Rectal cancer in Luxembourg : a national population-based data report, 1988–1998

BACKGROUND: Morphologic criteria which might help to support the need for a preventive strategy for early detection of rectal cancer were analysed. Population-based data on rectal adenomas with high-grade dysplastic changes (n = 199) and invasive adenocarcinomas (n = 912) registered by the national Morphologic Tumour Registry (MTR) and diagnosed in a central department of pathology in Luxembourg between 1988 and 1998 were considered. METHODS: The analysis concerned time trends in frequency, crude incidence, tumour-stage, the rectal "high-grade" adenoma/invasive adenocarcinoma-ratio and the survival rates. Histopathological tumour-stage parameters (UICC/AJCC, 1997) in a consecutive series of 641 resected rectal cancers and their relationship with the observed patient survival are investigated. RESULTS: The majority of invasive adenocarcinomas are diagnosed at a late stage (i.e. Stage II and III) into contrast with the highly significant increase (355 %) in frequency of rectal high-grade adenomas (Stage 0). During the two-time periods 1988–1992 and 1994–1998 Stage I and Stage IV-cases decreased by 11 % and 47 % respectively. Tumour-stage correlates with prognosis. The rectal high-grade adenoma / invasive adenocarcinoma-ratio improved significantly over the last five years. CONCLUSION: Over the study period, there has been a highly significant rise in the incidence of resected rectal adenomas with high-grade intraepithelial neoplasia. The ratio of early tumours to invasive cancers has risen while the numbers of colonoscopies and rectoscopies remained unchanged respectively decreased. As the number of advanced tumour-stages remained stable, mass-screening procedures focusing on the fifty to sixty age group should be reinforced

Lactococcus lactis strains delivering IL-10 protein or cDNA to the intestinal mucosa show anti-inflammatory properties in a TNBS-induced chronic colitis model

Interleukin-10 (IL-10) is the most important anti-inflammatory cytokine at intestinal level. Oral treatments with IL-10 are inefficient because of its sensitivity to the harsh conditions of the GI tract, and systemic treatments cause undesirable side effects. Our aim was to compare the protective effects of IL-10, delivered by recombinant lactoccoci using two novel expression systems, in a murine colitis model mimicking the relapsing nature of inflammatory bowel diseases. The first system is based on a stress-inducible promoter (pGroES/L) for the production and delivery of heterologous proteins in situ at mucosal surfaces, and the second allows the delivery to the host cells of an il-10 cDNA, harbored in a eukaryotic DNA expression vector (pValac). Colitis was induced in female BALB/c mice by intrarectal injection of TNBS. Mice that survived the challenge and recovered their body weight received one of the bacterial treatments or saline solution orally during 14 days. Colitis was reactivated 25 days after the first TNBS challenge with a second injection. Three days after colitis reactivation, cytokine profiles and inflammation in colon samples were evaluated. Animals receiving L. lactis delivering pGroES/L: il-10 or pValac: il-10 plasmids showed lower body weight loss and damage scores in their large intestines compared to inflamed non-treated mice. Both treatments also increased IL-10 concentration in the intestine, compared to the controls without treatment and maintained an increased ratio of IL-10/ pro-inflammatory cytokines. Our results confirm the protective effect of IL-10 delivered by L. lactis either as a protein or as a cDNA in a TNBS-induced chronic colitis model, and provides a step further in the use of genetically engineered bacteria as a valid system to deliver therapeutic molecules at mucosal level.Fil: del Carmen, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Martín, Rebeca. Institut National de la Recherche Agronomique; FranciaFil: Saraiva, Tessalia. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Zurita Turk, Meritxell. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Miyoshi, Anderson. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Azevedo, Vasco. Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas; BrasilFil: Langella, Philippe. Institut National de la Recherche Agronomique; FranciaFil: Bermúdez Humarán, Luis G.. Institut National de la Recherche Agronomique; FranciaFil: de Moreno, Maria Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; ArgentinaFil: Leblanc, Jean Guy Joseph. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Centro de Referencia para Lactobacilos; Argentina11th International Symposium on Lactic Acid Bacteria: Health, sustainability, diversity, and applicationEgmond aan ZeePaíses BajosFederation of European Microbiological SocietiesRoyal Netherlands Society for Microbiolog

An integrative in silico methodology for the identification of modulators of macrophage migration inhibitory factor (MIF) tautomerase activity

