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Background Patients with atrial fibrillation (AF) admitted to hospital commonly have comorbidities. Few studies have attempted to determine factors prognostic of mortality in hospitalized AF patients with multimorbidity. Aim To identify factors associated with mortality in hospitalized AF patients. Design Retrospective cohort study. Methods Patients with multimorbidity (≥2 chronic diseases), with or without AF, discharged from Lugo hospital (Spain) between 1 January 2000 and 31 December 2015. Data were extracted from hospital medical records. Results Of 74 220 patients (170 978 hospitalizations), 52 939 had multimorbidity (14 181 had AF; 38 758 no AF) and were included in our study. Patients with AF were older (mean ± standard deviation 78.6 ± 10.0 vs. 71.9 ± 14.2 years) and had a higher mortality rate (27.1 vs. 20.5%) than those without AF. Gender (female), age, stroke and congestive heart failure (CHF), but not AF, were independently associated with mortality. AF significantly increased the mortality risk in women [relative risk (RR) 1.091; 95% confidence interval (CI) 1.021–1.165; P  =   0.010] and in those aged >80 years (RR 1.153; 95% CI, 1.1–1.2; P  <   0.001). CHF independently increased the risk of mortality across all age groups (RR 1.496; 95% CI 1.422–1.574; P  <   0.001). Conclusions Hospitalized patients with AF have a higher mortality rate than those without AF. The prognostic significance of AF changes with age and gender while CHF is associated with the greatest risk of death. [ABSTRACT FROM AUTHOR]

Objectives: Although controversy exists regarding the efficacy of antibiotic prophylaxis for patients at risk of infective endocarditis, expert committees continue to publish recommendations for antibiotic prophylaxis regimens. This study aimed to evaluate the efficacy of four antimicrobial regimens for the prevention of bacteraemia following dental extractions.Methods: The study population included 266 adults requiring dental extractions who were randomly assigned to the following five groups: control (no prophylaxis); 1000/200 mg of amoxicillin/clavulanate intravenously; 2 g of amoxicillin by mouth; 600 mg of clindamycin by mouth; and 600 mg of azithromycin by mouth. Venous blood samples were collected from each patient at baseline and at 30 s, 15 min and 1 h after dental extractions. Samples were inoculated into BACTEC Plus culture bottles and processed in the BACTEC 9240. Conventional microbiological techniques were used for subcultures and further identification of the isolated bacteria. The trial was registered at ClinicalTrials.gov with ID number NCT02115776.Results: The incidence of bacteraemia in the control, amoxicillin/clavulanate, amoxicillin, clindamycin and azithromycin groups was: 96%, 0%, 50%, 87% and 81%, respectively, at 30 s; 65%, 0%, 10%, 65% and 49% at 15 min; and 18%, 0%, 4%, 19% and 18% at 1 h. Streptococci were the most frequently identified bacteria. The percentage of positive blood cultures at 30 s post-extraction was lower in the amoxicillin/clavulanate group than in the amoxicillin group (P < 0.001). The incidence of bacteraemia in the clindamycin group was similar to that in the control group.Conclusions: Bacteraemia following dental extractions was undetectable with amoxicillin/clavulanate prophylaxis. Alternative antimicrobial regimens should be sought for patients allergic to the β-lactams. [ABSTRACT FROM AUTHOR]

Background and Aims In mature quinoa (Chenopodium quinoa) seeds, the lasting endosperm forms a micropylar cone covering the radicle. The suspensor cells lie within the centre of the cone. During the final stage of seed development, the cells of the lasting endosperm accumulate protein and lipids while the rest are crushed and disintegrated. Both the suspensor and endosperm die progressively from the innermost layers surrounding the embryo and extending towards the nucellar tissue. Ricinosomes are endoplasmic reticulum-derived organelles that accumulate both the pro-form and the mature form of cysteine endopeptidase (Cys-EP), first identified in castor bean (Ricinus communis) endosperm during germination. This study sought to identify associations between the presence of ricinosomes and programmed cell death (PCD) hallmarks in suspensor and endosperm cells predestined to die during quinoa seed development. Methods A structural study using light microscopy and transmission electron microscopy was performed. To detect the presence of Cys-EP, both western blot and in situ immunolocalization assays were carried out using anti-R. communis Cys-EP antibody. A TUNEL assay was used to determine DNA fragmentation. Results and Conclusions Except for the one or two cell layers that constitute the lasting endosperm in the mature seed, ricinosomes were found in suspensor and endosperm cells. These cells were also the site of morphological abnormalities, including misshapen and fragmented nuclei, vesiculation of the cytosol, vacuole collapse and cell wall disorganization. It is proposed that, in suspensor and endosperm cells, the early detection of Cys-EP in ricinosomes predicts the occurrence of PCD during late seed development. [ABSTRACT FROM PUBLISHER]

The role of post-zygotic isolation in nonallopatric ecological speciation is still mostly unknown and information on the nature and strength of these barriers in well-known speciation models is essential for a deeper understanding of such processes. The Galician ecotypes of the marine snail Littorina saxatilis represent one of the best studied cases of nonallopatric ecological speciation. Here, we test the existence of incipient post-zygotic isolation by comparing the fertility of male hybrids with that of both pure forms [ridged and banded ( RB) and smooth and unbanded ( SU) ecotypes]. We analysed the degree of sperm DNA fragmentation ( SDF) of individuals morphologically classified as RB, SU and hybrids, sampled from two locations. SDF analyses were chosen to study sperm quality because, in other animal species, SDF rates correlate with important parameters for speciation research, such as fertilization and abortion rates and viability of adult progeny. In the present work, hybrids showed significantly higher SDF rates than RB and SU males in one location and significantly higher variances in both locations. These results suggest the existence of an incipient post-zygotic barrier, the strength of which may vary across the Galician shore, and highlight the potential of SDF analyses for speciation research. [ABSTRACT FROM AUTHOR]

The concept of webpage visibility is usually linked to search engine optimization, and it is based on global in-link metric, that is, the number of received links from other websites, but without considering the sources of these links. The purpose of this article is to demonstrate that this global idea of visibility is only weakly correlated with web metrics measured over a network of related institutions or organizations (local visibility) and research production. As a case study, global and local visibility measurements have been obtained for a set of Spanish Universities, and they have been correlated with results provided by international rankings like the Webometrics Ranking of World’s Universities and the Academic Ranking of World Universities by Shanghai Jiao Tung University. Obtained results suggest that the development of web indicators to be included as part of Universities evaluation programs should consider a local idea of visibility, considering a certain geographical context or similar related institutions. [ABSTRACT FROM AUTHOR]

