Role of cyclooxygenase-2 in Trypanosoma cruzisurvival in the early stages of parasite host-cell interaction

Chagas disease, caused by the intracellular protozoan Trypanosoma cruzi, is a serious health problem in Latin America. During this parasitic infection, the heart is one of the major organs affected. The pathogenesis of tissue remodelling, particularly regarding cardiomyocyte behaviour after parasite infection and the molecular mechanisms that occur immediately following parasite entry into host cells are not yet completely understood. When cells are infected with T. cruzi, they develop an inflammatory response, in which cyclooxygenase-2 (COX-2) catalyses rate-limiting steps in the arachidonic acid pathway. However, how the parasite interaction modulates COX-2 activity is poorly understood. In this study, the H9c2 cell line was used as our model and we investigated cellular and biochemical aspects during the initial 48 h of parasitic infection. Oscillatory activity of COX-2 was observed, which correlated with the control of the pro-inflammatory environment in infected cells. Interestingly, subcellular trafficking was also verified, correlated with the control of Cox-2 mRNA or the activated COX-2 protein in cells, which is directly connected with the assemble of stress granules structures. Our collective findings suggest that in the very early stage of the T. cruzi-host cell interaction, the parasite is able to modulate the cellular metabolism in order to survives.

Influencia de un programa de actividad física en niños y adolescentes obesos con apnea del sueño; protocolo de estudio.

Recent studies show an alarming increase in the rate of overweight / obesity among the infant - juvenile population. Obesity in childhood is associated with a significant number of complications, such as sleep apnea syndrome, insulin resistance and type 2 diabetes, hypertension, cardiovascular disease and some cancers. It is estimated that the prevalence of sleep apnea in children is 2-3% in the general population, while in obese adolescents, varies between 13% and 66%, according to various studies. It is associated with impairment of neurocognitive function, behavior, cardiovascular system, metabolic disorders and growth. Sleep apnea is a serious public health problem that increases when children and adolescents are overweight or obese. We hypothesize that aerobic endurance exercise can be an effective treatment for obesity and apnea at the same time. The aim of this study was to determine the influence of physical activity in children and adolescents with overweight / obesity in sleep apnea. An observational, descriptive, prospective, longitudinal study will be carried out in children with sleep apnea and obesity. The universe will be made up of 60 children and adolescents aged between 10 and 18 years, attending the endocrinology service for suffering of obesity in the Hospital Clinico San Cecilio of Granada during the period September 2012-September 2013. The smple will consist of children and adolescents that meet these characteristics and to hom their arents/tutors have authorized through the informed consent. Sleep apnea in children wil be measured by polysomnography and sleep quality questionnaire. There will also be a nutritional assessment by a food frequency questionnaire and an anthropometric assessment. Among the expected results are the lower overweight and obesity in children through the physical activity program. To reduce apnea and to improve sleep quality

Health literacy [Document électronique] : an economic perspective and data for Switzerland. Part 2, A review of health literacy measures and a cost assessment of limited health literacy

Summary : 1. Measuring health literacy in Switzerland: a review of six surveys: 1.1 Comparison of questionnaires - 1.2 Measures of health literacy in Switzerland - 1.3 Discussion of Swiss data on HL - 1.4 Description of the six surveys: 1.4.1 Current health trends and health literacy in the Swiss population (gfs-UNIVOX), 1.4.2 Nutrition, physical exercise and body weight : opinions and perceptions of the Swiss population (USI), 1.4.3 Health Literacy in Switzerland (ISPMZ), 1.4.4 Swiss Health Survey (SHS), 1.4.5 Survey of Health, Ageing and Retirement in Europe (SHARE), 1.4.6 Adult literacy and life skills survey (ALL). - 2 . Economic costs of low health literacy in Switzerland: a rough calculation. Appendix: Screenshots cost model

The effect of colostrum source (goat vs. sheep) and timing of the first colostrum feeding (2h vs. 14h after birth) on body weight and immune status of artificially reared newborn lambs.

Several factors can affect lamb body weight (BW) and immune status during the first days of life, including colostrum source and timing of the first colostrum feeding. The aim of this study was to evaluate the effects of colostrum source (goat or sheep) and timing of the first colostrum feeding (2 or 14h after birth) on lamb BW and immune status. In this study, 40 lambs were removed from their dams at birth and randomly assigned into 4 groups of 10 lambs each. Lambs were subsequently fed at 2 or 14h after birth with goat or sheep colostrum. Blood samples and BW recording were performed before feeding. Blood plasma was used to measure the immunoglobulin concentration (IgG and IgM), chitotriosidase activity, and complement system activity (total and alternative pathways). In general, no differences in any of the measured variables were observed among the 4 groups, indicating that neither colostrum source nor timing of the first colostrum feeding had an effect on these variables. These findings may improve management on lamb farms that raise animals under artificial conditions, because our results indicate that it is not necessary to feed colostrum to lambs immediately after birth and that goat colostrum may be used to feed newborn lambs.