Macrophage migration inhibitory factor (MIF) is a major proinflammatory cytokine that has been increasingly implicated in the pathogenesis of several inflammatory, autoimmune, infectious and oncogenic diseases. Accumulating evidence suggests that the tautomerase activity of MIF plays a role in modulating some of its intra- and extra-cellular activities. Therefore, the identification and development of small-molecule inhibitors targeting the catalytic activity of MIF has emerged as an attractive and viable therapeutic strategy to attenuate its function in health and disease. Herein we report a novel virtual screening protocol for the discovery of new inhibitors of MIF's tautomerase activity. Our protocol takes into account the flexibility and dynamics of the catalytic site by coupling molecular dynamics (MD) simulations aimed at modeling the protein's flexibility in solution to (i) docking with FlexX, or (ii) docking with FlexX and pharmacophoric filtering with Unity. In addition, we applied in parallel a standalone docking using the new version of Surflex software. The three approaches were used to screen the ChemBridge chemical library and the inhibitory activity of the top-ranked 333 compound obtained from each approach (1000 compound in total) was assessed in vitro using the tautomerase assay. This biochemical validation process resulted in the identification of 12 novel MIF inhibitors corresponding to a 1.2% hit rate. Six of these hits came from Surflex docking; two from FlexX docking with MD simulations and four hits were identified with MDS and pharmacophore filtering with minimal overlap between the hits from each approach. Six hits were identified with IC50 values lower than 10 microM (three hits with IC50 lower than 1 microM); four were shown to be suicide inhibitors and act via covalent modification of the N-terminal catalytic residues Pro1. One additional inhibitor, N-phenyl-N-1,3,4-thiadiazol-2-yl-thiourea, (IC50=300 nM) was obtained from FlexX docking combined to pharmacophoric filtering on one of the eight MD structures. These results demonstrate the power of integrative in silico approaches in the discovery of new modulator of MIF's tautomerase activity. The chemical diversity and mode of action of these compounds suggest that they could be used as molecular probes to elucidate the functions and biology of MIF and as lead candidates in drug developments of anti-MIF drugs

Tropical and subtropical cloud transitions in weather and climate prediction models: The GCSS/WGNE pacific cross-section intercomparison (GPCI)

International audienceA model evaluation approach is proposed in which weather and climate prediction models are analyzed along a Pacific Ocean cross section, from the stratocumulus regions off the coast of California, across the shallow convection dominated trade winds, to the deep convection regions of the ITCZ-the Global Energy and Water Cycle Experiment Cloud System Study/Working Group on Numerical Experimentation (GCSS/WGNE) Pacific Cross-Section Intercomparison (GPCI). The main goal of GPCI is to evaluate and help understand and improve the representation of tropical and subtropical cloud processes in weather and climate prediction models. In this paper, a detailed analysis of cloud regime transitions along the cross section from the subtropics to the tropics for the season June-July-August of 1998 is presented. This GPCI study confirms many of the typical weather and climate prediction model problems in the representation of clouds: underestimation of clouds in the stratocumulus regime by most models with the corresponding consequences in terms of shortwave radiation biases; overestimation of clouds by the 40-yrECMWFRe-Analysis (ERA-40) in the deep tropics (in particular) with the corresponding impact in the outgoing longwave radiation; large spread between the different models in terms of cloud cover, liquid water path and shortwave radiation; significant differences between the models in terms of vertical cross sections of cloud properties (in particular), vertical velocity, and relative humidity. An alternative analysis of cloud cover mean statistics is proposed where sharp gradients in cloud cover along the GPCI transect are taken into account. This analysis shows that the negative cloud bias of some models and ERA-40 in the stratocumulus regions [as compared to the first International Satellite Cloud Climatology Project (ISCCP)] is associated not only with lower values of cloud cover in these regimes, but also with a stratocumulus-to-cumulus transition that occurs too early along the trade wind Lagrangian trajectory. Histograms of cloud cover along the cross section differ significantly between models. Some models exhibit a quasi-bimodal structure with cloud cover being either very large (close to 100%) or very small, while other models show a more continuous transition. The ISCCP observations suggest that reality is in-between these two extreme examples. These different patterns reflect the diverse nature of the cloud, boundary layer, and convection parameterizations in the participating weather and climate prediction models. © 2011 American Meteorological Society

Morphinofobia: the situation among the general population and health care professionals in North-Eastern Portugal

<p>Abstract</p> <p>Background</p> <p>Morphinofobia among the general population (GP) and among health care professionals (HP) is not without danger for the patients: it may lead to the inappropriate management of debilitating pain. The aim of our study was to explore among GP and HP the representation and attitudes concerning the use of morphine in health care.</p> <p>Methods</p> <p>A cross-sectional study was done among 412 HP (physicians and nurses) of the 4 hospitals and 10 community health centers of Beira Interior (Portugal)and among 193 persons of the GP randomly selected in public places. Opinions were collected through a translated self-administered questionnaire.</p> <p>Results</p> <p>A significant difference of opinion exists among GP and HP about the use of morphine. The word morphine first suggests drug to GP (36,2%) and analgesia to HP (32,9%.). The reasons for not using morphine most frequently cited are: for GP morphine use means advanced disease (56%), risk of addiction (50%), legal requirements (49,7%); for HP it means legal risks (56,3%) and adverse side effects of morphine such as somnolence - sedation (30,5%) The socio-demographic situation was correlated with the opinions about the use of morphine.</p> <p>Conclusions</p> <p>False beliefs about the use of morphine exist among the studied groups. There seems to be a need for developing information campaigns on pain management and the use of morphine targeting. Better training and more information of HP might also be needed.</p

A data-driven analysis of workers' earnings on Amazon Mechanical Turk

A growing number of people are working as part of on-line crowd work. Crowd work is often thought to be low wage work. However, we know little about the wage distribution in practice and what causes low/high earnings in this setting. We recorded 2,676 workers performing 3.8 million tasks on Amazon Mechanical Turk. Our task-level analysis revealed that workers earned a median hourly wage of only ~2 USD/h, and only 4% earned more than 7.25 USD/h. While the average requester pays more than 11 USD/h, lower-paying requesters post much more work. Our wage calculations are influenced by how unpaid work is accounted for, e.g., time spent searching for tasks, working on tasks that are rejected, and working on tasks that are ultimately not submitted. We further explore the characteristics of tasks and working patterns that yield higher hourly wages. Our analysis informs platform design and worker tools to create a more positive future for crowd work

Analysis of Blood Stem Cell Activity and Cystatin Gene Expression in a Mouse Model Presenting a Chromosomal Deletion Encompassing Csta and Stfa2l1

The cystatin protein superfamily is characterized by the presence of conserved sequences that display cysteine protease inhibitory activity (e.g., towards cathepsins). Type 1 and 2 cystatins are encoded by 25 genes of which 23 are grouped in 2 clusters localized on mouse chromosomes 16 and 2. The expression and essential roles of most of these genes in mouse development and hematopoiesis remain poorly characterized. In this study, we describe a set of quantitative real-time PCR assays and a global expression profile of cystatin genes in normal mouse tissues. Benefiting from our collection of DelES embryonic stem cell clones harboring large chromosomal deletions (to be reported elsewhere), we selected a clone in which a 95-kb region of chromosome 16 is missing (Del16qB3Δ/+). In this particular clone, 2 cystatin genes, namely Csta and Stfa2l1 are absent along with 2 other genes (Fam162a, Ccdc58) and associated intergenic regions. From this line, we established a new homozygous mutant mouse model (Del16qB3Δ/16qB3Δ) to assess the in vivo biological functions of the 2 deleted cystatins. Stfa2l1 gene expression is high in wild-type fetal liver, bone marrow, and spleen, while Csta is ubiquitously expressed. Homozygous Del16qB3Δ/16qB3Δ animals are phenotypically normal, fertile, and not overtly susceptible to spontaneous or irradiation-induced tumor formation. The hematopoietic stem and progenitor cell activity in these mutant mice are also normal. Interestingly, quantitative real-time PCR expression profiling reveals a marked increase in the expression levels of Stfa2l1/Csta phylogenetically-related genes (Stfa1, Stfa2, and Stfa3) in Del16qB3Δ/16qB3Δ hematopoietic tissues, suggesting that these candidate genes might be contributing to compensatory mechanisms. Overall, this study presents an optimized approach to globally monitor cystatin gene expression as well as a new mouse model deficient in Stfa2l1/Csta genes, expanding the available tools to dissect cystatin roles under normal and pathological conditions