Airway-delivered short-chain fatty acid acetate boosts antiviral immunity during rhinovirus infection.

BACKGROUND: Microbiota are recognized to play a major role in regulation of immunity through release of immunomodulatory metabolites such as short-chain fatty acids (SCFAs). Rhinoviruses (RVs) induce upper respiratory tract illnesses and precipitate exacerbations of asthma and chronic obstructive pulmonary disease through poorly understood mechanisms. Local interactions between SCFAs and antiviral immune responses in the respiratory tract have not been previously investigated. OBJECTIVE: We sought to investigate whether pulmonary metabolite manipulation through lung-delivered administration of SCFAs can modulate antiviral immunity to RV infection. METHODS: We studied the effects of intranasal administration of the SCFAs acetate, butyrate, and propionate on basal expression of antiviral signatures, and of acetate in a mouse model of RV infection and in RV-infected lung epithelial cell lines. We additionally assessed the effects of acetate, butyrate, and propionate on RV infection in differentiated human primary bronchial epithelial cells. RESULTS: Intranasal acetate administration induced basal upregulation of IFN-ß, an effect not observed with other SCFAs. Butyrate induced RIG-I expression. Intranasal acetate treatment of mice increased interferon-stimulated gene and IFN-λ expression during RV infection and reduced lung virus loads at 8 hours postinfection. Acetate ameliorated virus-induced proinflammatory responses with attenuated pulmonary mucin and IL-6 expression observed at day 4 and 6 postinfection. This interferon-enhancing effect of acetate was confirmed in human bronchial and alveolar epithelial cell lines. In differentiated primary bronchial epithelial cells, butyrate treatment better modulated IFN-ß and IFN-λ gene expression during RV infection. CONCLUSIONS: SCFAs augment antiviral immunity and reduce virus load and proinflammatory responses during RV infection.

Molecular evolution of dengue virus: a Bayesian approach using 1581 whole-genome sequences from January 1944 to July 2022.

Dengue is a viral disease transmitted by mosquitoes that has spread rapidly across all continents in recent years. There are four distinct but closely related serotypes of the virus that causes dengue (DENV-1, DENV-2, DENV-3, and DENV-4). In the present study, we evaluated temporal spreading and molecular evolution of dengue virus (DENV) serotypes. Bayesian coalescent analysis was performed to study viral evolution, and it was estimated that the most recent common ancestor of DENV-1 was present in 1884 in Southeast Asia, that of DENV-2 was present in 1723 in Europe, that of DENV-3 was present in 1921 in Southeast Asia, and that of DENV-4 was present in 1876 in Southeast Asia. DENV appears to have originated in Spain in approximately 1682, and it was disseminated in Asia and Oceania in approximately 1847. After this period, the virus was introduced into North America in approximately 1890. In South America, it was first disseminated to Ecuador in approximately 1897 and then to Brazil in approximately 1910. Dengue has had a significant impact on global health worldwide, and the present study provides an overview of the molecular evolution of DENV serotypes.

Effect of the dietary inflammatory potential on the trajectory of body adiposity in a Brazilian cohort of university students.

OBJECTIVES: University students are vulnerable to unhealthy eating habits that characterize a proinflammatory diet. This study aimed to estimate the dietary inflammatory index (DII) and its association with the trajectory of body adiposity markers in university students. METHODS: The study analyzed data from 685 students entering a Brazilian public university in 2016 and 2017 and followed until 2018. DII was estimated from 39 dietary parameters obtained by 24-h dietary recall. Body adiposity was assessed by anthropometric markers and the percentage of body fat. Linear mixed-effects models were used to estimate the trajectory of adiposity markers according to DII tertiles. RESULTS: After adjustment for confounding variables, at baseline, DII showed a positive association with increased percentage of body fat among men (ß = 0.52; 95% CI: 0.01; 1.03) and waist-to-height ratio (WHtR; ß = 0.15; 95% CI: 0.12; 0.18) and among women with all body adiposity markers: BMI (ß = 0.68; 95% CI: 0.30; 1.05), percentage of body fat (ß = 1.43; 95% CI: 0.74; 2.11), WC (ß = 1.15; 95% CI: 0.41; 1.89) and WHtR (ß = 0.13; 95% CI:0,10; 0.16). The rate of change of the outcome variables over time was not associated with DII at baseline. CONCLUSIONS: The diet of university students in this Brazilian cohort study was characterized as proinflammatory and it was associated with body adiposity markers.