Hybrid zones of ecologically divergent populations are ideal systems to study the interaction between natural selection and gene flow during the initial stages of speciation. Here, we perform an amplified fragment length polymorphism ( AFLP) genome scan in parallel hybrid zones between divergent ecotypes of the marine snail Littorina saxatilis, which is considered a model case for the study of ecological speciation. Ridged-Banded ( RB) and Smooth-Unbanded ( SU) ecotypes are adapted to different shore levels and microhabitats, although they present a sympatric distribution at the mid-shore where they meet and mate (partially assortatively). We used shell morphology, outlier and nonoutlier AFLP loci from RB, SU and hybrid specimens captured in sympatry to determine the level of phenotypic and genetic introgression. We found different levels of introgression at parallel hybrid zones and nonoutlier loci showed more gene flow with greater phenotypic introgression. These results were independent from the phylogeography of the studied populations, but not from the local ecological conditions. Genetic variation at outlier loci was highly correlated with phenotypic variation. In addition, we used the relationship between genetic and phenotypic variation to estimate the heritability of morphological traits and to identify potential Quantitative Trait Loci to be confirmed in future crosses. These results suggest that ecology (exogenous selection) plays an important role in this hybrid zone. Thus, ecologically based divergent natural selection is responsible, simultaneously, for both ecotype divergence and hybridization. On the other hand, genetic introgression occurs only at neutral loci (nonoutliers). In the future, genome-wide studies and controlled crosses would give more valuable information about this process of speciation in the face of gene flow. [ABSTRACT FROM AUTHOR]

Backgrounds and Aims Functional–structural models are interesting tools to relate environmental and management conditions with forest growth. Their three-dimensional images can reveal important characteristics of wood used for industrial products. Like virtual laboratories, they can be used to evaluate relationships among species, sites and management, and to support silvicultural design and decision processes. Our aim was to develop a functional–structural model for radiata pine (Pinus radiata) given its economic importance in many countries. Methods The plant model uses the L-system language. The structure of the model is based on operational units, which obey particular rules, and execute photosynthesis, respiration and morphogenesis, according to their particular characteristics. Plant allometry is adhered to so that harmonic growth and plant development are achieved. Environmental signals for morphogenesis are used. Dynamic turnover guides the normal evolution of the tree. Monthly steps allow for detailed information of wood characteristics. The model is independent of traditional forest inventory relationships and is conceived as a mechanistic model. For model parameterization, three databases which generated new information relating to P. radiata were analysed and incorporated. Key Results Simulations under different and contrasting environmental and management conditions were run and statistically tested. The model was validated against forest inventory data for the same sites and times and against true crown architectural data. The performance of the model for 6-year-old trees was encouraging. Total height, diameter and lengths of growth units were adequately estimated. Branch diameters were slightly overestimated. Wood density values were not satisfactory, but the cyclical pattern and increase of growth rings were reasonably well modelled. Conclusions The model was able to reproduce the development and growth of the species based on mechanistic formulations. It may be valuable in assessing stand behaviour under different environmental and management conditions, assisting in decision-making with regard to management, and as a research tool to formulate hypothesis regarding forest tree growth and development. [ABSTRACT FROM PUBLISHER]

Aims: This project investigated the utility of HP selective medium to isolate H. pylori cells from seawater and from marine molluscs. Methods and Results: Nested-PCR was performed to reveal the presence of Helicobacter genus. All samples were cultured in HP selective medium and 16 cultures were initially selected as putative Helicobacter. Helicobacter spp. DNA were detected in 9/16 cultures and three of them had 99–100% homology to H. pylori based on 16S RNA gene sequence. Helicobacter pylori isolation was unsuccessful. On the basis of 16S RNA gene sequences the contaminating organisms were shown to be Proteus mirabilis and Vibrio cholerae. Conclusions: These results indicate the coexistence of three predominant bacterial genera in the cultures and that HP selective medium can grow other enteric bacteria besides Helicobacter. Additional assays will improve the HP selective medium formulation for marine samples avoiding P. mirabilis and V. cholerae interferents. Significance and Impact of the Study: This work shows the effectiveness of the selective HP medium for the Helicobacter culture from marine samples. [ABSTRACT FROM AUTHOR]

Aims: Enterococcus faecalis produces a cationic and circular enterocin, AS-48, of 7149 Da, the genetic determinants of which are located within the pMB2 plasmid. We have compared enterocin AS-48 production by different enterococci species with that of other ‘safe’ lactic acid bacteris (LAB) ( GRAS status) and looked into the subsequent application of this enterocin in food production. Methods and Results: In an effort to exploit this system for the heterologous expression of enterocin AS-48, a number of vectors containing the as-48 cluster were constructed and used to transform several LAB strains (genera Enterococcus, Lactococcus and Lactobacillus) Conclusion: Heterologous production of enterocin AS-48 failed when bacteria other than those belonging to the genus Enterococcus were used as hosts, although expression of a partial level of resistance against AS-48 were always detected, ruling out the possibility of a lack of recognition of the enterococcal promoters. Significance and Impact of the Study: Our results reveal the special capacity of species from the genus Enterococcus to produce AS-48, an enterocin that requires a post-transcriptional modification to generate a circular peptide with a wide range of inhibitory activity against pathogenic and spoilage bacteria. Preliminary experiments in foodstuffs using nonvirulent enterococci with interesting functional properties reveal the possibility of a biotechnological application of these transformants. [ABSTRACT FROM AUTHOR]

Mating patterns play a critical role in the maintenance of genetic variation. We analyzed the mating system in a recently fragmented population of the Andean oak (Quercus humboldtii) using four microsatellite loci. Five fragments in northeastern Colombia, South America, were selected consisting of 30.4 trees on average. We sampled about 30 seeds from three target trees in each fragment and genotyped them with four microsatellite loci with a total of 40 alleles across loci. Progenies were analyzed under the mixed mating system model (MLTR program) and the TwoGener pollen pool structure analyses. The number of unshared pollen donors per family (Nu) was estimated using gametotypic counts with the program HAPLOTYPES. Low selfing (3%) is occurring at the population and fragment level. Biparental inbreeding is present (4.9%), but reduced, in the largest fragment. The average pollen neighborhood size (Nep = 5.1 to 6.1) appears comparable to other oak species in sparse landscapes. In contrast, Nu consists of 2 to 4 main donors, although up to 12 are possible, with the mode positively correlated with fragment size. The Andean oak appears to be a resilient species capable of tolerating population subdivision, provided landscapes include large fragments. [ABSTRACT FROM AUTHOR]

s. rodríguez-echeverría, m.a. pérez-fernández, s. vlaar and t. finnan. 2003. This work analyses the diversity of rhizobia associated with some of the predominant shrubby legumes in central-western Spain. Symbiotic promiscuity and effectiveness were studied using cross-inoculation experiments with shrubby species. Six new bradyrhizobia strains were isolated from nodules collected from wild plants of six leguminous species, Cytisus balansae, C. multiflorus, C. scoparius, C. striatus, Genista hystrix and Retama sphaerocarpa. These isolates were genetically characterized by 16S rDNA partial sequencing and random amplification of polymorphic DNA–PCR fingerprinting. The phylogenetic analysis revealed that these isolates could represent three new Bradyrhizobium species. Shrubby legumes and bradyrhizobia displayed a high symbiotic promiscuity both for infectivity and effectiveness. Symbioses were effective in more than 70% of the associations established by four of the six plant species. Native woody legumes in western Spain are nodulated by Bradyrhizobium strains. The high degree of symbiotic promiscuity and effectiveness highlights the complex dynamics of these communities in wild ecosystems under a Mediterranean-type climate. Furthermore, the results from this study suggest a potential importance of inoculation for these legume species in soil-restoration projects. This is the first study, to our knowledge, that combines both molecular analysis and pot trials to study the rhizobia–legume symbiosis for wild legumes. [ABSTRACT FROM AUTHOR]

