O crédito bancário

The aim of the present dissertation is the analysis of the regime established by Decree-Law No. 227/2012 of 25 October. Reflecting on the referred regime, as a measure to prevent and manage situations of failure to meet the obligations assumed by consumers, the study focuses on the plan of action for debt risk and the extrajudicial procedure to regularize situations of default. The main point is to analyze the purpose and the scope of the regime, and to discuss some key-concepts relevant to its application. In addition, another two figures presented in the regime of Decree-Law No. 227/2012 are considered, namely: the Credit Mediator and the Extrajudicial Network for Bank Clients Support, making reference to their role and the scope of their intervention. Finally, along the work on the present Decree-Law, the some international practices are also analyzed, making reference to the problem of financial illiteracy, and mentioning three foreign examples regarding the adopted solutions to the problem of different legal systems, with reference to consumers’ over-indebtedness.

Insulin secretion is regulated by the glucose-dependent production of islet beta cell macrophage migration inhibitory factor.

Macrophage migration inhibitory factor (MIF), originally identified as a cytokine secreted by T lymphocytes, was found recently to be both a pituitary hormone and a mediator released by immune cells in response to glucocorticoid stimulation. We report here that the insulin-secreting beta cell of the islets of Langerhans expresses MIF and that its production is regulated by glucose in a time- and concentration-dependent manner. MIF and insulin colocalize by immunocytochemistry within the secretory granules of the pancreatic islet beta cells, and once released, MIF appears to regulate insulin release in an autocrine fashion. In perifusion studies performed with isolated rat islets, immunoneutralization of MIF reduced the first and second phase of the glucose-induced insulin secretion response by 39% and 31%, respectively. Conversely, exogenously added recombinant MIF was found to potentiate insulin release. Constitutive expression of MIF antisense RNA in the insulin-secreting INS-1 cell line inhibited MIF protein synthesis and decreased significantly glucose-induced insulin release. MIF is therefore a glucose-dependent, islet cell product that regulates insulin secretion in a positive manner and may play an important role in carbohydrate metabolism.

Monocyte differentiation toward regulatory dendritic cells is not affected by respiratory syncytial virus-induced inflammatory mediators.

Airway epithelial cells were shown to drive the differentiation of monocytes into dendritic cells (DCs) with a suppressive phenotype. In this study, we investigated the impact of virus-induced inflammatory mediator production on the development of DCs. Monocyte differentiation into functional DCs, as reflected by the expression of CD11c, CD123, BDCA-4, and DC-SIGN and the capacity to activate T cells, was similar for respiratory syncytial virus (RSV)-infected and mock-infected BEAS-2B and A549 cells. RSV-conditioned culture media resulted in a partially mature DC phenotype, but failed to up-regulate CD80, CD83, CD86, and CCR7, and failed to release proinflammatory mediators upon Toll-like receptor (TLR) triggering. Nevertheless, these DCs were able to maintain an antiviral response by the release of Type I IFN. Collectively, these data indicate that the airway epithelium maintains an important suppressive DC phenotype under the inflammatory conditions induced by infection with RSV.

Dilated cardiomyopathy and impaired cardiac hypertrophic response to angiotensin II in mice lacking FGF-2.

FGF-2 has been implicated in the cardiac response to hypertrophic stimuli. Angiotensin II (Ang II) contributes to maintain elevated blood pressure in hypertensive individuals and exerts direct trophic effects on cardiac cells. However, the role of FGF-2 in Ang II-induced cardiac hypertrophy has not been established. Therefore, mice deficient in FGF-2 expression were studied using a model of Ang II-dependent hypertension and cardiac hypertrophy. Echocardiographic measurements show the presence of dilated cardiomyopathy in normotensive mice lacking FGF-2. Moreover, hypertensive mice without FGF-2 developed no compensatory cardiac hypertrophy. In wild-type mice, hypertrophy was associated with a stimulation of the c-Jun N-terminal kinase, the extracellular signal regulated kinase, and the p38 kinase pathways. In contrast, mitogen-activated protein kinase (MAPK) activation was markedly attenuated in FGF-2-deficient mice. In vitro, FGF-2 of fibroblast origin was demonstrated to be essential in the paracrine stimulation of MAPK activation in cardiomyocytes. Indeed, fibroblasts lacking FGF-2 expression have a defective capacity for releasing growth factors to induce hypertrophic responses in cardiomyocytes. Therefore, these results identify the cardiac fibroblast population as a primary integrator of hypertrophic stimuli in the heart, and suggest that FGF-2 is a crucial mediator of cardiac hypertrophy via autocrine/paracrine actions on cardiac cells.

B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation.

