The Relationship Between Function and Disease Activity as Measured by the HAQ and DAS28 Varies Over Time and by Rheumatoid Factor Status in Early Inflammatory Arthritis (EIA). Results from the CATCH Cohort§

Objective: To investigate the relationship between function and disease activity in early inflammatory arthritis (EIA). Methods: Canadian Early Arthritis Cohort (CATCH) (n=1143) is a multi-site EIA cohort. Correlations between the Health Assessment Questionnaire Disability Index (HAQ) and DAS28 were done at every 3 months for the first year and then at 18 and 24 months. We also investigated the relationship between HAQ and DAS28 by age (<65 versus ≥65) and RF (positive vs negative). Results: Mean HAQ and DAS28 scores were highest at the initial visit with HAQ decreasing over 24 months from a baseline of 0.94 to 0.40 and DAS28 scores decreasing from 4.54 to 2.29. All correlations between HAQ and DAS28 were significant at all time points (p<0.01). The correlations between HAQ and DAS28 were variable over time. The strongest correlation between HAQ and DAS28 occurred at initial visit (most DMARD naive) (n=1,143) and 18 months (r=0.57, n=321) and 24 months (r=0.59, n=214). The baseline correlation between HAQ and DAS28 was significantly different than correlations obtained at 3, 6, and 12 months (p=0.02, 0.01, and 0.01, respectively). Age did not change the association between HAQ and DAS28 {<65 years old (r=0.50, n=868) versus ≥65 (r=0.48, n=254), p=0.49}. The correlation between HAQ and DAS28 was stronger with RF+ patients (r=0.63, n=636) vs RF negative (r=0.47, n=477), p=0.0043 Conclusion: Over 2 years in EIA, HAQ and DAS both improved; correlations at time points were different over 2 years and RF status affected the correlations

Squelette homotopique 3D pour le traitement et l'analyse du ventricule gauche en SPECT

Des images tomoscintigraphiques sont la représentation 3D de la distribution d'un traceur dans le ventricule gauche (VG). Le but de notre étude est de réussir à quantifier les défauts de fixations (zones d'atténuation) représentatifs d'une pathologie. Le squelette 3D du VG est utilisé pour reconstituer la forme originale du VG. Pour combler les lacunes liées aux pathologies, le squelette est complété conformément à un modèle. Un algorithme fondé sur la théorie de l'incertain (logique floue) utilise le squelette ainsi complété pour générer une nouvelle image avec un contraste plus élevé. Cette nouvelle image peut être plus facilement segmentée, et le VG est considéré dans son intégralité. Le VG peut alors être entièrement quantifié

Neuroethical issues in pharmacological cognitive enhancement.

This is the published manuscript. It is available online from the Wiley in Wiley Interdisciplinary Reviews: Cognitive Science here: http://onlinelibrary.wiley.com/doi/10.1002/wcs.1306/abstract;jsessionid=05002026F7F8502EFC9A9553EC8CE45C.f03t02.UNLABELLED: Neuroethics is an emerging field that in general deals with the ethics of neuroscience and the neuroscience of ethics. In particular, it is concerned with the ethical issues in the translation of neuroscience to clinical practice and in the public domain. Numerous ethical issues arise when healthy individuals use pharmacological substances known as pharmacological cognitive enhancers (PCEs) for non-medical purposes in order to boost higher-order cognitive processes such as memory, attention, and executive functions. However, information regarding their actual use, benefits, and harms to healthy individuals is currently lacking. Neuroethical issues that arise from their use include the unknown side effects that are associated with these drugs, concerns about the modification of authenticity and personhood, and as a result of inequality of access to these drugs, the lack of distributive justice and competitive fairness that they may cause in society. Healthy individuals might be coerced by social institutions that force them to take these drugs to function better. These drugs might enable or hinder healthy individuals to gain better moral and self-understanding and autonomy. However, how these drugs might achieve this still remains speculative and unknown. Hence, before concrete policy decisions are made, the cognitive effects of these drugs should be determined. The initiation of accurate surveys to determine the actual usage of these drugs by healthy individuals from different sections of the society is proposed. In addition, robust empirical research need to be conducted to delineate not only whether or not these drugs modify complex higher-order cognitive processes but also how they might alter important human virtues such as empathy, moral reasoning, creativity, and motivation in healthy individuals. WIREs Cogn Sci 2014, 5:533-549. doi: 10.1002/wcs.1306 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article

Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity

Abstract Introduction Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives. Methods Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry. Results We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait. Conclusions The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity

Ribonucleoprotein Particles Containing Non-Coding Y RNAs, Ro60, La and Nucleolin Are Not Required for Y RNA Function in DNA Replication

BACKGROUND: Ro ribonucleoprotein particles (Ro RNPs) consist of a non-coding Y RNA bound by Ro60, La and possibly other proteins. The physiological function of Ro RNPs is controversial as divergent functions have been reported for its different constituents. We have recently shown that Y RNAs are essential for the initiation of mammalian chromosomal DNA replication, whereas Ro RNPs are implicated in RNA stability and RNA quality control. Therefore, we investigate here the functional consequences of RNP formation between Ro60, La and nucleolin proteins with hY RNAs for human chromosomal DNA replication. METHODOLOGY/PRINCIPAL FINDINGS: We first immunoprecipitated Ro60, La and nucleolin together with associated hY RNAs from HeLa cytosolic cell extract, and analysed the protein and RNA compositions of these precipitated RNPs by Western blotting and quantitative RT-PCR. We found that Y RNAs exist in several RNP complexes. One RNP comprises Ro60, La and hY RNA, and a different RNP comprises nucleolin and hY RNA. In addition about 50% of the Y RNAs in the extract are present outside of these two RNPs. Next, we immunodepleted these RNP complexes from the cytosolic extract and tested the ability of the depleted extracts to reconstitute DNA replication in a human cell-free system. We found that depletion of these RNP complexes from the cytosolic extract does not inhibit DNA replication in vitro. Finally, we tested if an excess of recombinant pure Ro or La protein inhibits Y RNA-dependent DNA replication in this cell-free system. We found that Ro60 and La proteins do not inhibit DNA replication in vitro. CONCLUSIONS/SIGNIFICANCE: We conclude that RNPs containing hY RNAs and Ro60, La or nucleolin are not required for the function of hY RNAs in chromosomal DNA replication in a human cell-free system, which can be mediated by Y RNAs outside of these RNPs. These data suggest that Y RNAs can support different cellular functions depending on associated proteins

PAR1 is selectively over expressed in high grade breast cancer patients: a cohort study

<p>Abstract</p> <p>Background</p> <p>The protease-activated receptor (PAR1) expression is correlated with the degree of invasiveness in cell lines. Nevertheless it has never been directed involved in breast cancer patients progression. The aim of this study was to determine whether PAR1 expression could be used as predictor of metastases and mortality.</p> <p>Methods</p> <p>In a cohort of patients with infiltrating ductal carcinoma studied longitudinally since 1996 and until 2007, PAR1 over-expression was assessed by immunoblotting, immunohistochemistry, and flow citometry. Chi-square and log rank tests were used to determine whether there was a statistical association between PAR1 overexpression and metastases, mortality, and survival. Multivariate analysis was performed including HER1, stage, ER and nodes status to evaluate PAR1 as an independent prognostic factor.</p> <p>Results</p> <p>Follow up was 95 months (range: 2–130 months). We assayed PAR1 in a cohort of patients composed of 136 patients; we found PAR1 expression assayed by immunoblotting was selectively associated with high grade patients (50 cases of the study cohort; P = 0.001). Twenty-nine of 50 (58%) patients overexpressed PAR1, and 23 of these (46%) developed metastases. HER1, stage, ER and PAR1 overexpression were robustly correlated (Cox regression, P = 0.002, P = 0.024 and P = 0.002 respectively). Twenty-one of the 50 patients (42%) expressed both receptors (PAR1 and HER1 P = 0.0004). We also found a statistically significant correlation between PAR1 overexpression and increased mortality (P = 0.0001) and development of metastases (P = 0.0009).</p> <p>Conclusion</p> <p>Our data suggest PAR1 overexpression may be involved in the development of metastases in breast cancer patient and is associated with undifferentiated cellular progression of the tumor. Further studies are needed to understand PAR1 mechanism of action and in a near future assay its potential use as risk factor for metastasis development in high grade breast cancer patients.</p

