IFN-beta modulates the response to TLR stimulation in human DC: involvement of IFN regulatory factor-1 (IRF-1) in IL-27 gene expression

Type I IFN are cytokines which play a central role in host resistance to viral or microbial infections and are important components linking innate and adaptive immunity. We and others have previously demonstrated that the production of IFN-beta by DC following bacterial infections or TLR triggering influences, in an autocrine manner, their maturation. In this study, we investigated whether IFN-beta release modulates the phenotype of the immature DC and their response to a subsequent TLR stimulation. The induction of CD86, HLA-DR, CD38 and B7H1 and the absence of CCR7 and CD83 expression upon IFN-beta treatment suggest that IFN-beta-primed DC remain at the site of infection acquiring an activated phenotype. These results prompted us to investigate the response of IFN-beta-primed DC to TLR stimulation. While IFN-beta pretreatment increases slightly the expression of maturation markers in TLR2- or TLR4-stimulated DC, it is able to modulate selectively the secretion of inflammatory and immuno-regulating cytokines. Interestingly, IL-27p28 subunit was induced by IFN-beta alone or during LPS-induced maturation of DC in a type I IFN-dependent manner through IFN regulatory factor-1 (IRF-1) activation. Taken together, our results shed light on the capacity of IFN-beta to finely tune DC response to invading pathogens.     

A new method for quantitative analysis of dentinal tubules

Conventional methods to estimate the number of dentinal tubules cannot be considered reliable and repeatable, because results depends on the operator outlining of the tubules contours. In this study, we propose a totally automated computerized analysis technique to evaluate dentinal tubules and their surface area. The comparison test of these conventional with a semi-automatic methods shows that the automated analysis allowed a reliable identification and numbering of dentinal tubules, by means of high-quality images. No statistically significant difference exists in the number of tubules and the total tubule surface area between the control and test groups.     

Initial combination therapy with vildagliptin plus metformin in drug-naïve patients with T2DM: a 24-week real-life study from Asia

Aims: To assess the effectiveness and safety of vildagliptin/metformin initial combination therapy in drug-naïve patients with type 2 diabetes mellitus (T2DM).

Methods: INITIAL was a 24-week prospective, observational study in T2DM patients with glycated hemoglobin (HbA1c)?≥?7.5%, and prescribed vildagliptin/metformin as initial combination therapy. The primary endpoint was change in HbA1c from baseline to week 24. Key secondary endpoints were HbA1c change from baseline to week 12, proportion of patients achieving HbA1c ≤7.0%, change in body weight at 12 and 24 weeks, change in HbA1c by sub-groups (baseline HbA1c, age, body mass index [BMI], dosage strength, co-morbidities) from baseline to week 24, and safety.

Results: A total of 532 patients were enrolled. The mean age, HbA1c, and BMI were 49.6?±?11.27 years, 9.3?±?1.57%, and 26.7?±?4.50?kg/m², respectively. Cardiovascular risk factors present at baseline were dyslipidemia (30.1%), hypertension (29.7%), and obesity (20.9%). The mean reductions in HbA1c from baseline to week 12 (?1.6?±?1.59%) and 24 (?1.9?±?1.70%) were statistically significant (p?Conclusions: Overall, in a relatively young drug-naïve T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability.     

From transit hub to major supplier of illicit cigarettes to Argentina and Brazil: the changing role of domestic production and transnational tobacco companies in Paraguay between 1960 and 2003

Background

Paraguay has reportedly been a major transit hub for illicit tobacco products since the 1960s, initially to supply markets in Argentina and Brazil and, more recently, other regional markets and beyond. However, to date there has been no systematic analysis, notably independent of the tobacco industry, of this trade including the roles of domestic production and transnational tobacco companies (TTCs). This article fills that gap by detailing the history of Paraguay’s illicit cigarette trade to Brazil and Argentina of TTC products and Paraguayan production between 1960 and 2003. The effective control of illicit cigarette flows, under Article 15 of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) and the Protocol to Eliminate the Illicit Trade in Tobacco Products, requires fuller understanding of the changing nature of the illicit trade.