Summary We examined the local and systemic production of nitric oxide (NO) and the pattern of cytokine during the course of Leishmania mexicana infection in susceptible BALB/c and resistant C57BL/6 mice. NO derivatives were measured in serum, and the expression of inducible nitric oxide synthase (iNOS), interferon (IFN-γ), interleukin (IL-4) and epidermal Langerhans cells (LC) was measured in the lesions by immunohistology. Circulating NO concentrations, iNOS+ cell density, IFN-γ+ Th1 cells and CD205+ Langerhans cells were higher in early lesions of resistant C57BL/6 mice. In contrast, susceptible BALB/c mice developed chronic and progressive lesions with a predominance of IL-4+ Th2 cells. In both susceptible and resistant mice, lesion size and lymph node volume followed a similar course. The early local and systemic production of NO in resistant mice may be related with the premature production of IFN-γ observed, contributing to the resolution of the lesion. [ABSTRACT FROM AUTHOR]

The T Tauri star CVSO 30, also known as PTFO 8-8695, was studied intensively with ground-based telescopes as well as with satellites over the last decade. It showed a variable light curve with additional repeating planetary transit-like dips every ∼10.8 h. However, these dimming events changed in depth and duration since their discovery and from autumn 2018 on, they were not even present or near the predicted observing times. As reason for the detected dips and their changes within the complex light curve, e.g. a disintegrating planet, a circumstellar dust clump, stellar spots, possible multiplicity, and orbiting clouds at a Keplerian co-rotating radius were discussed and are still under debate. In this paper, we present additional optical monitoring of CVSO 30 with the meter class telescopes of the Young Exoplanet Transit Initiative in Asia and Europe over the last 7 yr and characterize CVSO 30 with the new Early Data Release 3 of the European Space Agency- Gaia mission. As a result, we describe the evolution of the dimming events in the optical wavelength range since 2014 and present explanatory approaches for the observed variabilities. We conclude that orbiting clouds of gas at a Keplerian co-rotating radius are the most promising scenario to explain most changes in CVSO 30's light curve. [ABSTRACT FROM AUTHOR]

The main purpose of this study was adapt and validate Female Genital Self-Image Scale (Herbenick & Reece, 2010) into Spanish by cross language translation procedure. Conclusions Spanish version of FGSIS seems to be a reliable three-dimensional scale to evaluate genital self-perception in women. In future studies it will be shown the relationships of FGSIS with sexual health, body image and self-steem in Spanish women. [Extracted from the article]

To explore the variability and reliability of a new parameter in clinical artery Doppler: the volume flow. Methods 79 healthy volunteer women were studied retrospectively by clitoral artery Doppler using a sagittal section technique. Volumetric blood flow measurement was obtained by the formula: V flow= Cross-sectional area x Time-averaged velocity (TAV). [Extracted from the article]

Hall & Robinson (2009) proposed and analysed the use of bagged cross-validation to choose the bandwidth of a kernel density estimator. They established that bagging greatly reduces the noise inherent in ordinary cross-validation, and hence leads to a more efficient bandwidth selector. The asymptotic theory of Hall & Robinson (2009) assumes that |$N$|⁠ , the number of bagged subsamples, is |$\infty$|⁠. We expand upon their theoretical results by allowing |$N$| to be finite, as it is in practice. Our results indicate an important difference in the rate of convergence of the bagged cross-validation bandwidth for the cases |$N=\infty$| and |$N<\infty$|⁠. Simulations quantify the improvement in statistical efficiency and computational speed that can result from using bagged cross-validation as opposed to a binned implementation of ordinary cross-validation. The performance of the bagged bandwidth is also illustrated on a real, very large, dataset. Finally, a byproduct of our study is the correction of errors appearing in the Hall & Robinson (2009) expression for the asymptotic mean squared error of the bagging selector. [ABSTRACT FROM AUTHOR]

Hot Jupiters have been perceived as loners devoid of planetary companions in close orbital proximity. However, recent discoveries based on space-borne precise photometry have revealed that at least some fraction of giant planets coexists with low-mass planets in compact orbital architectures. We report detecting a 1.446-d transit-like signal in the photometric time series acquired with the Transiting Exoplanet Survey Satellite (TESS) for the WASP-84 system, which is known to contain a hot Jupiter on a circular 8.5-d orbit. The planet was validated based on TESS photometry, and its signal was distilled in radial velocity measurements. The joint analysis of photometric and Doppler data resulted in a multiplanetary model of the system. With a mass of |$15\, \mathrm{ M}_{{\oplus }}$|⁠ , radius of |$2\, \mathrm{ R}_{{\oplus }}$|⁠ , and orbital distance of 0.024 au, the new planet WASP-84 c was classified as a hot super-Earth with the equilibrium temperature of 1300 K. A growing number of companions to hot Jupiters indicates that a non-negligible part of them must have formed under a quiescent scenario such as disc migration or in situ formation. [ABSTRACT FROM AUTHOR]

We have initiated a dedicated project to follow-up with ground-based photometry the transiting planets discovered by CoRoT in order to refine the orbital elements, constrain their physical parameters, and search for additional bodies in the system. From 2012 September to 2016 December we carried out 16 transit observations of six CoRoT planets (CoRoT-5 b, CoRoT-8 b, CoRoT-12 b, CoRoT-18 b, CoRoT-20 b, and CoRoT-27 b) at three observatories located in Germany and Spain. These observations took place between 5 and 9 yr after the planet's discovery, which has allowed us to place stringent constraints on the planetary ephemeris. In five cases we obtained light curves with a deviation of the mid-transit time of up to ∼115 min from the predictions. We refined the ephemeris in all these cases and reduced the uncertainties of the orbital periods by factors between 1.2 and 33. In most cases our determined physical properties for individual systems are in agreement with values reported in previous studies. In one case, CoRoT-27 b, we could not detect any transit event in the predicted transit window. [ABSTRACT FROM AUTHOR]

