Rheumatoid arthritis (RA) is characterized by inflammation of one or more joints, and affects ~1% of the adult population worldwide. Sulforaphane (SFN) is a natural compound that has been suggested as an antioxidant. Here, SFN&rsquo;s effects were evaluated in a murine mono-arthritis model. Mono-arthritis was induced in mice by a single intra-articular injection of Complete Freund&rsquo;s Adjuvant (CFA-10 &micro;g/joint, in 10 &micro;L) into the ipsilateral joint. The contralateral joint received an equal volume of PBS. On the 4th day post-joint inflammation induction, animals received either SFN (10 mg/kg) or vehicle (3% DMSO in saline), intraperitoneally (i.p.), twice a day for 3 days. Joint swelling and secondary mechanical allodynia and hyperalgesia were evaluated over 7 days post-CFA. After this period, animals were culled and their blood and synovial fluid samples were collected for analysis of cell populations, cytokine release and thioredoxin reductase (TrxR) activity. Knee joint samples were also collected for histology. SFN reduced joint swelling and damage whilst increasing the recruitment of Ly6C+ and Ly6G+ cells to CFA-injected joints. SFN-treated animals presented down-regulation of CD11b and CD62L on synovial fluid Ly6G+ cells. Synovial fluid samples obtained from CFA-injected joints and plasma samples of SFN-treated mice presented higher levels of IL-6 and increased activity of TrxR, in comparison with controls. These results indicate that SFN reduces knee joint damage by modulating cell activation/migration to the joints, cytokine production and increasing the activity of TrxR, and therefore, may represent an alternative treatment to joint inflammation

Immunomodulatory Effects of Cinnamaldehyde in <i>Staphylococcus aureus</i>-Infected Wounds

Cinnamaldehyde (CNM) is an essential-oil component with reported anti-infective, anti-inflammatory, and healing effects, making it an interesting compound for the treatment of wound infection. Herein, we evaluated the effects of topical administration of CNM in experimental wounds infected by Staphylococcus aureus. Swiss mice (n = 12/group) were randomly allocated into three groups (CON: animals with uninfected lesions; Sa: animals with untreated infected lesions; Sa + CNM: animals with infected wounds and treated with CNM). Excisional lesions (64 mm2) were induced at the dorsal area followed by the addition of S. aureus (80 μL of a 1.5 × 108 CFU/mL bacterial suspension). The wounds were treated with CNM (200 μg/wound/day) or vehicle (2% DMSO) for 10 days. Skin samples were taken on the 3rd or 10th treatment day for quantification of inflammatory mediators, bacterial load, immunophenotyping, and histological analysis. The treatment with CNM improved the healing process and attenuated the severity of skin lesions infected by S. aureus. These effects were associated with significant decreases in bacterial loads in CNM-treated wounds. The levels of neutrophils, TNF-α, IL-6, NO, and VEGF were decreased in the lesions treated with CNM. Taken together, these data provide further evidence of the effectiveness of CNM for the treatment of skin infections