Dominant-Negative Tumor Necrosis Factor Protects from Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and Endotoxin-Induced Liver Injury without Compromising Host Immunity to BCG and Mycobacterium tuberculosis

BackgroundTumor necrosis factor (TNF) is associated with the development of inflammatory pathologies. Antibodies and soluble TNF (solTNF) receptors that neutralize excessive TNF are effective therapies for inflammatory and autoimmune diseases. However, clinical use of TNF inhibitors is associated with an increased risk of infections MethodsA novel dominant-negative (DN) strategy of selective TNF neutralization, consisting of blocking solTNF while sparing transmembrane TNF (tmTNF), was tested in mouse models of mycobacterial infection and acute liver inflammation. XENP1595, a DN-TNF biologic, was compared with etanercept, a TNF receptor 2 (TNFR2)-IgG1 Fc fusion protein that inhibits murine solTNF and tmTNF ResultsXENP1595 protected mice from acute liver inflammation induced by endotoxin challenge in Mycobacterium bovis bacillus Calmette-Guérin (BCG)-infected mice, but, in contrast to etanercept, it did not compromise host immunity to acute M. bovis BCG and Mycobacterium tuberculosis infections in terms of bacterial burden, granuloma formation, and innate immune responses ConclusionsA selective inhibitor of solTNF efficiently protected mice from acute liver inflammation yet maintained immunity to mycobacterial infections. In contrast, nonselective inhibition of solTNF and tmTNF suppressed immunity to M. bovis BCG and M. tuberculosis. Therefore, selective inhibition of solTNF by DN-TNF biologics may represent a new therapeutic strategy for the treatment of inflammatory diseases without compromising host immunit

Lower expression of plasma-derived exosome miR-21 levels in HIV-1 elite controllers with decreasing CD4 T cell count

Exosome-derived miR-21 was independently associated with CD4 T cell decline in HIV-1-infected elite controllers (OR 0.369, 95% CI 0.137-0.994, p = 0.049). Also, a negative correlation between miR-21 expression and MCP-1 level was found (r = −0.649, p = 0.020), while no correlation between soluble biomarkers or cellular immune activation was found

“Nowadays, I work for myself”: caring at rural settlements connected to land, working and living

Objetivo: conhecer a percepção de cuidado nas famílias de um assentamento rural. Métodos: estudo qualitativo, de natureza etnográfica na enfermagem denominada etnoenfermagem. Utilizou-se o Modelo Observação-Participação-Reflexão. Os dados foram registrados em um diário de campo e coletados no período de fevereiro a maio de 2011. A coleta foi finalizada quando os dados responderam aos objetivos propostos. O número de famílias acompanhadas delimitou-se em quatro famílias. A análise ocorreu baseada no Guia das Fases de Análise dos Dados da Etnoenfermagem. Estudo aprovado pelo Comitê de Ética e Pesquisa da Universidade Federal de Santa Maria, sob o número 0356.0.243.000-10. Resultados: as famílias assentadas relacionam o cuidado com suas histórias de vida, principalmente a luta e aquisição da terra, o trabalho e a moradia. Considerações Finais: o estudo revela que as famílias assentadas consideram como elementos essenciais em suas vidas a terra, o trabalho e a moradia, constituindo-os em sinônimos de cuidado

Concepções de saúde de usuários e profissionais de uma estratégia de saúde da família

Aims: to identify the conceptions of health of users and health professionals of a Family Health Strategy located in a city of the south of Brazil. Methods: descriptive and qualitative study realized with key informants: six residents, six community health agents and seven other members of the family health team. For the data collection the Participatory Rapid Appraisal was used, with the observation and interview as data sources. A theme analysis was carrierd out with the data. Results: health was pointed out by the key informants as a condition for life maintenance, as a result of the interaction of various aspects, conditions and lifestyle, influenced by occupation and social interactions. Conclusions: the professionals should involve social, environmental and psychological aspects in the planning of the assistance, since these significantly appeared to be determining in regards to health.Objetivo: conocer las concepciones de salud de usuarios y profesionales de salud incluídos en una Estrategia de Salud de la Familia, localizada en un municipio del sur de Brasil. Métodos: estudio descriptivo y cualitativo, realizado con informantes-clave: seis residentes, seis agentes comunitarios de salud y otros siete miembros del equipo de salud de la familia. Para recolectar datos se utilizó la Estimativa Rápida Participativa, con fuente de datos de observación y entrevista. Los datos fueron analizados mediante análisis temático. Resultados: la salud fue señalada por los informantes-clave como condición para mantenimiento de la vida, resultante de la interacción de factores, condiciones y hábitos de vida, siendo influenciada por ocupación e interacciones sociales. Conclusión: los profesionales deben considerar las cuestiones sociales, ambientales y psicológicas en la planificación de la asistencia, ya que estas se revelaron de manera significativa como determinantes para la salud.Objetivo: conhecer as concepções de saúde dos usuários e profissionais de saúde inseridos em uma Estratégia de Saúde da Família, localizada em um município do sul do Brasil. Método: estudo descritivo, qualitativo, realizado com informantes-chave: seis moradores, seis agentes comunitários de saúde e sete dos demais integrantes da equipe de saúde da família. Para a coleta de dados utilizou-se a Estimativa Rápida Participativa, com fonte de dados da observação e entrevista. Os dados foram trabalhados pela análise temática. Resultados: a saúde foi apontada pelos informantes-chave como condição para manutenção da vida, resultante da interação de fatores, de condições e hábitos de vida e sendo influenciada pela ocupação e pelas interações sociais. Conclusões: os profissionais devem envolver as questões sociais, ambientais e psicológicas no planejamento da assistência, já que essas foram reveladas de forma significativa como determinantes em saúde

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary

Synthesis and antibacterial activities of cadiolides A, B and C and analogues

The one-pot multicomponent synthesis of natural butenolides named cadiolides A, B, C and analogues has been realized. The antibacterial structure activity relationship shows that the presence of phenolic hydroxyl groups and the number and position of bromine atoms on the different aromatic rings are important features for antibacterial activity, besides it was demonstrated the tolerance of both benzene and furan ring at position 3 of the butenolide nucleus. Furthermore, none of the most relevant antibacterial compounds showed any cytotoxicity in freshly isolated human neutrophils

Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients

Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays. Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity. Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14). Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (−17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity. Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile

Serological Studies of Neurologic Helminthic Infections in Rural Areas of Southwest Cameroon: Toxocariasis, Cysticercosis and Paragonimiasis

A total of 188 people (168 and 20 with and without symptoms confirmed by clinicians, respectively, 84.6% under 20 years old) were selected on a voluntary basis in Cameroon. Soil transmitted helminthic infections were prevalent among persons surveyed as is common in developing countries, since eggs of Ascaris lumbricoides, Trichuris trichiura and hookworms were found from 56 (33.3%), 72 (42.8%) and 19 (11.3%) persons, respectively. Serological analyses revealed that 61 (36.3%), 25 (14.9%) and 2 (1.2%) persons were positive to the diagnostic antigens specific for toxocariasis, paragonimiasis and cysticercosis, respectively. Among 14 people with epilepsy, 5 persons were seropositive to the antigen of Toxocara and one of them was simultaneously positive to the antigens of Paragonimus. Serological confirmation of cysticercosis in two children is very important, and we suggest that further serologic surveys of cysticercosis be carried out in both children and adults in this area for the promotion of a better quality of life including control and early treatment

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Validation study of mHealth technology in HIV to improve empowerment and healthcare utilisation: research and innovation to generate evidence for personalised care (EmERGE)

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