Study Question: What number of staff is sufficient to perform increasingly complicated processes in today's modern ART laboratories?Summary Answer: The adequate number of personnel required for the efficient and safe operation of modern ART laboratories needs to be calculated.What Is Known Already: In today's modern ART laboratories, the amount of time required to perform increasingly complicated processes has more than doubled, with a downward trend in the amount of work an embryologist can do. Different workload unit values have been used to evaluate each workload task and efficiency in a particular ART laboratory, as well as to occasionally compare one laboratory with another.Study Design, Size, Duration: Seven senior embryologists working at different IVF centers, three public and four private centers, participated in this multicenter study conducted between 2019 and 2020. We prepared a survey to create a calculator for staff using the average (of three attempts) time spent in every laboratory by each embryologist of the center to perform any ART process.Participants/materials, Setting, Methods: Different laboratory processes and activities related to quality control, time spent and conventional human double witnessing were included in the survey. To calculate the number of processes that each embryologist can perform per year, an embryologist was considered to be having a full-time contract and working 7 or 8 h/day. The times included in the calculation of each task were those corresponding to the 95th percentile. For the calculations, Microsoft® Office Excel® Professional Plus 2019 was used.Main Results and the Role Of Chance: The survey showed that the time needed per embryologist to perform the different processes necessary for a classic IVF cycle without time lapse (TL) was 8.11 h, and with TL, it was 10.27 h. The calculated time also considered the time spent in documentation handling, cycle preparation, database management and conventional human double witnessing verification. An ICSI without TL needed 8.55 h, and with TL, it needed 10.71 h. An ICSI-PGT without a TL cycle needed 11.75 h, and with TL, it needed 13.91 h. Furthermore, 1.81 h should be added for every vitrification support needed. The time needed to control more than 200 critical steps, including equipment control and culture parameters, was 30 min per day plus 3.9 min per device to control.The time spent in semen analysis (including documentation handling, cycle preparation and database management) or intrauterine insemination with a partner sperm was 2.7 h. For donor sperm, an additional hour was required for the management involved. The time required to perform a testicular biopsy and cryopreserve the sample was 4 h. Similarly, the time required to perform seminal cryopreservation was 3.7 h.Limitations, Reasons For Caution: The study was conducted considering a full-time contract embryologist working 7 or 8 h/day, 5 days a week, with days off according to the Spanish regulations. However, our findings can be adapted to foreign regulations using the developed online calculation platform.Wider Implications Of the Findings: A new advanced staff calculator allows any IVF laboratory to estimate the minimum number of embryologists necessary without compromising the security or success of the results. Nevertheless, we recommend a minimum of two qualified embryologists in every laboratory, regardless of the workload.Study Funding/competing Interest(s): This work was funded by the Asociación para el Estudio de la Biología de la Reproducción (ASEBIR). None of the authors has any conflict of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

We present a study of the prevalence of optical and radio nuclear activity with respect to the environment and interactions in a sample of the Sloan Digital Sky Survey (SDSS) galaxies. The aim is to determine the independent effects of distinct aspects of source environment on the triggering of different types of nuclear activity. We defined a local density parameter and a tidal force estimator and used a cluster richness estimator from the literature to trace different aspects of environment and interaction. The possible correlations between the environmental parameters were removed using a principal component analysis. By far, the strongest trend found for the active galactic nuclei (AGN) fractions, of all AGN types, is with galaxy mass. We therefore applied a stratified statistical method that takes into account the effect of possible confounding factors like the galaxy mass. We found that (at fixed mass) the prevalence of optical AGN is a factor of 2–3 lower in the densest environments, but increases by a factor of ∼2 in the presence of strong one-on-one interactions. These effects are even more pronounced for star-forming nuclei. The importance of galaxy interactions decreases from star-forming nuclei to Seyferts to low-ionization nuclear emission-line regions to passive galaxies, in accordance with previous suggestions of an evolutionary time-sequence. The fraction of radio AGN increases very strongly (by nearly an order of magnitude) towards denser environments, and is also enhanced by galaxy interactions. Overall, the results agree with a scenario in which the mechanisms of accretion into the black hole are determined by the presence and nature of a supply of gas, which in turn is controlled by the local density of galaxies and their interactions. A plentiful cold gas supply is required to trigger star formation, optical AGN and radiatively efficient radio AGN. This is less common in the cold-gas-poor environments of groups and clusters, but is enhanced by one-on-one interactions which result in the flow of gas into nuclear regions; these two factors compete against each other. In the denser environments where cold gas is rare, cooling hot gas can supply the nucleus at a sufficient rate to fuel low-luminosity radiatively inefficient radio AGN. However, the increased prevalence of these AGN in interacting galaxies suggests that this is not the only mechanism by which radiatively inefficient AGN can be triggered. [ABSTRACT FROM AUTHOR]

Autoimmune thyroid diseases (AITD) are considered as prototypic organ-specific autoimmune diseases, yet their underlying aetiology remains poorly understood. Among the various pathophysiological mechanisms considered, a failure of central tolerance has received little attention. Here we present evidence in favour of dysregulated thymic function playing a role in AITD. Flow-cytometric analyses conducted in peripheral blood lymphocytes from 58 AITD patients and 48 age- and-sex-matched controls showed that AITD patients have significantly higher blood levels of CD4+CD45RA+, CD4+CD31+ and CD4/CD8 double-positive T lymphocytes, all markers of recent thymic emigrants (RTE). In addition, the α-signal joint T cell receptor excision circles (TRECs) content (a molecular marker of RTEs) was higher in the group of AITD patients older than 35 years than in age-matched controls. This was independent from peripheral T cell expansion as assessed by relative telomere length. Comparisons of TREC levels in peripheral blood lymphocytes and intrathyroidal lymphocytes in paired samples showed higher levels within the thyroid during the initial 30 months of the disease, indicating an influx of RTE into the thyroid during the initial stages of AITD. Additionally, a lack of correlation between TREC levels and forkhead box P3 expression suggests that the intrathyroidal RTE are not natural regulatory T cells. These results uncover a hitherto unknown correlation between altered thymic T cell export, the composition of intrathyroidal T cells and autoimmune pathology. [ABSTRACT FROM AUTHOR]

The ADH2 gene codes for the Arabidopsis glutathione-dependent formaldehyde dehydrogenase (FALDH), an enzyme involved in formaldehyde metabolism in eukaryotes. In the present work, we have investigated the potential role of FALDH in detoxification of exogenous formaldehyde. We have generated a yeast (Saccharomyces cerevisiae) mutant strain (sfa1Δ) by in vivo deletion of the SFA1 gene that codes for the endogenous FALDH. Overexpression of Arabidopsis FALDH in this mutant confers high resistance to formaldehyde added exogenously, which demonstrates the functional conservation of the enzyme through evolution and supports its essential role in formaldehyde metabolism. To investigate the role of the enzyme in plants, we have generated Arabidopsis transgenic lines with modified levels of FALDH. Plants overexpressing the enzyme show a 25% increase in their efficiency to take up exogenous formaldehyde, whereas plants with reduced levels of FALDH (due to either a cosuppression phenotype or to the expression of an antisense construct) show a marked slower rate and reduced ability for formaldehyde detoxification as compared with the wild-type Arabidopsis. These results show that the capacity to take up and detoxify high concentrations of formaldehyde is proportionally related to the FALDH activity in the plant, revealing the essential role of this enzyme in formaldehyde detoxification. [ABSTRACT FROM AUTHOR]

Climate change affects distribution and persistence of species. However, forecasting species' responses to these changes requires long-term data series that are often lacking in ecological studies. We used 15 years of small mammal trapping data collected between 1978 and 2015 in 3 areas at Doñana National Park (southwest Spain) to (i) describe changes in species composition and (ii) test the association between local climate conditions and size of small mammal populations. Overall, 5 species were captured: wood mouse Apodemus sylvaticus, algerian mouse Mus spretus, greater whitetoothed shrew Crocidura russula, garden dormouse Eliomys quercinus, and black rat Rattus rattus. The temporal pattern in the proportion of captures of each species suggests that the small mammal diversity declined with time. Although the larger species (e.g., E. quercinus), better adapted to colder climate, have disappeared from our trapping records, M. spretus, a small species inhabiting southwest Europe and the Mediterranean coast of Africa, currently is almost the only trapped species. We used 2-level hierarchical models to separate changes in abundance from changes in probability of capture using records of A. sylvaticus in all 3 areas and of M. spretus in 1. We found that heavy rainfall and low temperatures were positively related to abundance of A. sylvaticus, and that the number of extremely hot days was negatively related to abundance of M. spretus. Despite other mechanisms are likely to be involved, our findings support the importance of climate for the distribution and persistence of these species and raise conservation concerns about potential cascading effects in the Doñana ecosystem. [ABSTRACT FROM AUTHOR]