Methods

We systematically searched internal industry documents to understand the activities and strategies of leading TTCs in Paraguay and subregion over time. We also mapped illicit trade volume and patterns using US government and UN data on the cigarette trade involving Paraguay. We then estimated Paraguay’s cigarette production from 1989 to 2003 using tobacco leaf flows from the United Nations Commodity Trade Statistics Database (UN Comtrade).

Results

We identify four phases in the illicit tobacco trade involving Paraguay: 1) Paraguay as a transit hub to smuggle BAT and PMI cigarettes from the U.S. into Argentina and Brazil (from the 1960s to the mid-1970s); 2) BAT and PMI competing in north-east Argentina (1989–1994); 3) BAT and PMI competing in southern and southern-east Brazil (mid to late 1990s); and 4) the growth in the illicit trade of Paraguayan manufactured cigarettes (from the mid- 1990s onwards). These phases suggest the illicit trade was seeded by TTCs, and that the system of supply and demand on lower priced brands they developed in the 1990s created a business opportunity for manufacturing in Paraguay. Brazil’s efforts to fight this trade, with a 150% tax on exports to Latin American countries in 1999, further prompted supply of the illicit trade to shift from TTCs to Paraguayan manufacturers.

Conclusion

This paper extends evidence of the longstanding complicity of TTCs in the illicit trade to this region and the consequent growth of Paraguayan production in the 1990s. Our findings confirm the need to better understand the factors influencing how the illicit tobacco trade has changed over time, in specific regional contexts, and amid tobacco industry globalization. In Paraguay, the changing roles of TTC and domestic production have been central to shifting patterns of illicit supply and distribution since the 1960s. Important questions are raised, in turn, about TTCs efforts to participate as legitimate partners in global efforts to combat the problem, including a leading role in data gathering and analysis.

     

Spatial analyzes of HLA data in Rio Grande do Sul,south Brazil: genetic structure and possible correlation with autoimmune diseases

Background

HLA genes are the most polymorphic of the human genome and have distinct allelic frequencies in populations of different geographical regions of the world, serving as genetic markers in ancestry studies. In addition, specific HLA alleles may be associated with various autoimmune and infectious diseases. The bone marrow donor registry in Brazil is the third largest in the world, and it counts with genetic typing of HLA-A, -B, and -DRB1. Since 1991 Brazil has maintained the DATASUS database, a system fed with epidemiological and health data from compulsory registration throughout the country.

Methods

In this work, we perform spatial analysis and georeferencing of HLA genetic data from more than 86,000 bone marrow donors from Rio Grande do Sul (RS) and data of hospitalization for rheumatoid arthritis, multiple sclerosis and Crohn’s disease in RS, comprising the period from 1995 to 2016 obtained through the DATASUS system. The allele frequencies were georeferenced using Empirical Bayesian Kriging; the diseases prevalence were georeferenced using Inverse Distance Weighted and cluster analysis for both allele and disease were performed using Getis-Ord Gi* method. Spearman’s test was used to test the correlation between each allele and disease.

Results

The results indicate a HLA genetic structure compatible with the history of RS colonization, where it is possible to observe differentiation between regions that underwent different colonization processes. Spatial analyzes of autoimmune disease hospitalization data were performed revealing clusters for different regions of the state for each disease analyzed. The correlation test between allelic frequency and the occurrence of autoimmune diseases indicated a significant correlation between the HLA-B*08 allele and rheumatoid arthritis.

Conclusions

Genetic mapping of populations and the spatial analyzes such as those performed in this work have great economic relevance and can be very useful in the formulation of public health campaigns and policies, contributing to the planning and adjustment of clinical actions, as well as informing and educating professionals and the population.

     

Association of Polypharmacy With 1-Year Trajectories of Cognitive and Physical Function in Nursing Home Residents: Results From a Multicenter European Study

Objectives

To test the association between polypharmacy and 1-year change in physical and cognitive function among nursing home (NH) residents.