Modulatory effect of myricitrin against chromosome instability and cytostasis induced by bleomycin and oxaliplatin in CHO-K1 cells.

Myricitrin (MYR), a flavonol consumed in the leaves and fruits of plants of the Myrtaceae family, presents anti-proliferative, anti-inflammatory, anti-diabetic, and antioxidant properties in humans. However, there are few studies regarding the cyto-genotoxicity and the chemopreventive potential of MYR. Using the in vitro Micronucleus test, the cytostasis, mutagenicity, and modulatory effect of MYR in CHO-K1 cells were assessed. The concentrations of 39 and 78 µg/mL (p < 0.001.) of MYR decrease the cytokinesis-block proliferation index (CBPI) in the short exposure treatment (4 h), while in the extended treatment (24 h), concentrations of 4.8, 9.7, 19.5, 39 and 78 µg/mL (p < 0.001.) decreased the CBPI. MYR associated with oxaliplatin decreased CBPI at all tested concentrations in the pre-(p < 0.001) and post-treatments (p < 0.001), but there was no decrease when associated with bleomycin. As for chromosome instability, MYR did not increase the frequency of micronuclei (MNi), nucleoplasmic bridges (NPBs), or nuclear buds (NBUDs) in the 4 h exposure time, however, in the 24 h treatment, MYR increased the frequency of MNi and NPBs at concentration 19.5 µg/mL (p < 0.001). As for the modulatory effect, MYR associated with bleomycin decreased the frequency of MNi, NPBs, and NBUDs at all concentrations in the pretreatment (MNi and NPBs p < 0.001, NBUDs p < 0.05) and simultaneously (MNi, NPBs and NBUDs p < 0.001). When associated with oxaliplatin, the simultaneous treatment decreased the frequency of MNi (p < 0.001) and NBUDs (p < 0.01) at all concentrations, however, in the post-treatment, MYR increased MNi (p < 0.001) and NPBs p < 0.05) in CHO-K1 cells, when compared to oxaliplatin alone. The results demonstrated that MYR could modulate the mutagenic and cytostatic actions of bleomycin and oxaliplatin, demonstrating distinct behaviors, depending on the mechanism of action of the chemotherapeutic agent.

Evidence-based pharmacological prophylaxis recommendations for venous thromboembolism in hospitalized acutely ill medical patients: a systematic review of clinical practice guidelines.

Venous thromboembolism is a complex multifactorial disease considered the most common cause of preventable deaths in hospitalized patients. Recommendations about pharmacological venous thromboembolism prophylaxis in adult hospitalized patients are available in clinical practice guidelines for optimization of healthcare delivery and improvement of patient outcomes. We conducted a systematic review of clinical practice guidelines using ADAPTE to synthesize recommendations for pharmacological prophylaxis of venous thromboembolism in hospitalized medical patients at a medium complexity university hospital. Recommendations for pharmacological prophylaxis were extracted from seven clinical practice guidelines considered of high quality after assessment with the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. These recommendations will support discussion with specialists and implementation of practices in the setting of the hospital studied.

O tromboembolismo venoso é uma doença multifatorial complexa, considerada uma causa comum de óbitos evitáveis em pacientes hospitalizados. Recomendações sobre profilaxia farmacológica de tromboembolismo venoso em pacientes adultos hospitalizados estão disponíveis em diretrizes clínicas para otimizar os cuidados à saúde e contribuir com a melhora do desfecho do paciente. Dessa forma, foi conduzida uma revisão sistemática de diretrizes clínicas utilizando a metodologia ADAPTE para sintetizar as recomendações para profilaxia farmacológica de tromboembolismo venoso em pacientes clínicos adultos hospitalizados em um hospital universitário de média complexidade. As recomendações para profilaxia farmacológica foram extraídas de sete diretrizes clínicas consideradas de alta qualidade após avaliação pelo Appraisal of Guidelines for Research and Evaluation (AGREE II). Essas recomendações servirão de apoio para discussão com especialistas e implementação de práticas dentro do contexto do hospital estudado.