Study Question: Is permeable cryoprotectant-free vitrification of native sperm samples a good alternative to conventional slow freezing?Summary Answer: The permeable cryoprotectant-free sperm vitrification protocol tested in this study renders considerably better recovery rates of good quality sperm compared to slow freezing.What Is Known Already: Slow freezing is currently the most commonly used technique for sperm cryopreservation, though this method has been repeatedly shown to have negative effects on both structural and functional sperm features. New alternative methods such as vitrification have been established as a successful alternative in other reproductive cell types, but vitrification of spermatozoa is still a rather unexplored methodology, with limited studies showing its efficacy in male gametes.Study Design Size, Duration: This study included 18 normozoospermic sperm samples from patients seeking ART treatment between 2014 and 2015. The effects of a new vitrification protocol on functional and structural sperm quality parameters in comparison to fresh and slow-frozen samples were assessed.Participants/materials, Setting, Methods: All samples were divided into three aliquots: fresh (F), slow freezing-thawing (S) and vitrification-warming (V). Sperm concentration, motility, morphology, vitality, DNA fragmentation, cytoskeleton integrity and spontaneous acrosome reaction were assessed and compared between the groups.Main Results and the Role Of Chance: Results showed improved preservation of sperm features after vitrification compared to conventional freezing. Permeable cryoprotectant-free vitrification presented a significantly higher percentage of live spermatozoa, than slow freezing, better preservation of acrosomes was achieved in vitrified samples and DNA fragmentation was reduced approximately one-third on average compared to slow freezing. Regarding tubulin assay, three different labelling patterns were observed. The frequency of these labelling patterns was similar in F and V groups but this was not the case of the S group. The multivariate analysis of all sperm quality parameters studied revealed that the V group presented features that are closer to the F group than the S group, indicating that samples are better preserved through vitrification than slow freezing.Limitations Reasons For Caution: This validation has been undertaken only on normozoospermic sperm samples. It would be necessary to compare these results in pathological samples and also to evaluate the influence of the application of this methodology on clinical outcomes.Wider Implications Of the Findings: The sperm vitrification protocol here described warrants better maintenance of sperm quality parameters than traditional freezing methods and may be a good alternative to preserve sperm samples from patients seeking IVF treatment.Study Funding/competing Interest(s): This study was funded by IVF-Spain Foundation. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection.Patients and methods: Twenty patients with acute/recent HIV-1 infection were randomized to receive ART alone (tenofovir, emtricitabine and lopinavir/ritonavir) or associated with 8 weeks of cyclosporine A (0.3-0.6 mg/kg twice daily). The impact on viral load, immune response and integrated and non-integrated DNA viral reservoir at 0, 8 and 36 weeks of treatment was evaluated.Results: The estimated median time from HIV-1 infection to ART onset was 63 days (IQR 53; 79.5) with 90% of patients at Fiebig V stage. No significant differences were observed in viral load decay, CD4 T cell recovery, immune response markers or the evolution of integrated DNA at week 8 (end of cyclosporine A) and week 36 between groups. However, non-integrated DNA significantly increased in the cyclosporine A arm between weeks 0 and 36. Cyclosporine A was well tolerated.Conclusions: Adding cyclosporine A to ART during acute/recent infection did not improve immune recovery. However, unintegrated DNA increased in the cyclosporine A group, suggesting an anti-integration effect, a point warranting further research (ClinicalTrials.gov Identifier: NCT00979706). [ABSTRACT FROM AUTHOR]

We study the internal radial gradients of stellar population properties within 1.5 Re and analyse the impact of galaxy environment. We use a representative sample of 721 galaxies with masses ranging between 109 M⊙ and 1011.5 M⊙ from he SDSS-IV survey MaNGA. We split this sample by morphology into early-type and late-type galaxies. Using the full spectral fitting code FIREFLY, we derive the light and mass-weighted stellar population properties, age and metallicity, and calculate the gradients of these properties. We use three independent methods to quantify galaxy environment, namely the Nth nearest neighbour, the tidal strength parameter Q and distinguish between central and satellite galaxies. In our analysis, we find that early-type galaxies generally exhibit shallow light-weighted age gradients in agreement with the literature and mass-weighted median age gradients tend to be slightly positive. Late-type galaxies, instead, have negative light-weighted age gradients. We detect negative metallicity gradients in both early- and late-type galaxies that correlate with galaxy mass, with the gradients being steeper and the correlation with mass being stronger in late-types. We find, however, that stellar population gradients, for both morphological classifications, have no significant correlation with galaxy environment for all three characterizations of environment. Our results suggest that galaxy mass is the main driver of stellar population gradients in both early and late-type galaxies, and any environmental dependence, if present at all, must be very subtle. [ABSTRACT FROM AUTHOR]

CVSO 30 is a unique young low-mass system, because, for the first time, a close-in transiting and a wide directly imaged planet candidates are found around a common host star. The inner companion, CVSO 30 b, is the first possible young transiting planet orbiting a previously known weak-lined T Tauri star. With five telescopes of the 'Young Exoplanet Transit Initiative' located in Asia, Europe and South America, we monitored CVSO 30 over three years in a total of 144 nights and detected 33 fading events. In two more seasons we carried out follow-up observations with three telescopes. We can confirm that there is a change in the shape of the fading event between different observations and that the fading event even disappears and reappears. A total of 38 fading event light curves were simultaneously modelled. We derived the planetary, stellar and geometrical properties of the system and found them slightly smaller but in agreement with the values from the discovery paper. The period of the fading event was found to be 1.36 s shorter and 100 times more precise than the previous published value. If CVSO 30 b would be a giant planet on a precessing orbit, which we cannot confirm, yet, the precession period may be shorter than previously thought. But if confirmed as a planet it would be the youngest transiting planet ever detected and will provide important constraints on planet formation and migration time-scales. [ABSTRACT FROM AUTHOR]

Background: Despite the relevance of monocytes as promoters of the inflammatory response, whether human immunodeficiency virus (HIV) infection induces premature age-related changes to the phenotype and function of monocytes or whether these alterations are different and/or specifically driven by HIV remains to be mechanistically determined.Methods: We assayed the activation phenotype and the responsiveness in vitro to Toll-like receptor (TLR) agonists in classical, intermediate, and nonclassical subsets of monocytes by assessing intracellular interleukin 1α (IL-1α), IL-1β, interleukin 6 (IL-6), interleukin 8, tumor necrosis factor α, and interleukin 10 (IL-10) production in 20 HIV-infected patients receiving combination antiretroviral therapy (cART) and 2 groups of uninfected controls (20 age-matched young individuals and 20 older individuals aged >65 years).Results: HIV-infected patients showed a more activated phenotype of monocytes than older controls. Regarding functionality, under unstimulated conditions HIV-infected patients showed a higher percentage of classical monocytes producing IL-6 and IL-10 than control subjects. The percentage of cells with production of multiple cytokines (polyfunctionality), including IL-10, in response to TLR agonists was greater among HIV-infected patients than among control subjects.Conclusions: Inflammatory alterations associated with monocytes during HIV infection are different from those in aging individuals. This monocyte dysfunction, mainly characterized by high levels of IL-6- and IL-10-producing monocytes, may have clinical implications in HIV-infected patients that are different from those in aging individuals. [ABSTRACT FROM AUTHOR]