B and T lymphocyte attenuator (BTLA) is a negative regulator of T cell activation, but its function in vivo is not well characterized. Here we show that mice deficient in full-length BTLA or its ligand, herpesvirus entry mediator, had increased number of memory CD8(+) T cells. The memory CD8(+) T cell phenotype resulted from a T cell-intrinsic perturbation of the CD8(+) T cell pool. Naive BTLA-deficient CD8(+) T cells were more efficient than wild-type cells at generating memory in a competitive antigen-specific system. This effect was independent of the initial expansion of the responding antigen-specific T cell population. In addition, BTLA negatively regulated antigen-independent homeostatic expansion of CD4(+) and CD8(+) T cells. These results emphasize two central functions of BTLA in limiting T cell activity in vivo.

Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells.

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

Validation of the German version of the Career Adapt-Abilities Scale and its relation to orientations to happiness and work stress

Career adapt-ability has recently gained momentum as a psychosocial construct that not only has much to offer the field of career development, but also contributes to positive coping, adjustment and self-regulation through the four dimensions of concern, control, curiosity and confidence. The positive psychology movement, with concepts such as the orientations to happiness, explores the factors that contribute to human flourishing and optimum functioning. This research has two main contributions; 1) to validate a German version of the Career Adapt-Abilities Scale (CAAS), and 2) to extend the contribution of adapt-abilities to the field of work stress and explore its mediating capacity in the relation between orientations to happiness and work stress. We used a representative sample of the German-speaking Swiss working population including 1204 participants (49.8% women), aged between 26 and 56 (Mage = 42.04). Results indicated that the German version of the CAAS is valid, with overall high levels of model fit suggesting that the conceptual structure of career adapt-ability replicates well in this cultural context. Adapt-abilities showed a negative relationship to work stress, and a positive one with orientations to happiness. The engagement and pleasure scales of orientations to happiness also correlated negatively with work stress. Moreover, career adapt-ability mediates the relationship between orientations to happiness and work stress. In depth analysis of the mediating effect revealed that control is the only significant mediator. Thus control may be acting as a mechanism through which individuals attain their desired life at work subsequently contributing to reduced stress levels.

Monitoring of human CD4 T cell responses in metastatic melanoma and arthritic patients

SUMMARY : Detailed knowledge of the different components of the immune system is required for the development of new immunotherapeutic strategies. CD4 T lymphocytes represent a highly heterogeneous group of cells characterized by various profiles of cytokine production and effector vs. regulatory functions. They are central players in orchestrating adaptive immune responses: unbalances between the different subtypes can lead either to aggressive autoimmune disorders or can favour the uncontrolled growth of malignancies. In this study we focused on the characterization of human CD4 T cells in advanced stage melanoma patients as well as in patients affected by various forms of autoimmune inflammatory spondyloarthropathies. In melanoma patients we report that a population of FOXP3 CD4 T cells, known as regulatory T cells, is overrepresented in peripheral blood, and even more in tumor-infitrated lymph nodes as well as at tumor sites, as compared to healthy donors. In tumor-infiltrated lymph nodes, but not in normal lymph nodes or in peripheral blood, FOXP3 CD4 T cells feature a highly differentiated phenotype (CD45RA-CCR7+/-), which suggests for a recent encounter with their cognate antigen. FOXP3 CD4 T cells have been described to be an important component of the several known immune escape mechanisms. We demonstrated that FOXP3 CD4 T cells isolated from melanoma patients exert an in vitro suppressive action on autologous CD4 T cells, thus possibly inhibiting an efficient anti-tumor response. Next, we aimed to analyse CD4 T cells at antigen-specific level. In advanced stage melanoma patients, we identified for the first time, using pMHCII multimers, circulating CD4 T cells specific for the melanoma antigen Melan-A, presented by HLA-DQB1 *0602. Interestingly, in a cohort of melanoma patients enrolled in an immunotherapy trails consisting of injection of a Melan-A derived peptide, we did not observe signif cant variations in the ex vivo frequencies of Melan-A specific CD4 T cells, but important differences in the quality of the specific CD4 T cells. In fact, up to 50% of the ex vivo Melan-A/DQ6 specific CD4 T cells displayed a regulatory phenotype and were hypoproliferative before vaccination, while more effector, cytokine-secreting Melan-A/DQ6 specific CD4 T cells were observed after immunization. These observations suggest that peptide vaccination may favourably modify the balance between regulatory and effector tumor-specific CD4 T cells. Finally, we identified another subset of CD4 T cells as possible mediator of pathology in a group of human autoimmune spondyloarthropathies, namely Th17 cells. These cells were recently described to play a critical role in the pathogenesis of some marine models of autommunity. We document an elevated presence of circulating Th17 cells in two members of seronegative spondyloarthropathies, e.g. psoriatic arthritis and ankylosing spondylitis, while we do not observe increased frequencies of Th17 cells in peripheral blood of rheumatoid arthritic patients. In addition, Th17 cells with a more advanced differentiation state (CD45RA-CCR7-CD27-) and polyfunctionality (concomitant secretion of IL-17, IL-2 and TNFα) were observed exclusively in patients with seronegative spondylarthropathies. Together, our observations emphasize the importance of CD4 T cells in various diseases and suggest that immunotherapeutic approaches considering CD4 T cells as targets should be evaluated in the future.

