Reprogramming of lysosomal gene expression by interleukin-4 and Stat6.

BACKGROUND: Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control. RESULTS: As transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H⁺ ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4. CONCLUSIONS: The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling

Saliency-driven system models for cell analysis with deep learning.

Background and objectivesSaliency refers to the visual perception quality that makes objects in a scene to stand out from others and attract attention. While computational saliency models can simulate the expert's visual attention, there is little evidence about how these models perform when used to predict the cytopathologist's eye fixations. Saliency models may be the key to instrumenting fast object detection on large Pap smear slides under real noisy conditions, artifacts, and cell occlusions. This paper describes how our computational schemes retrieve regions of interest (ROI) of clinical relevance using visual attention models. We also compare the performance of different computed saliency models as part of cell screening tasks, aiming to design a computer-aided diagnosis systems that supports cytopathologists.MethodWe record eye fixation maps from cytopathologists at work, and compare with 13 different saliency prediction algorithms, including deep learning. We develop cell-specific convolutional neural networks (CNN) to investigate the impact of bottom-up and top-down factors on saliency prediction from real routine exams. By combining the eye tracking data from pathologists with computed saliency models, we assess algorithms reliability in identifying clinically relevant cells.ResultsThe proposed cell-specific CNN model outperforms all other saliency prediction methods, particularly regarding the number of false positives. Our algorithm also detects the most clinically relevant cells, which are among the three top salient regions, with accuracy above 98% for all diseases, except carcinoma (87%). Bottom-up methods performed satisfactorily, with saliency maps that enabled ROI detection above 75% for carcinoma and 86% for other pathologies.ConclusionsROIs extraction using our saliency prediction methods enabled ranking the most relevant clinical areas within the image, a viable data reduction strategy to guide automatic analyses of Pap smear slides. Top-down factors for saliency prediction on cell images increases the accuracy of the estimated maps while bottom-up algorithms proved to be useful for predicting the cytopathologist's eye fixations depending on parameters, such as the number of false positive and negative. Our contributions are: comparison among 13 state-of-the-art saliency models to cytopathologists' visual attention and deliver a method that the associate the most conspicuous regions to clinically relevant cells

Malaria in Brazil: an overview

Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease

Factors associated with crisis pregnancies in Ireland: Findings from three nationally representative sexual health surveys

Background: Findings on the demographic and sexual health characteristics associated with the experience of a crisis pregnancy is important to inform the public health policy of a country, including Ireland. Findings from other jurisdictions have suggested that certain demographic groups are at risk for unintended pregnancies and the disparity between the groups have been growing in recent years. Ireland is a country which experienced much economic and societal change in the first decade of the 21st century, changes which are likely to have affected demographic variables pertaining to sexual health. The current study had two aims: to investigate changes in the socioeconomic characteristics associated with crisis pregnancies over a seven year period [2003 to 2010], and to investigate the recent [2010] socioeconomic risk factors associated with crisis pregnancies in Ireland. Methods: The study compared the results from 18-45 year old women using data from three broadly similar nationally representative Irish sexual health surveys carried out in 2003, 2004-2006 and 2010. Chi square analysis compared of the socioeconomic characteristics across the seven year period and found that a higher proportion of women with two or more children and women for whom religion was not important reported a crisis pregnancy in 2010 compared with earlier years. A logistic regression then investigated the sexual health history and socioeconomic factors associated with the experience of a recent crisis pregnancy using the most recent 2010 data. Results: Receipt of sex education and contraception use at first sex significantly predicted the experiencing of a recent crisis pregnancy. Younger women and those with a lower level of education were more likely to report having experienced a recent crisis pregnancy. Conclusion: Similar demographic groups are at risk for experiencing a crisis pregnancy in Ireland compared with international research, yet the disparities between demographic groups who have experienced a crisis pregnancy appear to be decreasing rather than increasing over a seven year period. Recommendations are made with regard to the provision of continued sex education throughout the lifespan, particularly for those women who are at an increased risk of experiencing a crisis pregnancy

Aerobic capacity, activity levels and daily energy expenditure in male and female adolescents of the kenyan nandi sub-group

