The biological in vitro effect and selectivity of aromatic dicationic compounds on Trypanosoma cruzi

Trypanosoma cruzi is a parasite that causes Chagas disease, which affects millions of individuals in endemic areas of Latin America. One hundred years after the discovery of Chagas disease, it is still considered a neglected illness because the available drugs are unsatisfactory. Aromatic compounds represent an important class of DNA minor groove-binding ligands that exhibit potent antimicrobial activity. This study focused on the in vitro activity of 10 aromatic dicationic compounds against bloodstream trypomastigotes and intracellular forms of T. cruzi. Our data demonstrated that these compounds display trypanocidal effects against both forms of the parasite and that seven out of the 10 compounds presented higher anti-parasitic activity against intracellular parasites compared with the bloodstream forms. Additional assays to determine the potential toxicity to mammalian cells showed that the majority of the dicationic compounds did not considerably decrease cellular viability. Fluorescent microscopy analysis demonstrated that although all compounds were localised to a greater extent within the kinetoplast than the nucleus, no correlation could be found between compound activity and kDNA accumulation. The present results stimulate further investigations of this class of compounds for the rational design of new chemotherapeutic agents for Chagas disease

Prácticas del enfermero en el contexto de la atención básica: scoping review

Objective: to identify and categorize the practices performed by nurses working in Primary Health Care and Family Health Strategy Units in light of responsibilities established by the profession’s legal and programmatic frameworks and by the Brazilian Unified Health System. Method: a scoping review was conducted in the following databases: LILACS, IBECS, BDENF, CINAHL and MEDLINE, and the Cochrane and SciELO libraries. Original research papers written by nurses addressing nursing practices in the primary health care context were included. Results: the review comprised 30 studies published between 2005 and 2014. Three categories emerged from the analysis: practices in the service; practices in the community; and management and education practices. Conclusion: the challenges faced by nurses are complex, as care should be centered on the population’s health needs, which requires actions at other levels of clinical and health responsibility. Brazilian nursing has achieved important advancements since the implementation of policies intended to reorganize work. There is, however, a need to shift work processes from being focused on individual procedures to being focused on patients so that an enlarged clinic is the ethical-political imperative guiding the organization of services and professional intervention.Objetivo: identificar e categorizar as práticas exercidas pelos enfermeiros junto às Unidades Básicas e às Equipes de Saúde da Família, à luz das atribuições previstas pelos marcos legais e programáticos da profissão e do Sistema Único de Saúde. Método: realizou-se uma revisão da literatura com o método scoping review, nas bases LILACS, IBECS, BDENF, CINAHL e MEDLINE, e nas bibliotecas Cochrane e SciELO. Incluíram-se artigos de pesquisa original, produzidos com enfermeiros, sobre as práticas de enfermagem no contexto dos cuidados de saúde primários. Resultados: a revisão abrangeu trinta estudos publicados entre 2005 e 2014. Da análise, resultaram três categorias: práticas no serviço, práticas na comunidade e práticas de gestão e formação. Conclusão: os desafios dos enfermeiros são complexos, posto que o cuidado deve estar centrado nas necessidades de saúde da população, o que remete à ação para outros níveis de responsabilidade clínica e sanitária. A enfermagem brasileira mostra importantes avanços desde a implantação das políticas de reorganização do trabalho. Necessita, entretanto, avançar no que se refere ao deslocamento dos processos de trabalho, focados em procedimentos individuais, para um processo mais voltado aos usuários, onde a clínica ampliada seja o imperativo ético-político da organização dos serviços e da intervenção profissional.Objetivo: identificar y categorizar las prácticas ejercidas por los enfermeros en las Unidades Básicas y los Equipos de Salud de la Familia, desde el punto de vista de las atribuciones previstas por los marcos legales y programáticos de la profesión y del Sistema Único de la Salud. Método: se realizó una revisión de la literatura con el método scoping review, en las bases LILACS, IBECS, BDENF, CINAHL y MEDLINE, y en las bibliotecas Cochrane y SciELO. Se incluyeron artículos de investigación original, producidos con enfermeros, sobre las prácticas de enfermería en el contexto de los cuidados de salud primarios. Resultados: la revisión abarcó treinta estudios publicados entre 2005 y 2014. Del análisis, resultaron tres categorías: prácticas en el servicio; prácticas en la comunidad; y, prácticas de administración y formación. Conclusión: los desafíos de los enfermeros son complejos, ya que el cuidado debe estar centrado en las necesidades de salud de la población, lo que conduce a la acción para otros niveles de responsabilidad clínica y sanitaria. La enfermería brasileña muestra importantes avances a partir de la implantación de las políticas de reorganización del trabajo. Necesita, entre tanto, avanzar en lo que se refiere al desplazamiento de los procesos de trabajo, enfocados en procedimientos individuales, para un proceso más dirigido a los usuarios, en donde la clínica ampliada sea el imperativo ético político de la organización de los servicios y de la intervención profesional.info:eu-repo/semantics/publishedVersio

Prevalence and correlates of inadequate glycaemic control: results from a nationwide survey in 6,671 adults with diabetes in Brazil