The XadA Trimeric Autotransporter Adhesins in Xylella fastidiosa Differentially Contribute to Cell Aggregation, Biofilm Formation, Insect Transmission and Virulence to Plants.

Surface adhesion strategies are widely employed by bacterial pathogens during establishment and systemic spread in their host. A variety of cell-surface appendages such as pili, fimbriae, and afimbrial adhesins are involved in these processes. The phytopathogen Xylella fastidiosa employs several of these structures for efficient colonization of its insect and plant hosts. Among the adhesins encoded in the X. fastidiosa genome, three afimbrial adhesins, XadA1, Hsf/XadA2, and XadA3, are predicted to be trimeric autotransporters with a C-terminal YadA-anchor membrane domain. We analyzed the individual contributions of XadA1, XadA2, and XadA3 to various cellular behaviors both in vitro and in vivo. Using isogenic X. fastidiosa mutants, we found that cell-cell aggregation and biofilm formation were severely impaired in the absence of XadA3. No significant reduction of cell-surface attachment was found with any mutant under flow conditions. Acquisition by insect vectors and transmission to grapevines were reduced in the XadA3 deletion mutant. While the XadA3 mutant was hypervirulent in grapevines, XadA1 or XadA2 deletion mutants conferred lower disease severity than the wild-type strain. This insight of the importance of these adhesive proteins and their individual contributions to different aspects of X. fastidiosa biology should guide new approaches to reduce pathogen transmission and disease development. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

In vitro and in silico assessment of cytotoxicity and chromosome instability induced by saxitoxin in human derived neural cell line.

In freshwater, saxitoxins (STX) are produced by different cyanobacteria genera, including Raphidiopsis. Data regarding cytogenotoxicity effects of STX on human cells are scarse, this merit further studies of its toxicology. This study assessed the cytotoxicity and the chromosome instability of STX on SHSY-5Y human cell line. The CBMN assay allows the detection of chromosome breaks and abnormal chromosomal segregation. Additionally, in silico systems biology approach, used to search for known and predicted interaction networks, was applied to study the interactions between STX and SHSY-5Y cellular components. The results of the CBMN assay demonstrated that STX concentrations of 2.5 - 10 µg/L induced cytostasis and chromosome instability in a dose-response relationship. Apoptosis was detected after exposure of SHSY-5Y cultured cells to STX concentration of 10 µg/L. The results of the systems biology analysis revealed the interaction of STX with proteins related with acetylcoline pathway, cell cycle regulation and apoptosis. Furthermore, combining the in vitro and in silico approachs, it was possible to suggest a mechanism of action of STX in SHSY-5Y cells. Overall, the data demonstrated the cytotoxicity and mutagenicity of environmentally relevant concentrations of STX. These results should be considered when setting up guidelines for monitoring STX in water supply.

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling.

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants. Currently, ribavirin, a nucleoside analog containing a 1,2,4-triazole-3-carboxamide moiety, is a first-line drug for its treatment, however, its clinical use has been limited due to its side effects. Here, we designed two new nitroaryl-1,2,3-triazole triterpene derivatives as novel anti-RSV drugs. Their anti-RSV and cytotoxic activity were evaluated in vitro, RSV protein F gene effects by RT-PCR and molecular modeling with inosine monophosphate dehydrogenase (IMPDH) were performed. Compound 8 was the best performing compound, with an EC50 value of 0.053 µM, a TI of 11160.37 and it inhibited hRSV protein F gene expression by approximately 65%. Molecular docking showed a top-ranked solution located in the same region occupied by crystallographic ligands in their complex with IMPDH. The results obtained in this study suggest that compound 8 might be a new anti-RSV candidate.