The subjectivist interpretation of probability and the problem of individualisation in forensic science

This paper presents and discusses further aspects of the subjectivist interpretation of probability (also known as the 'personalist' view of probabilities) as initiated in earlier forensic and legal literature. It shows that operational devices to elicit subjective probabilities - in particular the so-called scoring rules - provide additional arguments in support of the standpoint according to which categorical claims of forensic individualisation do not follow from a formal analysis under that view of probability theory.

The required beta cell research for improving treatment of type 2 diabetes.

In healthy individuals, insulin resistance is associated with physiological conditions such as pregnancy or body weight gain and triggers an increase in beta cell number and insulin secretion capacity to preserve normoglycaemia. Failure of this beta cell compensation capacity is a fundamental cause of diabetic hyperglycaemia. Incomplete understanding of the molecular mechanisms controlling the plasticity of adult beta cells mechanisms and how these cells fail during the pathogenesis of diabetes strongly limits the ability to develop new beta cell-specific therapies. Here, current knowledge of the signalling pathways controlling beta cell plasticity is reviewed, and possible directions for future research are discussed.

Patients' and physicians' preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a discrete choice experiment.

OBJECTIVE To assess Spanish and Portuguese patients' and physicians' preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects. METHODS An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model. RESULTS Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m(2), 41.8% received oral + injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: €68.14 [95% confidence interval: 54.55-85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: €54.80 [23.29-82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: €287.18 [95% confidence interval: 160.31-1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: €166.87 [88.63-843.09] and €154.30 [98.13-434.19], respectively). Physicians and patients were willing to pay €125.92 (73.30-622.75) and €24.28 (18.41-30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and €143.30 (73.39-543.62) and €42.74 (23.89-61.77) to avoid nausea. CONCLUSION Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively.

Changes in Body Composition in Anorexia Nervosa: Predictors of Recovery and Treatment Outcome.

The restoration of body composition (BC) parameters is considered to be one of the most important goals in the treatment of patients with anorexia nervosa (AN). However, little is known about differences between AN diagnostic subtypes [restricting (AN-R) and binge/purging (AN-BP)] and weekly changes in BC during refeeding treatment. Therefore, the main objectives of our study were twofold: 1) to assess the changes in BC throughout nutritional treatment in an AN sample and 2) to analyze predictors of BC changes during treatment, as well as predictors of treatment outcome. The whole sample comprised 261 participants [118 adult females with AN (70 AN-R vs. 48 AN-BP), and 143 healthy controls]. BC was measured weekly during 15 weeks of day-hospital treatment using bioelectrical impedance analysis (BIA). Assessment measures also included the Eating Disorders Inventory-2, as well as a number of other clinical indices. Overall, the results showed that AN-R and AN-BP patients statistically differed in all BC measures at admission. However, no significant time×group interaction was found for almost all BC parameters. Significant time×group interactions were only found for basal metabolic rate (p = .041) and body mass index (BMI) (p = .035). Multiple regression models showed that the best predictors of pre-post changes in BC parameters (namely fat-free mass, muscular mass, total body water and BMI) were the baseline values of BC parameters. Stepwise predictive logistic regressions showed that only BMI and age were significantly associated with outcome, but not with the percentage of body fat. In conclusion, these data suggest that although AN patients tended to restore all BC parameters during nutritional treatment, only AN-BP patients obtained the same fat mass values as healthy controls. Put succinctly, the best predictors of changes in BC were baseline BC values, which did not, however, seem to influence treatment outcome.

A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Influence of structural heterogeneities and of large scale topography on imbricate gravitational rock slope failures: New insights from 3-D physical modeling and geomorphological analysis

Initial topography and inherited structural discontinuities are known to play a dominant role in rock slope stability. Previous 2-D physical modeling results demonstrated that even if few preexisting fractures are activated/propagated during gravitational failure all of those heterogeneities had a great influence on mobilized volume and its kinematics. The question we address in the present study is to determine if such a result is also observed in 3-D. As in 2-D previous models we examine geologically stable model configuration, based upon the well documented landslide at Randa, Switzerland. The 3-D models consisted of a homogeneous material in which several fracture zones were introduced in order to study simplified but realistic configurations of discontinuities (e.g. based on natural example rather than a parametric study). Results showed that the type of gravitational failure (deep-seated landslide or sequential failure) and resulting slope morphology evolution are the result of the interplay of initial topography and inherited preexisting fractures (orientation and density). The three main results are i) the initial topography exerts a strong control on gravitational slope failure. Indeed in each tested configuration (even in the isotropic one without fractures) the model is affected by a rock slide, ii) the number of simulated fracture sets greatly influences the volume mobilized and its kinematics, and iii) the failure zone involved in the 1991 event is smaller than the results produced by the analog modeling. This failure may indicate that the zone mobilized in 1991 is potentially only a part of a larger deep-seated landslide and/or wider deep seated gravitational slope deformation.