Diabetes is a significant public health burden on the basis of its increased incidence, morbidity, and mortality. This study aimed to estimate the prevalence of inadequate glycaemic control and its correlates in a large multicentre survey of Brazilian patients with diabetes. A cross-sectional study was conducted in a consecutive sample of patients aged 18 years or older with either type 1 or type 2 diabetes, attending health centres located in ten large cities in Brazil (response rate = 84%). Information about diabetes, current medications, complications, diet, and satisfaction with treatment were obtained by trained interviewers, using a standardized questionnaire. Glycated haemoglobin (HbA1c) was measured by high-performance liquid chromatography in a central laboratory. Patients with HbA1c ≥ 7 were considered to have inadequate glycaemic control. Overall 6,701 patients were surveyed, 979 (15%) with type 1 and 5,692 (85%) with type 2 diabetes. The prevalence of inadequate glycaemic control was 76%. Poor glycaemic control was more common in patients with type 1 diabetes (90%) than in those with type 2 (73%), P < 0.001. Characteristics significantly associated with improved glycaemic control included: fewer years of diabetes duration, multi professional care, participation in a diabetes health education program, and satisfaction with current diabetes treatment. Despite increased awareness of the benefits of tight glycaemic control, we found that few diabetic patients in Brazil met recommended glycaemic control targets. This may contribute to increased rates of diabetic complications, which may impact health care costs. Our data support the public health message of implementation of early, aggressive management of diabetes

Expression-Based In Silico Screening of Candidate Therapeutic Compounds for Lung Adenocarcinoma

BACKGROUND:Lung adenocarcinom (AC) is the most common form of lung cancer. Currently, the number of medical options to deal with lung cancer is very limited. In this study, we aimed to investigate potential therapeutic compounds for lung adenocarcinoma based on integrative analysis. METHODOLOGY/PRINCIPAL FINDINGS:The candidate therapeutic compounds were identified in a two-step process. First, a meta-analysis of two published microarray data was conducted to obtain a list of 343 differentially expressed genes specific to lung AC. In the next step, expression profiles of these genes were used to query the Connectivity-Map (C-MAP) database to identify a list of compounds whose treatment reverse expression direction in various cancer cells. Several compounds in the categories of HSP90 inhibitor, HDAC inhibitor, PPAR agonist, PI3K inhibitor, passed our screening to be the leading candidates. On top of the list, three HSP90 inhibitors, i.e. 17-AAG (also known as tanespimycin), monorden, and alvespimycin, showed significant negative enrichment scores. Cytotoxicity as well as effects on cell cycle regulation and apoptosis were evaluated experimentally in lung adenocarcinoma cell line (A549 or GLC-82) with or without treatment with 17-AAG. In vitro study demonstrated that 17-AAG alone or in combination with cisplatin (DDP) can significantly inhibit lung adenocarcinoma cell growth by inducing cell cycle arrest and apoptosis. CONCLUSIONS/SIGNIFICANCE:We have used an in silico screening to identify compounds for treating lung cancer. One such compound 17-AAG demonstrated its anti-lung AC activity by inhibiting cell growth and promoting apoptosis and cell cycle arrest

Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide: A Molecular Dynamics Simulation Study

Background: It has been extensively developed in recent years that cell-permeable small molecules, such as polyamide, can be programmed to disrupt transcription factor-DNA interfaces and can silence aberrant gene expression. For example, cyclic pyrrole-imidazole polyamide that competes with glucocorticoid receptor (GR) for binding to glucocorticoid response elements could be expected to affect the DNA dependent binding by interfering with the protein-DNA interface. However, how such small molecules affect the transcription factor-DNA interfaces and gene regulatory pathways through DNA structure distortion is not fully understood so far. Methodology/Principal Findings: In the present work, we have constructed some models, especially the ternary model of polyamides+DNA+GR DNA-binding domain (GRDBD) dimer, and carried out molecular dynamics simulations and free energy calculations for them to address how polyamide molecules disrupt the GRDBD and DNA interface when polyamide and protein bind at the same sites on opposite grooves of DNA. Conclusions/Significance: We found that the cyclic polyamide binding in minor groove of DNA can induce a large structural perturbation of DNA, i.e. a.4 A ˚ widening of the DNA minor groove and a compression of the major groove by more than 4A ˚ as compared with the DNA molecule in the GRDBD dimer+DNA complex. Further investigations for the ternary system of polyamides+DNA+GRDBD dimer and the binary system of allosteric DNA+GRDBD dimer revealed that the compression o

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Using Genomic Sequencing for Classical Genetics in E. coli K12

We here develop computational methods to facilitate use of 454 whole genome shotgun sequencing to identify mutations in Escherichia coli K12. We had Roche sequence eight related strains derived as spontaneous mutants in a background without a whole genome sequence. They provided difference tables based on assembling each genome to reference strain E. coli MG1655 (NC_000913). Due to the evolutionary distance to MG1655, these contained a large number of both false negatives and positives. By manual analysis of the dataset, we detected all the known mutations (24 at nine locations) and identified and genetically confirmed new mutations necessary and sufficient for the phenotypes we had selected in four strains. We then had Roche assemble contigs de novo, which we further assembled to full-length pseudomolecules based on synteny with MG1655. This hybrid method facilitated detection of insertion mutations and allowed annotation from MG1655. After removing one genome with less than the optimal 20- to 30-fold sequence coverage, we identified 544 putative polymorphisms that included all of the known and selected mutations apart from insertions. Finally, we detected seven new mutations in a total of only 41 candidates by comparing single genomes to composite data for the remaining six and using a ranking system to penalize homopolymer sequencing and misassembly errors. An additional benefit of the analysis is a table of differences between MG1655 and a physiologically robust E. coli wild-type strain NCM3722. Both projects were greatly facilitated by use of comparative genomics tools in the CoGe software package (http://genomevolution.org/)