IL-21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1 year. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via interleukin (IL) 21 secretion. In this study, we evaluated whether RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/interleukin-21 receptor (IL-21R) in Tfh cells and upregulated programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs in the lung. It also decreased regulatory follicular T cells, and increased Tfh cells, B cells, antibody avidity and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified immunoglobulin G from IL-21-treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells, highlighting the importance of an IL-21-PD-L1 axis for the generation of protective responses to RSV infection.

TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3-/- mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue.Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1-/- mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.

Intestinal Microbiota in the SARS-CoV-2 Infection: What Is Known?

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, emerged last year in China and quickly spread to millions of people around the world. This virus infects cells in different tissues and causes pulmonary (e.g., pneumonia and acute respiratory distress syndrome), neurological, cardiovascular, and intestinal manifestations, which can be the result of a direct viral effect or secondary to endothelial, thrombotic, or immunological alterations. In this chapter, we discuss recent studies which highlighted the relevance of the intestinal microbiota for other infectious respiratory diseases. We present the "altered microbiota" (dysbiotic) as a point of connection between conditions that are risk factors for the development of severe forms of COVID-19. In addition, we describe the findings of recent studies reporting alterations of microbiota composition in COVID-19 patients and speculate on how this may impact in development of the disease.

Evaluation of the genetic toxicity of sofosbuvir and simeprevir with and without ribavirin in a human-derived liver cell line.

Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C. Sofosbuvir and simeprevir are prescribed worldwide. However, there is a scarcity of information regarding their genotoxicity. Therefore, the present study assessed the cytotoxic and genotoxic effects of sofosbuvir and simeprevir, alone and combined with ribavirin. HepG2 cells were analyzed using the in vitro cytokinesis-block micronucleus cytome assay. Cells were treated for 24 h with sofosbuvir (0.011-1.511 mM), simeprevir (0.156-5.0 µM), and their combinations with ribavirin (0.250-4.0 mM). No significant differences were observed in the nuclear division cytotoxicity index, reflecting the absence of cytotoxic effects associated to sofosbuvir. However, the highest concentration of simeprevir showed a significant difference for the nuclear division cytotoxicity index. Moreover, significant results were observed for nuclear division cytotoxicity index in two combinations of sofosbuvir plus ribavirin and only in the highest combination of simeprevir plus ribavirin. Additionally, our results showed that sofosbuvir did not increase the frequency of chromosomal damage, but simeprevir significantly increased the frequency of micronuclei at the highest concentrations. The combination index demonstrated that both sofosbuvir and simeprevir produced antagonism to the genotoxic effects of ribavirin. In conclusion, our results showed that simeprevir, but not sofosbuvir, has genotoxic effects in HepG2 cells.

Binge eating and alcohol consumption: an integrative review.

OBJECTIVE: To identify the relationship between binge eating and alcohol consumption. METHODS: This is an integrative literature review of publications from 2015 to 2019, using the Pubmed, Cinhahl, Psynet, Lilacs, Embase and Web of Science virtual databases and the descriptors ("Binge-Eating" OR "Bulimia") AND Alcohol* in English, Spanish and Portuguese. RESULTS: A total of 964 articles were found. After reading the titles and abstracts and excluding duplicates, 36 articles were included in the final sample (35 in English and one in Portuguese). They were grouped into three thematic categories: "sample profile and characterization", "genetic and environmental factors", and "emotions and behavior". CONCLUSIONS: The data indicate the existence of a relationship between binge eating and alcohol use, and some factors were associated with this comorbidity. Still, there were few publications on the theme at the national level, indicating the need for developing more research. These findings may support therapeutic actions and strategies for identification of cases, embracing approaches and more effective treatments to meet the individual's biopsychosocial demands. LEVEL OF EVIDENCE: Level V, narrative review.

Application of remote sensing in environmental impact assessment: a case study of dam rupture in Brumadinho, Minas Gerais, Brazil.