Background: Medical illnesses are associated with a modest increase in crash risk, although many individuals with acute or chronic conditions may remain safe to drive, or pose only temporary risks. Despite the extensive use of national guidelines about driving with medical illness, the quality of these guidelines has not been formally appraised. Aim: To systematically evaluate the quality of selected national guidelines about driving with medical illness. Design: A literature search of bibliographic databases and Internet resources was conducted to identify the guidelines, each of which was formally appraised. Methods: Eighteen physicians or researchers from Canada, Australia, Ireland, USA and UK appraised nine national guidelines, applying the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. Results: Relative strengths were found in AGREE II scores for the domains of scope and purpose, stakeholder involvement and clarity of presentation. However, all guidelines were given low ratings on rigour of development, applicability and documentation of editorial independence. Overall quality ratings ranged from 2.25 to 5.00 out of 7.00, with modifications recommended for 7 of the guidelines. Intra-class coefficients demonstrated fair to excellent appraiser agreement (0.57-0.79). Conclusions: This study represents the first systematic evaluation of national-level guidelines for determining medical fitness to drive. There is substantive variability in the quality of these guidelines, and rigour of development was a relative weakness. There is a need for rigorous, empirically derived guidance for physicians and licensing authorities when assessing driving in the medically ill. [ABSTRACT FROM AUTHOR]

We report on CO (J = 2 → 1) mapping with the IRAM 30-m HEtrodyne Receiver Array (HERA) of CGCG 97-079, an irregular galaxy in the merging galaxy cluster Abell 1367 (z = 0.022). We find that ~80 per cent of the detected CO (J = 2 → 1) is projected within a 16 arcsec² (6.5 kpc²) region to the north and west of the optical/NIR centre, with the intensity maximum offset ~10 arcsec (4 kpc) NW of the optical/NIR centre and ~7 arcsec (3 kpc) south-east of the H I intensity maximum. Evolutionary synthesis models indicate CGCG 97-079 experienced a burst of star formation ~108 yr ago, most likely triggered by a tidal interaction with CGCG 97-073. For CGCG 97-079 we deduce an infall velocity to the cluster of ~1000 km s−1 and moderate ram pressure (Pram ≈ 10−11 dyne cm−2). The observed offset in CGCG 97-079 of the highest density H I and CO (J = 2 → 1) from the stellar components has not previously been observed in galaxies currently undergoing ram pressure stripping, although previous detailed studies of gas morphology and kinematics during ram pressure stripping were restricted to significantly more massive galaxies with deeper gravitational potential wells. We conclude the observed cold gas density maxima offsets are most likely the result of ram pressure and/or the high-speed tidal interaction with CGCG 97-073. However ram pressure stripping is likely to be playing a major role in the perturbation of lower density gas. [ABSTRACT FROM AUTHOR]

We report on CO (J = 2 → 1) mapping with the IRAM 30-m HEtrodyne Receiver Array (HERA) of CGCG 97-079, an irregular galaxy in the merging galaxy cluster Abell 1367 (z = 0.022). We find that â80 per cent of the detected CO (J = 2 → 1) is projected within a 16 arcsec2 (6.5 kpc2) region to the north and west of the optical/NIR centre, with the intensity maximum offset â10 arcsec (4 kpc) NW of the optical/NIR centre and â7 arcsec (3 kpc) south-east of the HI intensity maximum. Evolutionary synthesis models indicate CGCG 97- 079 experienced a burst of star formation â108 yr ago, most likely triggered by a tidal interaction with CGCG 97-073. For CGCG 97-079 we deduce an infall velocity to the cluster of â1000 km sâ'1 and moderate ram pressure (Pram â 10â'11 dyne cmâ'2). The observed offset in CGCG 97-079 of the highest density HI and CO (J = 2→1) from the stellar components has not previously been observed in galaxies currently undergoing ram pressure stripping, although previous detailed studies of gas morphology and kinematics during ram pressure stripping were restricted to significantly more massive galaxies with deeper gravitational potential wells. We conclude the observed cold gas density maxima offsets are most likely the result of ram pressure and/or the high-speed tidal interaction with CGCG 97-073. However ram pressure stripping is likely to be playing a major role in the perturbation of lower density gas. [ABSTRACT FROM AUTHOR]

Persistent cytomegalovirus (CMV) infection has been suggested to be a major driving force in the immune deterioration and an underlying source of age-related diseases in the elderly. CMV antibody titers are associated with lower responses to vaccination, cardiovascular diseases, frailty, and mortality. CMV infection is also associated with shorter T-cell telomeres and replicative senescence. Although an age-related deregulation of CMV-specific T-cell responses could be an underlying cause of the relationship between CMV and immune defects, strong and polyfunctional responses are observed in elderly individuals, casting uncertainty on their direct role in age-related immune frailty. In this study, we longitudinally followed a cohort of healthy donors aged over 50 years, assessing their mortality rates and time to death during a 2-year period. Specific T-cell responses to the immunodominant antigen pp65 (IFNγ, TNFα, IL2, MIP1α, CD107a, and perforin production) were analyzed at the beginning of the 2-year observation period. A cytotoxic CD8 pp65-specific T-cell response, without cytokine or chemokine coexpression, was independently associated with all-cause mortality in these elderly individuals. This pp65-specific CD8 T-cell response could be a useful tool to identify individuals with depressed immune function and a higher risk of death. [ABSTRACT FROM AUTHOR]

Although WASP-14 b is one of the most massive and densest exoplanets on a tight and eccentric orbit, it has never been a target of photometric follow-up monitoring or dedicated observing campaigns. We report on new photometric transit observations of WASP-14 b obtained within the framework of Transit Timing Variations @ Young Exoplanet Transit Initiative (TTV@YETI). We collected 19 light curves of 13 individual transit events using six telescopes located in five observatories distributed in Europe and Asia. From light-curve modelling, we determined the planetary, stellar, and geometrical properties of the system and found them in agreement with the values from the discovery paper. A test of the robustness of the transit times revealed that in case of a non-reproducible transit shape the uncertainties may be underestimated even with a wavelet-based error estimation methods. For the timing analysis, we included two publicly available transit times from 2007 and 2009. The long observation period of seven years (2007?2013) allowed us to refine the transit ephemeris. We derived an orbital period 1.2 s longer and 10 times more precise than the one given in the discovery paper. We found no significant periodic signal in the timing-residuals and, hence, no evidence for TTV in the system. [ABSTRACT FROM AUTHOR]

