Easy-To-Synthesize Spirocyclic Compounds Possess Remarkable in Vivo Activity against Mycobacterium tuberculosis

Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome

Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women

Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome

A história cultural do cuidado paliativo em sociedades primitivas: uma revisão integrativa

The objective of this study is to describe the evolution of palliative care in order to reflect on the possibility of its origin in primitive cultures and their relationship with the beginnings of the cult of the dead. It describes the change in the symbolic structures and social interactions involved in palliative care during prehistory: functional unit, functional framework and functional element. The theoretical framework is based on cultural history, the dialectical structural model and symbolic interactionism. Categorization techniques, cultural history and dialectic structuralism analyses were performed. Palliative care existed in primitive societies, mostly associated with the rites of passage with a high symbolic content. The social structures – functional unit, functional framework and functional element – are the pillars that supported palliative care in prehistory societies.Este estudio tiene el objetivo de describir la evolución de los cuidados paliativos, reflexionando sobre la posibilidad de su origen en las culturas primitivas y su relación con el inicio del culto a los muertos. Se describe el cambio producido en las estructuras, las interacciones simbólicas y sociales implicadas en el desempeño de cuidados paliativos durante la prehistoria: unidad funcional, marco funcional y elemento funcional. El marco teórico se fundamenta en la historia cultural, el modelo estructural dialéctico y el interaccionismo simbólico. Se aplicaron técnicas de categorización y análisis de la historia cultural y el estructuralismo dialéctico. Los cuidados paliativos ya existían en las sociedades primitivas vinculados, en gran medida, a los ritos de transición con un alto contenido simbólico. Las estructuras sociales: unidad funcional, marco funcional y elemento funcional; constituyen los pilares sobre los que se sustentaron los cuidados paliativos en las sociedades prehistóricas.Este estudo tem como objetivo descrever a evolução dos cuidados paliativos para refletir sobre a possibilidade de sua origem em culturas primitivas e suas relações com o início do culto dos mortos. Há a descrição das mudanças nas estruturas simbólicas e interações sociais envolvidas no desempenho de cuidados paliativos, durante a pré-história: unidade funcional, o quadro funcional e elemento funcional. O referencial teórico é baseado na história cultural, no modelo estrutural dialético e no interacionismo simbólico. Aplicaram-se técnicas de categorização e análises da história cultural e do estruturalismo dialético. Conclui-se que os cuidados paliativos existiam nas sociedades primitivas ligadas, em grande medida, aos rituais de passagem com alto conteúdo simbólico. As estruturas sociais – unidade funcional, o quadro funcional e elemento funcional – são os pilares sobre os quais se basearam os cuidados paliativos nas sociedades pré-históricas

Simpósio Ibero-Americano de História da Enfermagem: novas perspectivas da produção intelectual em história da enfermagem Coloquio Ibero-Americano de Historia de la Enfermería: nuevas perspectivas de la producción intelectual en historia de la enfermería Ibero-American Symposium on History of Nursing: new perspectives of intellectual production in the history of nursing

A produção intelectual apresentada no I Simpósio Ibero-Americano de História da Enfermagem foi organizada a partir de três eixos temáticos: antropologia do cuidado, história das instituições de ensino, de assistência e agremiações de enfermagem e história de vida, totalizando 198 estudos. Mediante os resultados apresentados a produção mostrada no simpósio apontou para a tendência dos estudos em história da enfermagem, nos eixos temáticos, pela ordem de interesse dos pesquisadores em: história das instituições, antropologia do cuidado e história de vida.<br>La producción intelectual presentada en el I Simposio Ibero-Americano de Historia de la Enfermería fue organizada a partir de tres bases temáticas: antropología del cuidado, historia de las instituciones de enseñanza, asistencia y agremiaciones de enfermería y historia de vida, totalizando 198 estudios. Mediante los resultados presentados, la producción presentada en el simposio reveló la tendencia de los estudios en historia de la enfermería, en las bases temáticas, por la orden de interés de los investigadores en: historia de las instituciones, antropología del cuidado y historia de vida.<br>Intellectual production presented in the I Symposium Ibero-American of Nursing History was organized in three thematic bases: anthropology care, history of the institutions of teaching, caring and associations of nursing and history of life, totalizing 198 researches. Results of production in the Symposium showed that tendency of the researches in the nursing history in the thematic bases, according with interest of researchers in: history of institutions, anthropology of care and history of life