The collapse of mining tailing dams in Brumadinho, Minas Gerais, Brazil, that occurred in 2019 was one of the worst environmental and social disasters witnessed in the country. In this sense, monitoring any impacted areas both before and after the disaster is crucial to understand the actual scenario and problems of disaster management and environmental impact assessment. In order to find answers to that problem, the aim of this study was to identify and analyze the spatiality of the impacted area by rupture of the tailing dam of the Córrego do Feijão mine in Brumadinho, Minas Gerais, by using orbital remote sensing. Land use and land occupation, phytoplankton chlorophyll-a, water turbidity, total suspended solids on water, and carbon sequestration efficiency by vegetation (CO2Flux) were estimated by orbital imagery from the Landsat-8/OLI and MSI/Sentinel-2 sensors in order to assess the environmental impacts generated by the disaster. Data were extracted from spectral models in which the variables that best demonstrated the land use variation over the years were sought. Mean comparison by t-test was performed to compare the time series analyzed, that is, before and after the disaster. Through the analysis of water quality, it was observed that the environmental impact was calamitous to natural resources, especially water from Córrego do Feijão.

Ready for the journey: a comparative proteome profiling of porcine cauda epididymal fluid and spermatozoa.

In the present study, we describe the proteome of porcine cauda epididymis fluid and spermatozoa by means of Multidimensional Protein Identification Technology (MudPIT). Ten sexually mature healthy boars were surgically castrated and epididymides were dissected to obtain the cauda epididymal content. Polled protein extracts of cauda epididymal fluid (CEF) and spermatozoa (CESperm) were loaded in an Agilent 1100 quaternary HPLC and peptides eluted from the microcapillary column were electro-sprayed directly into a LTQ Orbitrap XL mass spectrometer. Using bioinformatics, identified proteins were classified by their molecular functions, involvement in biological processes and participation in relevant metabolic pathways associated with spermatozoa physiology, fertility potential and protection. A total of 645 proteins were identified in the CEF, with epididymal-specific lipocalin-5, beta-hexosaminidase subunit beta precursor and phosphatidylethanolamine-binding protein 4 being the most abundant proteins found. A total of 2886 proteins were identified in the CESperm proteome with 81 proteins being considered more abundant (spectral counts > 100). CEF and CESperm data were compared and 345 proteins were present in both proteomes. Phosphatidylethanolamine-binding protein 4 precursor was the only protein found most abundant in both CEF and CESperm proteomes. Based on Gene Ontology analysis, we identified CEF and CESperm proteins associated with sperm protection against ROS and immune mediated response, glycosaminoglycan degradation, ubiquitin-proteasome system, metabolic process and maturation, modulation of acrosome reaction and ZP binding and oocyte penetration. These results provide a better comprehension about the molecular process and biological pathways involved in sperm epididymis maturation and establishment of the cauda epididymis sperm reservoir.

Effect of the topical administration of N-(2-(4-bromophenylamino)-5-(trifluoromethyl)phenyl)nicotinamide compound in a murine subcutaneous melanoma model.

Conventional treatments for metastatic melanomas are still ineffective and generate numerous side effects, justifying the search for new therapies. The antimetastatic effect of the named N-(2-(4-bromophenylamino)-5-(trifluoromethyl)phenyl)nicotinamide (SRVIC30) compound has been previously demonstrated in murine melanoma. Herein, we aimed to evaluate its effect when topically administrated in a murine subcutaneous melanoma model. For that, mice C57BL/6 were injected subcutaneously with 2 × 10 B16-F10 cells. Topical treatment began when tumors became visible on animal's back. Therefore, tumor volume was measured three times a week until it reaches 12 mm approximately. At this point, 40 mg oil-in-water cream (Lanette) without (control mice; n = 10) or with SRVIC30 compound (SRVIC30 group; n = 10 animals) were spread daily over the tumor external surface using a small brush for 14 days. The treatments increased the percentage of peroxidase antioxidant enzyme and dead cells via caspase-3 activation, with a consequent deposit of collagen fibers in the tumors. In addition, the skin of treated animals showed the presence of inflammatory infiltrate. Finally, SRVIC30 did not show signs of toxicity. Thus, we concluded that the topic administration of SRVIC30 was able to influence crucial anticancer processes such as tumor cells apoptosis and surrounding microenvironment.

