Antiproliferative, Ultrastructural, and Physiological Effects of Amiodarone on Promastigote and Amastigote Forms of Leishmania amazonensis

Amiodarone (AMIO), the most frequently antiarrhythmic drug used for the symptomatic treatment of chronic Chagas' disease patients with cardiac compromise, has recently been shown to have also specific activity against fungi, Trypanosoma cruzi and Leishmania. In this work, we characterized the effects of AMIO on proliferation, mitochondrial physiology, and ultrastructure of Leishmania amazonensis promastigotes and intracellular amastigotes. The IC50 values were 4.21 and 0.46 μM against promastigotes and intracellular amastigotes, respectively, indicating high selectivity for the clinically relevant stage. We also found that treatment with AMIO leads to a collapse of the mitochondrial membrane potential (ΔΨm) and to an increase in the production of reactive oxygen species, in a dose-dependent manner. Fluorescence microscopy of cells labeled with JC-1, a marker for mitochondrial energization, and transmission electron microscopy confirmed severe alterations of the mitochondrion, including intense swelling and modification of its membranes. Other ultrastructural alterations included (1) presence of numerous lipid-storage bodies, (2) presence of large autophagosomes containing part of the cytoplasm and membrane profiles, sometimes in close association with the mitochondrion and endoplasmic reticulum, and (3) alterations in the chromatin condensation and plasma membrane integrity. Taken together, our results indicate that AMIO is a potent inhibitor of L. amazonensis growth, acting through irreversible alterations in the mitochondrial structure and function, which lead to cell death by necrosis, apoptosis and/or autophagy

Abstracts

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Epidemiological Profile of Children Infected with Bordetella pertussis at Varela Santiago Children’s Hospital: a Retrospective Study

Abstract Background: Pertussis, also called whooping cough, is an acute infectious disease of high transmissibility transmitted through aerosol particles released during the catarrhal phase and paroxysmal cough. Since the 1990s its incidence has increased and atypical clinical forms have been identified, mainly in newborns and adults. We hypothesized that there is a relationship between the high incidence of pertussis infection in children up to 6 months of age and genetic changes in the circulating strains of B. pertussis leading to inefficacy of diphtheria, tetanus, and pertussis vaccine (DTP). Methods: Data were obtained from the medical records of hospitalized patients at the Varela Santiago Children’s Hospital in Brazil from January 1, 2013 to December 31, 2013. Results: A total of 33 cases of pertussis hospitalizations were found, where 75.7% (25/33) of the patients were 6 months of age or younger (6 patients were 30 days old or younger while 19 ranged in age from 31 days to 6 months). Of these, 54.5% (14/25) were in exclusive breastfed children. Only 18.2% (6/33) of the patients had the appropriate administration of DTP doses according to their age. Signs and symptoms were: cough 100%, cyanosis 63.6%, fever 48.5% and inspiratory winch 33.3%. Azithromycin was used as monotherapy in 90% (30/33) of the cases and the mean time of hospitalization was 9.48 days ranging from 6 to 30 days. No patient died. Conclusion: We identified a high prevalence (75.7%) of B. pertussis infection in children up to 6 months of age. This is likely explained by the low vaccination rate (18.2%) and the low percentage of exclusive breastfeeding of the studied population. The low rate of vaccination is unexpected, given that there has been greater access to vaccination in recent decades in Brazil. In addition, the cases evolved with an atypical clinical presentation, since the classic symptoms of the catarrhal stage were absent or had a such short duration that such symptoms were no longer present at the time of hospitalization. Our study does not exclude the possibility that genetic changes are occurring in the circulating strains of B. pertussis and that DTP seems to have less efficacy on these new strains, but future studies will be needed to specifically test this hypothesis. Disclosures All authors: No reported disclosures

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Perinatal Case Fatality Rate Related to Congenital Zika Syndrome in Brazil: a Cross-Sectional Study

Abstract Background: Many studies have demonstrated a causal link between Zika virus (ZIKV) infection, microcephaly (MCP), and other congenital abnormalities (CA). This study aimed to determine perinatal case fatality rate in cases of Congenital Zika Syndrome (CZS) in the Rio Grande do Norte State (RN), a Brazilian Northeast State highly impacted by the Zika virus outbreak. Methods: A cross-sectional study was conducted using data obtained through the State Health Department (SHD) for cases of MCP and CA in Rio Grande do Norte from April 2015 to February 5, 2016. Definition of perinatal period: commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth. Results: During the study period, there were 486 cases of MCP and others CA notified in RN, of which 142 were confirmed and 108 remain under investigation. The remaining 236 cases have been ruled out by presenting normal examinations or due to presenting microcephaly by noninfectious causes. Of the total confirmed cases, 26.7% (38/142) died after birth or during pregnancy. 15.78% (06/38) of confirmed deaths had ZIKV infection during pregnancy and 2.63% (01/38) had a positive TORCH blood test. The six cases related to ZIKV were confirmed by RT–PCR and/or IgM/IgG antibodies against ZIKV. The remaining cases of deaths remain either under investigation or have been ruled out. Conclusion: This study highlights a high rate of perinatal lethality (15.78%) in cases of CZS. Despite the growing number of CZS cases, the real incidence and prevalence might be higher due to the underreporting and lack of resources for confirmatory diagnostic tests (laboratory and imaging). Due to the high rate of lethality and the ongoing uncontrolled ZIKV outbreak, this study predicts an increase in the infant mortality rate in Brazil and highlights the need for developing public health programs to control the ZIKV outbreak. Disclosures All authors: No reported disclosures

Agricultura e biodiversidade nas ciências sociais brasileiras: alimentando a comunicação entre ciência e políticas públicas.

O presente artigo decorre de uma reflexão sustentada em dois pressupostos: a) que as ciências e, em particular, as sociais, podem contribuir para informar as tomadas de decisão e a formulação de políticas públicas visando a melhoria da vida das pessoas no planeta e b) que o papel da agricultura na conservação da biodiversidade é uma questão atual de extrema relevância e que merece ser aprofundada. A relação entre a agricultura e a biodiversidade tem sido objeto de questionamentos recentes na sociedade e no campo das políticas públicas. Contudo, se os estudos relacionados à biodiversidade e à agricultura, separadamente, têm observado um considerável crescimento no Brasil, poucos são os investimentos de pesquisa sobre a relação entre esses dois grandes temas. A partir dessas considerações, seguimos dois objetivos principais: 1) investigar como o papel da agricultura familiar na preservação da biodiversidade tem sido abordado pelas Ciências Sociais no Brasil, particularmente nos artigos publicados em periódicos brasileiros nos últimos 20 anos; 2) testar uma metodologia de revisão bibliográfica, criteriosa, que possa ser útil aos tomadores de decisão em políticas públicas e demais interessados

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets