Controller therapy for asthma: montelukast versus fluticasone

Introducción: El asma es un trastorno inflamatorio crónico de las vías aéreas. Esta inflamación genera un aumento asociado de la hiperreactividad de las vías aéreas a una variedad de estímulos y una limitación del flujo aéreo. El tratamiento controlador del asma tiene como objetivos lograr y mantener control de los síntomas, prevenir las exacerbaciones, mantener la función pulmonar lo mas cerca posible a la normalidad, evitar efectos adversos de la medicación, prevenir obstrucción irreversible de la vía aérea y disminuir la mortalidad. Los medicamentos utilizados para este fin son los antinflamatorios dentro de los cuales se incluyen los grupos de corticoesteroides, cromonas y antileucotrienos. Objetivo: El objetivo de esta revisión bibliográfica es indicar las evidencias encontradas sobre mayor efectividad en este cuadro clínico entre Fluticasona y Montelukast. Material y métodos: Se realizó una revisión bibliográfica, en la cual se utilizo para la búsqueda de información las bases de datos PUBMED, MEDLINE y BIBLIOTECA VIRTUAL DE SALUD artículos científicos publicados en los últimos 5 años que comparan el tratamientote ambos fármacos. Conclusión: El fármaco más efectivo como monoterapia para el tratamiento controlador del asma en niños es la fluticasona frente al montelukast, por lo que esta es considerada la terapia de primera línea.Introduction: Asthma is a chronic inflammatory disorder of the airways. This inflammation is an associated increase in Nonspecific hyperresponsiveness airway to a variety of stimuli and airflow limitation. The asthma controller therapy aims to achieve and maintain control of symptoms, prevent exacerbations, maintaining lung function as close as possible to normal, avoid adverse effects of medication, prevent irreversible obstruction of the airway and reduce mortality . Medicines used for this purpose are the anti-inflammatory within which groups include corticosteroids, chromones and leukotriene. Objective: Fluticasone (inhaled corticosteroid) and montelukast (antileukotriene) are commonly used drugs for the treatment of pediatric asthma controller so that the objective of this review is to summarize the evidence on which of the two showed greater effectiveness in the treatment. Methods: A literature review, which was used to search for information databases PUBMED, MEDLINE and HEALTH LIBRARY scientific articles published over the past 5 years, comparing treatment with fluticasone and montelukast. Conclusion: The most effective drug as monotherapy for asthma controller therapy in children is fluticasone compared with montelukast, so this is considered first-line therapy.Fil: Acevedo, Maria E..Fil: Cano, Alejandra A..Fil: Lopez, Vanina A..Fil: Viola, Luciana S..Fil: Gerometta, Rosana María del Rosario. Universidad Nacional del Nordeste. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Context-dependent neocentromere activity in synthetic yeast chromosome VIII

Pioneering advances in genome engineering, and specifically in genome writing, have revolutionized the field of synthetic biology, propelling us toward the creation of synthetic genomes. The Sc2.0 project aims to build the first fully synthetic eukaryotic organism by assembling the genome of Saccharomyces cerevisiae. With the completion of synthetic chromosome VIII (synVIII) described here, this goal is within reach. In addition to writing the yeast genome, we sought to manipulate an essential functional element: the point centromere. By relocating the native centromere sequence to various positions along chromosome VIII, we discovered that the minimal 118-bp CEN8 sequence is insufficient for conferring chromosomal stability at ectopic locations. Expanding the transplanted sequence to include a small segment (~500 bp) of the CDEIII-proximal pericentromere improved chromosome stability, demonstrating that minimal centromeres display context-dependent functionality </p

Debugging and consolidating multiple synthetic chromosomes reveals combinatorial genetic interactions

The Sc2.0 project is building a eukaryotic synthetic genome from scratch. A major milestone has been achieved with all individual Sc2.0 chromosomes assembled. Here, we describe the consolidation of multiple synthetic chromosomes using advanced endoreduplication intercrossing with tRNA expression cassettes to generate a strain with 6.5 synthetic chromosomes. The 3D chromosome organization and transcript isoform profiles were evaluated using Hi-C and long-read direct RNA sequencing. We developed CRISPR Directed Biallelic URA3-assisted Genome Scan, or ‘‘CRISPR D-BUGS,’’ to map phenotypic variants caused by specific designer modifications, known as ‘‘bugs.’’ We first fine-mapped a bug in synthetic chromosome II (synII) and then discovered a combinatorial interaction associated with synIII and synX, revealing an unexpected genetic interaction that links transcriptional regulation, inositol metabolism, and tRNASer CGA abundance. Finally, to expedite consolidation, we employed chromosome substitution to incorporate the largest chromosome (synIV), thereby consolidating &gt;50% of the Sc2.0 genome in one strain </p

ARIEL4: An International, Multicenter, Randomized Phase 3 Study of the PARP Inhibitor Rucaparib vs Chemotherapy in Germline or Somatic BRCA1- or BRCA2-Mutated, Relapsed, High-Grade Ovarian Carcinoma

Описание In high-grade ovarian cancer, including fallopian tube and primary peritoneal cancers, approximately 18% of patients have tumors with a germline BRCA1 or BRCA2 mutation and approximately 7% of patients have tumors with a somatic BRCA1 or BRCA2 mutation1• The poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib has demonstrated efficacy in tumors with homologous recombination deficiency (HRD), including a BRCA1 or BRCA2 mutation2-5–In cells with HRD, PARP inhibition results in accumulation of double-strand ..