Structural modelling of the equine protein disulphide isomerase A1 and its quantification in the epididymis and seminal plasma.

The protein disulphide isomerase A1 (PDIA1) is an important chaperone involved in protein quality control and redox regulation. Also, the ability of PDIA1 to bind to oestrogens suggests that it may play a role in epididymal maturation and male fertility. The goals of this study were to (a) verify the possible interaction between 17ß-estradiol and equine PDIA1 using bioinformatics; (b) identify and quantify PDIA1 protein in equine cauda epididymis throughout peripuberty; and (c) determine whether the amounts of PDIA1 in equine seminal plasma and spermatozoa are associated with fertility. Using in silico analysis, we were able to predict the tertiary structure of equine PDIA1 and to demonstrate the interaction between 17ß-estradiol and the putative binding site in domains b and b'. Colts under 24 months of age had lower relative amounts of PDIA1 in cauda epididymal fluid in comparison with older males (p < .01). No difference was observed in seminal plasma PDIA1 between fertile and subfertile stallions. Our study demonstrates that PDIA1 expression in the epididymis increases during peripuberty. However, in the adult stallion, its quantity in seminal plasma is not associated with fertility.

Assessment of complex genomic alterations induced by AZT, 3TC, and the combination AZT +3TC.

Highly active antiretroviral therapy (HAART) regimens are based on the use of nucleoside reverse transcriptase inhibitors (NRTIs), which are the main drugs used by patients infected with the human immunodeficiency virus (HIV). The use of NRTIs combinations has afforded clear clinical benefits to patients undergoing HAART. However, the combination of two NRTIs may increase the risk of genomic instability in comparison with the drugs administered individually. We analyzed the ability of zidovudine (AZT) and lamivudine (3TC), and the combination AZT +3TC to induce complex genomic alterations using the cytokinesis-block micronucleus (CBMN) assay in Chinese hamster ovary (CHO)-K1 cells. The 24-h cell treatment with individual NRTIs showed that AZT increased micronucleus frequencies and nucleoplasmic bridges (NPBs). No significant differences were observed for any parameters investigated after exposure of CHO-K1 cells to 3TC. The combination AZT +3TC significantly increased micronucleus frequencies. Analysis of interaction between these drugs suggested that antagonism occurs in all AZT +3TC concentrations. These results highlight the importance to investigate the genotoxic profile of NRTIs to develop safer intervention strategies in antiretroviral treatment protocols.

Macrophage migration inhibitory factor (MIF) controls cytokine release during respiratory syncytial virus infection in macrophages.

OBJECTIVE AND DESIGN: Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. METHODS: We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. RESULTS: We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. CONCLUSIONS: In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.

Cut-off points of anthropometric markers associated with hypertension in the Brazilian population: National Health Survey, 2013.

OBJECTIVE: To identify cut-off points for waist circumference (WC), waist-to-height ratio (WHtR) and BMI associated with hypertension in the Brazilian adult and elderly population. DESIGN: Cross-sectional study. The receiver-operating characteristic (ROC) curve was used to determine the cut-off points of WC, WHtR and BMI in the prediction of hypertension. Those who had systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg and those who reported use of antihypertensive medication were considered hypertensive. SETTING: Brazil.ParticipantsParticipants from the National Health Survey, the Brazilian household-based survey conducted in 2013, of both sexes and age ≥20 years. RESULTS: Cut-off points for WC and WHtR increased with age in both sexes. WC cut-off limits ranged between 88·0 and 95·9 cm in men and between 85·0 and 93·2 cm in women. For WHtR, cut-off scores ranged from 0·51 to 0·58 for men and from 0·53 to 0·61 for women. Additionally, the area under the ROC curve (AUC) for all age and sex groups was greater than 0·60 while the lower limit of the AUC 95 % CI for both WC and WHtR was not less than 0·50. The performance of BMI was similar to that of indicators of fat location. CONCLUSIONS: All analysed anthropometric indicators had similar performance in identifying hypertension in the Brazilian population.