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination.

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen-specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen-specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen-specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM-mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Is Internet use unhealthy? A cross-sectional study of adolescent Internet overuse.

OBJECTIVE: To assess whether problematic internet use is associated with somatic complaints and whether this association remains when checking for internet activity among a random sample of adolescents living in the canton of Vaud, Switzerland. METHODS: Cross-sectional survey of 3,067 8th graders (50.3% females) divided into average (n = 2,708) and problematic (n = 359) Internet users and compared for somatic complaints (backache, overweight, headaches, musculoskeletal pain, sleep problems and sight problems) controlling for sociodemographic and internet-related variables. Logistic regressions were performed for each complaint and for all of them simultaneously controlling variables significant at the bivariate level. RESULTS: At the multivariate level, when taken separately, problematic internet users were more likely to have a chronic condition (adjusted odds ratio [aOR] with 95% CI: 1.58 [1.11:2.23]) and to report back pain (aOR: 1.46 [1.04:2.05]), overweight (aOR: 1.74 [1.03:2.93]), musculoskeletal pain (aOR: 1.36 [1.00:1.84]) and sleep problems (aOR: 2.16 [1.62:2.88]). When considered in the full model, only sleep problems remained significant (aOR: 2.03 [1.50:2.74]). CONCLUSIONS: Our results confirm that problematic internet users report health problems more frequently, with lack of sleep being the most strongly associated and seeming to act as mediator regarding the other ones. Clinicians should remember to screen for excessive internet use their patients complaining of sleep-related problems, back or musculoskeletal pain or overweight. Clinicians should advise parents to limit the amount of time their adolescent children can spend online for leisure activities. Furthermore, limiting the number of devices used to connect to the internet could help warrant enough sleeping time.

Risk perception, emotion regulation and impulsivity as predictors of risk behaviours among adolescents in Switzerland

The purpose of this study was to explore the frequency of risk behaviours among Swiss adolescents and their links with risk perception, impulsivity and emotion regulation abilities, operationalized with the concepts of alexithymia and emo- tional openness. We recruited 144 subjects (aged 14-20), who completed the Risk Involvement and Perception Scale (RIPS-R), the UPPS Impulsive Behavior Scale, the 20-item Toronto Alexithymia Scale (TAS-20), and the 20-item Dimensions of Openness to Emotional Experiences (DOE-20) questionnaire. Findings revealed that a greater perception of benefits and a higher level of sensation seeking were associated with more involvement in risk behaviours, which are essentially socially accepted behaviours. Notably, the path model indicated that the perception of benefits was a mediator in the relationship between sensation seeking and risk behaviours. The results add to the psychological understanding of factors associated with risk behaviours in adolescence. The limitations and implications of these results for developmental theories, research, and prevention are stated.

The study of ligand binding specificities of the lipid binding proteins : recombinant human a-tocopherol transport protein (a-ttp), supernatant protein factor (spf) and S. cerevisiae Sec 14p for vitamin e (rrr-a-tocopherol) and other hydrophobic ligands.

One of the various functions of proteins in biological systems is the transport of small molecules, for this purpose proteins have naturally evolved special mechanisms to allow both ligand binding and its subsequent release to a target site; a process fundamental to many biological processes. Transport of Vitamin E (a-tocopherol), a lipid soluble antioxidant, to membranes helps in the protection of polyunsaturated fatty acids against peroxidative damage. In this research, the ligand binding characteristics of several members of the CRALTRIO family of lipid binding proteins was examined; the recombinant human a-Tocopherol Transfer Protein (a-TIP), Supernatant Protein Factor (SPF)ffocopherol Associated Protein (TAP), Cellular Retinaldehyde Binding Protein (CRALBP) and the phosphatidylinositol transfer protein from S. cerevisiae Sec 14p. Recombinant Sec 14p was expressed and purified from E. coli for comparison of tocopherol binding to the two other recombinant proteins postulated to traffic a-tocopherol. Competitive binding assays using [3H]-a-tocopherol and Lipidex-l000 resin allowed determination of the dissociation constants ~) of the CRAL-TRIO proteins for a-tocopherol and - 20 hydrophobic ligands for evaluation of the possible biological relevance of the binding interactions observed. The KIs (nM) for RRR-a-tocopherol are: a-TIP: 25.0, Sec 14p: 373, CRALBP: 528 and SPFffAP: 615. This indicates that all proteins recognize tocopherol but not with the same affinity. Sec 14p bound its native ligand PI with a KI of381 whereas SPFffAP bound PI (216) and y-tocopherol (268) similarly in contrast to the preferential binding ofRRR-a-tocopherol by a-TIP. Efforts to adequately represent biologically active SPFff AP involved investigation of tocopherol binding for several different recombinant proteins derived from different constructs and in the presence of different potential modulators (Ca+2, Mg+2, GTP and GDP); none of these conditions enhanced or inhibited a-tocopherol binding to SPF. This work suggests that only aTTP serves as the physiological mediator of a-tocopherol, yet structural homology between proteins allows common recognition of similar ligand features. In addition, several photo-affmity analogs of a-tocopherol were evaluated for their potential utility in further elucidation of a-TTP function or identification of novel tocopherol binding proteins.