Objective Thyroid hormones (THs) are crucial for the correct maturation of the CNS and the neurodevelopment of the child. We aimed to investigate the association of TSH and free thyroxine (FT4) levels with cognitive functioning in children from the INMA-Granada cohort studied during their follow-up at the age of 9-11 years. Design We evaluated 300 children from the original cohort, which comprised 668 eligible mother-son pairs recruited at birth from 2000 to 2002 in Granada (Spain). Methods FT4 and TSH concentrations were measured, and cognitive development was assessed using neuropsychological tests (n=187). Children with chronic disease related to thyroid function and/or cognitive development were excluded. Results Median TSH and FT4 levels were 3.1μIU/ml and 1.2ng/dl respectively. In multivariable regression analyses adjusted for maternal and child characteristics, children with TSH levels in the top tertile had worse verbal comprehension and immediate and long-term recall. Children with FT4 levels in the top tertile had better attention and lower impulsivity and were at a lower risk of scoring below the 20th percentile in intelligence quotient (OR=0.24; 95% CI=0.08-0.74; P=0.013) and in abstract reasoning ability (OR=0.28; 95% CI=0.09-0.88; P=0.029). Conclusion Our findings indicate that circulating THs and TSH may in the top tertile have an impact on cognitive functions; thus, higher TSH slightly but significantly increased the risk of a lower score in certain neuropsychological tests. [ABSTRACT FROM AUTHOR]

Background Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known. Methods We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. Results Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls. Conclusions Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART. [ABSTRACT FROM PUBLISHER]

Activating transcription factor 5 (ATF5) is a basic-leucine-zipper transcription factor of the ATF/CREB family. The Atf5 gene generates two transcripts, Atf5α and Atf5β, of which Atf5α is known to be selectively translated upon endoplasmic reticulum stress response in non-neuronal cells. ATF5 is highly expressed in the developing brain where it modulates proliferation of neural progenitor cells. These cells show a high level of ATF5 that has to decrease to allow them to differentiate into mature neurons or glial cells. This has led to the extended notion that differentiated neural cells do not express ATF5 unless they undergo tumourigenic transformation. However, no systematic analysis of the distribution of ATF5 in adult brain or of its potential role in neuronal endoplasmic reticulum stress response has been reported. By immunostaining here we confirm highest ATF5 levels in neuroprogenitor cells of the embryonic and adult subventricular zone but also found ATF5 in a large variety of neurons in adult mouse brain. By combining Atf5 in situ hybridization and immunohistochemistry for the neuronal marker NeuN we further confirmed Atf5 messenger RNA in adult mouse neurons. Quantitative reverse transcriptase polymerase chain reaction demonstrated that Atf5α is the most abundant transcript in adult mouse encephalon and injection of the endoplasmic reticulum stress inducer tunicamycin into adult mouse brain increased neuronal ATF5 levels. Accordingly, ATF5 levels increased in hippocampal neurons of a mouse model of status epilepticus triggered by intra-amygdala injection of kainic acid, which leads to abnormal hippocampal neuronal activity and endoplasmic reticulum stress. Interestingly, ATF5 upregulation occurred mainly in hippocampal neuronal fields that do not undergo apoptosis in this status epilepticus model such as CA1 and dentate gyrus, thus suggesting a neuroprotective role. This was confirmed in a primary neuronal culture model in which ATF5 overexpression resulted in decreased endoplasmic reticulum stress-induced apoptosis and the opposite result was achieved by Atf5 RNA interference. Furthermore, in vivo administration of the eIF2α phosphatase inhibitor salubrinal resulted in increased ATF5 hippocampal levels and attenuated status epilepticus-induced neuronal death in the vulnerable CA3 subfield. In good agreement with the neuroprotective effect of increased ATF5, we found that apoptosis-resistant epileptogenic foci from patients with temporal lobe epilepsy also showed increased levels of ATF5. Thus, our results demonstrate that adult neurons express ATF5 and that they increase its levels upon endoplasmic reticulum stress as a pro-survival mechanism, thus opening a new field for neuroprotective strategies focused on ATF5 modulation. [ABSTRACT FROM AUTHOR]

Objectives Hepatitis C virus (HCV) antiviral therapy might lead to decreased chronic immune activation and endothelial dysfunction associated with cardiovascular risk. The aim was to evaluate the effect of HCV eradication on serum markers of inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients. Methods We carried out a retrospective study of 69 HIV/HCV co-infected patients on interferon (IFN)-α plus ribavirin. In addition, 47 HIV-infected subjects were selected as a control group. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Tumour necrosis factor (TNF) receptor-1 (TNF-R1), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured using a multiplex immunoassay kit. Results HIV/HCV co-infected patients had higher values of soluble TNF-R1 (sTNF-R1), sE-selectin and sICAM-1 than HIV mono-infected patients (P < 0.05). SVR patients had a decrease in sTNF-R1, sP-selectin, sE-selectin and sICAM-1 during anti-HCV treatment (P < 0.05) and, at the end of treatment, SVR patients had lower values of sTNF-R1, sE-selectin and sVCAM-1 than non-responder patients (P < 0.05), although the values of sTNF-R1, sP-selectin, sE-selectin and sICAM-1 remained higher than in HIV mono-infected patients (P < 0.05). Moreover, we found a significant positive relationship between an increase in sTNF-R1 and increases in sP-selectin, sE-selectin and sICAM-1 during anti-HCV therapy. Conclusions Chronic hepatitis C infection induces alterations of markers of inflammation and endothelial dysfunction. Eradication of HCV, following IFN-α and ribavirin therapy, reduces immune activation as well as markers of inflammation and endothelial dysfunction. [ABSTRACT FROM PUBLISHER]

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-beta responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-beta non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-beta, and type I interferon-regulated genes may be used as response markers in interferon-beta treatment. [ABSTRACT FROM AUTHOR]

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-β in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-β for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-β responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-β non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-β, and type I interferon-regulated genes may be used as response markers in interferon-β treatment. [ABSTRACT FROM PUBLISHER]

CD160/BY55 is a glucosyl-phosphatidylinositol (GPI)-anchored cell membrane receptor that is expressed primarily in natural killer (NK) cells. Its presence in CD8+ T lymphocytes is considered to be a marker of cytotoxic activity, although there are few data in this regard. In the present work, we analysed the expression of CD160 in subpopulations of cytomegalovirus (CMV)-specific CD8+ T cells. Subpopulations were defined by CD28 and CD57 expression and exhibited varying degrees of differentiation and cytotoxic potential, as evaluated by the expression of perforin, interferon (IFN)-γ and interleukin (IL)-7Rα/CD127. We included subjects with different intensities of anti-viral immune response. Results showed that the terminally differentiated CD28– CD57+ subset displaying the highest level of perforin expressed CD160 at a level similar to that of memory CD28+ CD57–perforin– cells. A comparison of the expression of perforin in CD160+ cells versus CD160– cells showed that expression was significantly higher in the absence of CD160. Interestingly, the CMV-specific CD8+ T cell subset from a patient with ongoing CMV reactivation did not begin to express CD160 until day +92 of the follow-up period. Taken together, our data show that CD160 cannot be considered a cytotoxic marker in CMV-specific CD8+ T cells. [ABSTRACT FROM AUTHOR]