Manipulating the 3D organization of the largest synthetic yeast chromosome

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field. Here, we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp yeast chromosome resulting from extensive genome streamlining and modification. We developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction. Besides the drastic sequence changes, we further manipulated the 3D structure of synIV to explore spatial gene regulation. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of synIV sheds light on higher-order architectural design of the synthetic genomes. </p

Synthesis of the land carbon fluxes of the Amazon region between 2010 and 2020

The Amazon is the largest continuous tropical forest in the world and plays a key role in the global carbon cycle. Human-induced disturbances and climate change have impacted the Amazon carbon balance. Here we conduct a comprehensive synthesis of existing state-of-the-art estimates of the contemporary land carbon fluxes in the Amazon using a set of bottom-up methods (i.e., dynamic vegetation models and bookkeeping models) and a top-down inversion (atmospheric inversion model) over the Brazilian Amazon and the whole Biogeographical Amazon domain. Over the whole biogeographical Amazon region bottom-up methodologies suggest a small average carbon sink over 2010-2020, in contrast to a small carbon source simulated by top-down inversion (2010-2018). However, these estimates are not significantly different from one another when accounting for their large individual uncertainties, highlighting remaining knowledge gaps, and the urgent need to reduce such uncertainties. Nevertheless, both methodologies agreed that the Brazilian Amazon has been a net carbon source during recent climate extremes and that the south-eastern Amazon was a net land carbon source over the whole study period (2010-2020). Overall, our results point to increasing human-induced disturbances (deforestation and forest degradation by wildfires) and reduction in the old-growth forest sink during drought

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

NFAT1 Transcription Factor Regulates Pulmonary Allergic Inflammation and Airway Responsiveness

Submitted by Sandra Infurna ([email protected]) on 2018-09-22T00:04:32Z No. of bitstreams: 1 luciana_coelho_etal_IOC_2009.pdf: 571588 bytes, checksum: 7957a1cca5fbefdfb65220689b3ac19a (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-09-22T00:15:37Z (GMT) No. of bitstreams: 1 luciana_coelho_etal_IOC_2009.pdf: 571588 bytes, checksum: 7957a1cca5fbefdfb65220689b3ac19a (MD5)Made available in DSpace on 2018-09-22T00:15:37Z (GMT). No. of bitstreams: 1 luciana_coelho_etal_IOC_2009.pdf: 571588 bytes, checksum: 7957a1cca5fbefdfb65220689b3ac19a (MD5) Previous issue date: 2009Instituto Nacional de Câncer. Divisão de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Fisiologia e Farmacodinâmica. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Fisiologia e Farmacodinâmica. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Fisiologia e Farmacodinâmica. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Hospital Universitário Clementino Fraga Filho. Laboratório Multidisciplinar. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Fisiologia e Farmacodinâmica. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Câncer. Divisão de Biologia Celular. Rio de Janeiro, RJ, Brasil.Allergic asthma is a chronic inflammatory disease of the lung whose incidence and morbidity continues to rise in developed nations. Despitebeingahallmarkofasthma,themolecularmechanismsthat determine airway hyperresponsiveness (AHR) are not completely established. Transcription factors of the NFAT family are involved in the regulation of several asthma-related genes. It has been shown thattheabsenceofNFAT1leadstoanincreasedpleuraleosinophilic allergic response accompanied by an increased production of Th2 cytokines, suggesting a role for NFAT1 in the regulation of allergic diseases. Herein, we analyze NFAT12/2 mice to address the role of NFAT1inamodelofallergicairwayinflammationanditsinfluencein AHR. NFAT12/2 mice submitted to airway inflammation display a significant exacerbation of several features of the allergic disease, including lung inflammation, eosinophilia, and serum IgE levels, which were concomitant with elevated Th2 cytokine production. However, in spite of the increased allergic phenotype, NFAT12/2 mice failed to express AHR after methacholine aerosol. Refractoriness of NFAT12/2 mice to methacholine was confirmed in naı ¨ve mice, suggesting that this refractoriness occurs in an intrinsic way, independentofthelunginflammation.Inaddition,NFAT12/2mice exhibit increased AHR in response to serotonin inhalation, suggesting a specific role for NFAT1 in the methacholine pathway of bronchoconstriction. Taken together, these data add support to the interpretation that NFAT1 acts as a counterregulatory mechanism to suppress allergic inflammation. Moreover, our findings suggest a novel role for NFAT1 protein in airway responsiveness mediated by the cholinergic pathway