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission

Identification and prioritization of critical success factors in faith-based and non-faith-based organizations’ humanitarian supply chain

In the last few decades, an exponential increase in the number of disasters, and their complexity has been reported, which ultimately put much pressure on relief organizations. These organizations cannot usually respond to the disaster on their own, and therefore, all actors involved in relief efforts should have end-to-end synchronization in order to provide relief effectively and efficiently. Consequently, to smoothen the flow of relief operation, a shared understanding of critical success factors in humanitarian supply chain serves as a pre-requisite for successful relief operation. Therefore, any member of the humanitarian supply chain might disrupt this synchronization by neglecting one or several of these critical success factors. However, in this study, we try to investigate how faith-based and non-faith-based relief organizations treat these critical success factors. Moreover, we also try to identify any differences between Islamic and Christian relief organizations in identifying and prioritizing these factors. To achieve the objective of this study, we used a two-stage approach; in the first stage, we collected the critical success factors from existing humanitarian literature. Whereas, in the second stage, using an online questionnaire, we collected data on the importance of selected factors from humanitarian relief organizations from around the world in collaboration with World Association of Non-Governmental Organizations (WANGO). Later, responses were analyzed to answer the research questions using non-parametric Binomial and Wilcoxon Rank-Sum tests. Test results indicate that for RQ1, two but all factors are significant for successful relief operation. For RQ2, we found significant differences for some CSF among faith-based and non-faith-based relief organizations. Similarly for RQ3, we found significant differences for some CSF among Islamic and Christian relief organizations

The activation of Proteinase-Activated Receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion

<p>Abstract</p> <p>Background</p> <p>In addition to regulating platelet function, the G protein-coupled sub-family member Proteinase-activated receptor-1 (PAR1) has a proposed role in the development of various cancers, but its exact role and mechanism of action in the invasion, metastasis, and proliferation process in gastric cancer have yet to be completely elucidated. Here, we analyzed the relationship between PAR1 activation, proliferation, invasion, and the signaling pathways downstream of PAR1 activation in gastric cancer.</p> <p>Methods</p> <p>We established a PAR1 stably transfected MKN45 human gastric cancer cell line (MKN45/PAR1) and performed cell proliferation and invasion assays employing this cell line and MKN28 cell line exposed to PAR1 agonists (α-thrombin and TFLLR-NH₂). We also quantified NF-κB activation by electrophoretic mobility shift assay (EMSA) and the level of Tenascin-C (TN-C) expression in conditioned medium by ELISA of MKN45/PAR1 following administration of α-thrombin. A high molecular weight concentrate was derived from the resultant conditioned medium and subsequent cultures of MKN45/PAR1 and MKN28 were exposed to the resultant concentrate either in the presence or absence of TN-C-neutralizing antibody. Lysates of these subsequent cells were probed to quantify levels of phospholyrated Epidermal Growth Factor Receptor (EGFR).</p> <p>Result</p> <p>PAR1 in both PAR1/MKN45 and MKN28 was activated by PAR1 agonists, resulting in cell proliferation and matrigel invasion. We have shown that activation of NF-κB and EGFR phosphorylation initially were triggered by the activation of PAR1 with α-thrombin. Quantitative PCR and Western blot assay revealed up-regulation of mRNA and protein expression of NF-κB target genes, especially TN-C, a potential EGFR activator. The suppressed level of phosphorylated EGFR, observed in cells exposed to concentrate of conditioned medium in the presence of TN-C-neutralizing antibody, identifies TN-C as a putative autocrine stimulatory factor of EGFR possibly involved in the sustained PAR1 activation responses observed.</p> <p>Conclusion</p> <p>Our data indicate that in gastric carcinoma cells, PAR1 activation can trigger an array of responses that would promote tumor cell growth and invasion. Over expression of NF-κB, EGFR, and TN-C, are among the effects of PAR1 activation and TN-C induces EGFR activation in an autocrine manner. Thus, PAR1 is a potentially important therapeutic target for the treatment of gastric cancer.</p