An international investigation on the validity of the CSAPPA scale in screening for developmental coordination disorder /

The main objective of the present investigation was to continue the research initiated by Hay and colleagues (2004) in examining the efficacy of the Children's Self-Perceptions of Adequacy in and Predilection for Physical Activity (CSAPPA) scale as a proxy for the short form of the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP-SF) in screening for Developmental Coordination Disorder (DCD) in children. To better appreciate DCD knowledge outside Canada, the measurements of this investigation were expanded in Greece. A translated Greek CSAPP A scale and the BOTMP-SF were administered for the first time in Greek children. A second objective was to investigate the relationship between DCD and various risk factors of coronary artery disease (CAD) in Canadian and Greek children. A sample of 591 (Ms=322; Fs=269) Canadian and 392 (Ms=211; Fs=181) Greek children, aged 9 to 13 years, consented to the BOTMP-SF, CSAPP A Scale, participation in physical activity questionnaire, Leger 20-meter Multistage Shuttle Run test, and body fat using bioelectric impedance. Prevalence of DCD in Canada and Greece was 8% and 19%, respectively. Significant agreement (pmediator in the clumsiness-aerobic fitness relationship. It is concluded that the CSAPPA scale is an accurate, practical, and inexpensive screening tool for DCD, and that motoric competence is associated with aerobic fitness through physical activity participation.

Stress, social support, and health risk behaviours as mediators of the forgiveness-health relation /

The mediating roles of stress, social support, and health risk behaviours in the relationships between dispositional forgiveness and mental and physical health were examined. Participants were 748 undergraduate students (554 women, 194 men) entering their first year of studies at Brock University. Participants, ranging in age from 17 to 25 years, completed the Brock University First Year Health Study and were provided monetary compensation. Dispositional forgiveness, stress, social support, health risk behaviours, mental health, and physical health were measured using self-report methods. The data were analyzed separately for women and men because there were significant mean differences on many of the study'S variables. Analyses revealed that the mediated relationships between dispositional forgiveness and health were generally stronger for women than men. Stress was the most robust mediator of the forgiveness-health relation for both women and men. The only health risk behaviour that mediated the forgivenesshealth relation was physical fitness and this result was found for women only. Social support mediated several of the relationships between forgiveness and health but not others. Results were discussed with reference to the literature on forgiveness and health. Several directions for future research were offered, such as conducting longitudinal research designs to assess the direction of causality better, investigating moderator variables of the forgiveness-health relation, and building models, which incorporate multiple mediators using structural equation modelling techniques.

The link between extracurricular activities and academic achievement for youth in grades 5 and 7 /

This study examined the link between involvement in extracurricular activities and academic success for 504 youth in grades 5 and 7, using the first-year survey data from a longitudinal study conducted by Youth Lifestyle Choices-Community University Research Alliance (YLC-CURA). Specifically, the study investigated whether a linear or curvilinear relation existed between extracurricular activities and academic achievement for both in- and out-of-school activities. It was hypothesized that stress may be a possible mediator in the link between extracurricular activities and achievement Results indicated that students in grades 5 and 7 were involved in club and sport activities both inside and outside of school at fairly equal fi-equencies, with a mean frequency of approximately once a month. The hypothesis that a positive relation j between in- and out-of-school extracurricular activities and achievement was supported. The hypothesis that a curvilinear relation would exist between extracurricular activities and achievement was only supported for out-of-school activities. This finding supports the argument that too much or too little involvement in out-of-school activities is related negatively to a student's academic success; however, a moderate amount of involvement appears to be positive. The hypothesis that there would be a relation between involvement in extracurricular activities and stress level for both in-school and out-ofschool activities was not supported. Results were discussed in terms of educational implications and community resources for extracurricular activities.