Aims: To assess the inhibitory activity on Gram-positive and Gram-negative bacteria of several species of enterococci recovered from a natural corn silage. Methods and Results: The inhibitory activity of strains of Enterococcus faecalis (58), Enterococcus faecium (35), Enterococcus gallinarum (3) and Enterococcus casseliflavus (4) were studied employing indicator strains from various sources (clinical, food and ATCC). Enterococcus faecalis MR99, the only strain with inhibitory activity, inhibited other enterococci, Listeria spp., Staphylococcus aureus, Clostridium spp., Bacillus spp., Escherichia coli, Shigella sonnei and Shigella flexneri. The bacterium contained only one conjugative pheromone-responsive plasmid. The partially chromatography-purified MR99 enterocin (PPE) had a molecular weight of approx. 5000 Da and a pI of 6·2, was sensitive to proteolytic enzymes and could be extracted in benzene and butanol. It appeared stable to adjustment of pH 4·0, 5·0, 6·0, 7·0 and 8·0 and was resistant to heat. Inactivation was at 15 min at 121°C. Enterocin MR99 was bactericidal on strains of Listeria monocytogenes, Staph. aureus, and bovine mastitis agents, it was bacteriostatic on E. coli. Although enterocins MR99 and AS48 have inhibitory activity on Gram-negative bacilli, PCR studies demonstrated a lack of relationship between them. Conclusions: The active component had a protein nature, was resistant to heat and presented a wide inhibitory spectrum. Significance and Impact of the Study: The biological properties of Ent. faecalis MR99 suggest that this strain merits further investigations so it can be applied in human and veterinary health programmes. [ABSTRACT FROM AUTHOR]

The objective of this study was to monitor the changes in the immune system of HIV-infected children with moderate or severe immunodeficiency after highly active antiretroviral therapy (HAART), comprising a follow-up study in 14 HIV-infected children on HAART at two time points separated approximately by 11·8 ± 0·4 (9·9; 15·4) months. HIV-infected children had significantly lower TREC levels than the control group, but 1 year after HAART the levels increased significantly ( P < 0·05). In contrast, viral load (VL) did not change significantly. A positive correlation between T cell receptor excision circle (TREC) levels and both CD4+ T cell absolute counts ( r = 0·558; P = 0·05) and percentages ( r = 0·625; P = 0·030) was found. During follow-up on HAART, the percentages and absolute counts of naive CD4+ and CD8+ T cell subsets were increased significantly ( P < 0·05). CD4+ CD45RAhi+ CD62L+, CD4+ CD45RA+ and CD4+ CD38+ percentages, and the CD8+ CD45RAhi+ CD62L+ counts reached similar values to the control group. Also, CD8+ CD45RO+ CD38+ and CD8+ CD45RO+ percentages, and CD8+ CD45RO+ CD38+ absolute counts ( P < 0·05) decreased with respect to the baseline. Lymphoproliferative responses to pokeweed mitogen (PWM) before HAART were lower in HIV-infected children than the control group, but they recovered to normal levels after a year on HAART. Tumour necrosis factor (TNF)- α and interferon (IFN)- γ production by PHA-activated peripheral blood mononuclear cells (PBMC) was lower before HAART ( P < 0·001), but reached similar levels to the control group 1 year after HAART. In HIV-infected children IgG, IgG1 and IgG3 plasma levels decreased significantly after HAART. The immune system reconstitution induced by HAART in HIV-infected children seems to be the consequence of decreased immune system activation and naive T cell reconstitution, mainly of thymic origin. [ABSTRACT FROM AUTHOR]

An observational study of children vertically infected with human immunodeficiency virus type 1 (HIV-1) was performed to determine the role of CD38 expression in CD8[sup+] T cells as prognostic marker of virological failure in children receiving HAART. We studied 42 children who were receiving antiretroviral therapy and who had an undetectable virus load (uVL), and we found a negative correlation between CD38 expression in CD8[sup+] T cells and the duration of uVL. We selected 17 HIV-1­infected children with CD38 values close to the baseline level (i.e., the first uVL achieved), and we distributed the children into 2 groups on the basis of median CD38 value in CD8[sup+] T cells. Children with CD38 values in CD8[sup+] T cells that were higher than the median had a higher incidence and relative risk of virological failure than did those with values lower than the median. In conclusion, we demonstrate for the first time that CD8[sup+]CD38[sup+] T cell count is a good prognostic marker of therapeutic failure in HIV-1­infected children. [ABSTRACT FROM AUTHOR]

An observational study was performed involving 95 children with vertically transmitted human immunodeficiency virus type 1 infection to assess the sustainability of undetectable viral loads (VLs) and increased CD4[sup+] T lymphocyte percentages after 48 months of highly active antiretroviral therapy (HAART). The median time to achieve a 10% increase in the CD4[sup+] T lymphocyte percentages was 11.01 months. The median time to achieve an undetectable VL was 6.4 months. At the end of the study, 64.2% of the children had achieved an undetectable VL. Of the patients with an initial VL of >3.6 log[sub10] copies/mL, 74.7% had a decrease in the VL of 1 log[sub10] copies/mL. By contrast, of the patients who presented with an initial VL of >4.6 log[sub10] copies/mL, 37.9% had a decrease of &gt2; log[sub10] copies/mL. Higher VL at baseline, antiretroviral therapy regimens received before HAART, and multiple drug switches while receiving antiretroviral therapy were all inversely associated with an undetectable VL. A CD 4[sup+] T lymphocyte percentage of gt;25% was directly associated with undetectable VL during the follow-up period. In conclusion, first-line HAART induces beneficial virological and immunological outcome responses in children. [ABSTRACT FROM AUTHOR]

SUMMARY The objective of this study was to study immune system status in long-term asymptomatic (LTA) HIV-1-infected children. A cross-sectional study was used, involving HIV-1-infected children over 7 years of age who were rated into two groups according to their clinical and immunological classification: (a) LTA: 7 asymptomatic HIV-1-infected children in A1; (b) Rapid progressor (RP): 14 age-matched C3 HIV-1-infected children. The control group consisted of 17 age-matched uninfected children. The characterization of CD4+ T-cell subsets was determined by three-colour flow cytometry. The proliferative response and cytokine production by activated peripheral blood T-cells were also measured. IL-7 levels were measured in serum. Thymic production of T-cells was quantified by TCR rearrangement excision circles (TRECs). The LTA children showed similar proliferative responses to PHA, PWM and anti-CD3+ anti-CD28, but lower responses to tetanus toxoid and streptokinase, in comparison with the controls but always higher responses in comparison with the RP group. The production of TNF-α and IFN-γ was similar in the LTA and control groups, and both were higher than the levels in the RP group. The LTA group showed a lower percentage of memory CD4+ T-cells (CD4+ CD45RO+, CD4+ CD45RA-CD62L+) than the control and RP groups. The LTA group also showed lower percentages of CD4+ CD7- cells than the controls. As for naïve CD4+ T-cells (CD4+ CD45RA+ CD62L+), CD4+ CD45RA+ and CD4+ CD62L+ cells, the LTA group showed higher values than the control and RP groups. The LTA group showed higher percentages of CD4+ HLA-DR+ CD38+ than the controls, but lower values than the RP group. In contrast, the LTA group had percentages of CD4+ HLA-DR-CD38+ T-cells higher than both the control and RP groups, whereas CD4+ CD38+ levels were only higher in the LTA group in comparison with the controls. CD4+ HLA-DR+ CD38- and CD4+ HLA-DR+ cell numbers were lower in the LTA group in... [ABSTRACT FROM AUTHOR]