The relative importance of genetic and socio-cultural influences contributing to the success of east Africans in endurance athletics remains unknown in part because the pre-training phenotype of this population remains incompletely assessed. Here cardiopulmonary fitness, physical activity levels, distance travelled to school and daily energy expenditure in 15 habitually active male (13.9±1.6 years) and 15 habitually active female (13.9±1.2) adolescents from a rural Nandi primary school are assessed. Aerobic capacity ([Formula: see text]) was evaluated during two maximal discontinuous incremental exercise tests; physical activity using accelerometry combined with a global positioning system; and energy expenditure using the doubly labelled water method. The [Formula: see text] of the male and female adolescents were 73.9±5.7 ml(.) kg(-1.) min(-1) and 61.5±6.3 ml(.) kg(-1.) min(-1), respectively. Total time spent in sedentary, light, moderate and vigorous physical activities per day was 406±63 min (50% of total monitored time), 244±56 min (30%), 75±18 min (9%) and 82±30 min (10%). Average total daily distance travelled to and from school was 7.5±3.0 km (0.8-13.4 km). Mean daily energy expenditure, activity-induced energy expenditure and physical activity level was 12.2±3.4 MJ(.) day(-1), 5.4±3.0 MJ(.) day(-1) and 2.2±0.6. 70.6% of the variation in [Formula: see text] was explained by sex (partial R(2) = 54.7%) and body mass index (partial R(2) = 15.9%). Energy expenditure and physical activity variables did not predict variation in [Formula: see text] once sex had been accounted for. The highly active and energy-demanding lifestyle of rural Kenyan adolescents may account for their exceptional aerobic fitness and collectively prime them for later training and athletic success

Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a high-concentration formulation of buprenorphine in conscious cats

The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats

Choice of activity-intensity classification thresholds impacts upon accelerometer-assessed physical activity-health relationships in children

It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Adesão à terapêutica antirretroviral de pessoas vivendo com HIV/aids em um município do interior paulista

RESUMO Objetivo Avaliar a adesão aos antirretrovirais de pessoas vivendo com o HIV/AIDS e identificar sua associação com variáveis sociodemográficas e clínicas. Métodos Estudo analítico transversal que utilizou instrumento sociodemográfico e o CEAT-HIV, com dados coletados no período de 2014 a 2015. Resultados Identificou-se 75,0% com grau de adesão bom/adequado. Verificou-se que os indivíduos com idade entre 40 e 59 anos (p=0,029) e com mais de oito anos de estudo (p=0,043) obtiveram maior grau de adesão, assim como aqueles com diagnóstico de HIV/AIDS há mais de 10 anos (p=0,002), contagem de TCD4 >350 células/mm3 (p<0,001) e carga viral indetectável (p=0,025). Conclusão Nesse estudo, identificou-se uma boa adesão entre os sujeitos e observou-se que indivíduos de maior faixa etária, maior grau de escolaridade, maior tempo de diagnóstico, elevada contagem de células TCD4 e carga viral indetectável estiveram associados a uma maior adesão ao tratamento

Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction – a randomised placebo-controlled trial (KARE): study protocol

Abstract Background Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover. Methods/design This will be a prospective, randomised, double-blind, allocation-concealed, placebo-controlled, phase 2, multicentre trial. Randomisation will be stratified by presence of severe sepsis requiring vasopressors. Patients in an ICU fulfilling the American–European Consensus Conference Definition of acute lung injury will be randomised in a 1:1 ratio to receive an intravenous bolus of either keratinocyte growth factor (palifermin, 60 μg/kg) or placebo (0.9% sodium chloride solution) daily for a maximum of 6 days. The primary endpoint of this clinical study is to evaluate the efficacy of palifermin to improve the oxygenation index at day 7 or the last available oxygenation index prior to patient discontinuation from the study.A formal statistical analysis plan has been constructed. Analyses will be carried out on an intention-to-treat basis. A single analysis is planned at the end of the trial. P = 0.05 will be considered statistically significant and all tests will be two-sided. For continuously distributed outcomes, differences between groups will be tested using independent-sample t tests, analysis of variance and analysis of covariance with transformation of variables to normality or nonparametric equivalents. The trial will be reported in line with the Consolidated Standards of Reporting Trials (Consort 2010 guidelines). Trial registration http://ISRCTN9569067