2

The pharmacokinetic profile of imatinib has been assessed in healthy subjects and in population studies among thousands of patients with CML or GIST. Imatinib is rapidly and extensively absorbed from the GI tract, reaching a peak plasma concentration (Cmax) within 1-4 h following administration. Imatinib bioavailability is high (98%) and independent of food intake. Imatinib undergoes rapid and extensive distribution into tissues, with minimal penetration into the central nervous system. In the circulation, it is approximately 95% bound to plasma proteins, principally α1-acid glycoprotein (AGP) and albumin. Imatinib undergoes metabolism in the liver via the cytochrome P450 enzyme system (CYP), with CYP3A4 being the main isoenzyme involved. The N-desmethyl metabolite CGP74588 is the major circulating active metabolite. The typical elimination half-life for imatinib is approximately 14-22 h. Imatinib is characterized by large inter-individual pharmacokinetic variability, which reflects in a wide spread of concentrations observed under standard dosage. Besides adherence, several factors have been shown to influence this variability, especially demographic characteristics (sex, age, body weight and disease diagnosis), blood count characteristics, enzyme activity (mainly CYP3A4), drug interactions, activity of efflux transporters and plasma levels of AGP. Additionally, recent retrospective studies have shown that drug exposure, reflected in either the area under the concentration-time curve (AUC) or more conveniently the trough level (Cmin), correlates with treatment outcomes. Increased toxicity has been associated with high plasma levels, and impaired clinical efficacy with low plasma levels. While no upper concentration limit has been formally established, a lower limit for imatinib Cmin of about 1000 ng/mL has been proposed repeatedly for improving outcomes in CML and GIST patients. Imatinib is licensed for use in chronic phase CML and GIST at a fixed dose of 400 mg once daily (600 mg in some other indications) despite substantial pharmacokinetic variability caused by both genetic and acquired factors. The dose can be modified on an individual basis in cases of insufficient response or substantial toxic effects. Imatinib would, however, meet traditional criteria for a therapeutic drug monitoring (TDM) program: long-term therapy, measurability, high inter-individual but restricted intra-individual variability, limited pharmacokinetic predictability, effect of drug interactions, consistent association between concentration and response, suggested therapeutic threshold, reversibility of effect and absence of early markers of efficacy and toxic effects. Large-scale, evidence-based assessments of drug concentration monitoring are therefore still warranted for the personalization of imatinib treatment.

Assessment of particulate exposure and surface characteristics in association with urinary levels of 8-hydroxy-2'-deoxyguanosine, considered as marker of oxidative stress

Epidemiological studies have demonstrated that exposure to fine particles is associated to adverse health effects, including cancer, respiratory and cardiovascular diseases. However, mechanisms by which particles induce health effects remain unclear. According to one of the most investigated hypotheses, particles cause adverse effects through the production of reactive oxygen species (ROS), which are very hazardous compounds able to attack directly biological structures, including the DNA strand or the lipid bilayer of the cells. If the defense mechanisms, constituted of antioxidants, are not able to counter ROS, then these compounds will cause in the body a range of oxidation reactions called "oxidative stress". The aim of the present research project was to better understand mechanisms by which exposure to fine particles induces oxidative stress. The first point of this project was to check whether exposure to high levels of fine particles is directly linked to oxidative stress, and whether this oxidative stress is accompanied by the activation of the defense mechanisms (antioxidants). The second point was to study the role played by the particle surface characteristics in the oxidative stress process. For that purpose, a study was conducted in bus depots with the participation of 40 mechanics. First, occupational exposure to particles (PM4) and to other pollutants (NOx, O3) was measured over a two-day period. Then, urine samples of mechanics were collected in order to measure levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and antioxidants. 8OHdG is a molecule formed by the oxidation of DNA and allowing to assess the oxidative stress status of the mechanics. Finally, particles were collected on filters, and functional groups located on the particle surface were analyzed in the laboratory using a Knudsen flow reactor. This technique allows not only to quantify functional groups on the particle surface, but also to measure the reaction kinetics. Results obtained during the field campaign in bus depots showed that mechanics were exposed to rather low levels of PM4 (20-85 μg/m3) and of pollutants (NOx: 100-1000 ppb; O3: <15 ppb). However, despite this low exposure, urinary levels of the oxidative stress biomarker (8OHdG) increased significantly for non-smoking workers over a two-day period of shift. This oxidative stress was accompanied by an increase of antioxidants, indicating the activation of defense mechanisms. On the other hand, the analysis of functional groups on the particle surface showed important differences, depending on the workplace, the date and the activities of workers. The particle surface contained simultaneously antagonistic functional groups which did not undergo internal reactions (such as acids and bases), and was usually characterized by a high density of carbonyl functions and a low density of acidic sites. Reaction kinetics measured using the Knudsen flow reactor pointed out fast reactions of oxidizable groups and slow reactions of acidic sites. Several exposure parameters were significantly correlated with the increase of the oxidative stress status: the presence of acidic sites, carbonyl functions and oxidizable groups on the particle surface; reaction kinetics of functional groups on the particle surface; particulate iron and copper concentrations; and NOx concentration.