Effect of cytomix and sedative drugs on mitochondrial electron transport chain of cultured primary human astrocytes

Septic shock is a major cause of death among patients in intensive care units worldwide. Despite the recent developments and progression in medical research, sepsis remains a challenge. Multiple‐organ failure including brain dysfunction (septic encephalopathy) is the predominant cause of death in septic patients. Elevations of cytokine concentrations in the brain have been described in both experimental and clinical studies. Furthermore, mitochondrial dysfunction has also been described in septic encephalopathy. Since also sedative drugs interfere with brain function, they may contribute to septic encephalopathy

Intrusion Detection Recording System with Biometric Lock

We are coming across cases, where the education system is being distorted and perverted. As the present security of our education system has several loopholes that can be exploited to obtain access to the locations were question papers are being kept, posing a significant threat to society, to address this problem we engineered an intrusion detection recording system with a biometric lock. Our project is a result of combination of two already existing methodologies – Wireless Biometric Lock and Noise detector with automatic recording system. This combination provides us with a more secure system than the existing individual implementation. Thus, our project is a noise sensor-based device with an automatic recording system that can also lock the locker or door using a fingerprint-based biometric interface which not only detects intrusion but also traps the person who tries to intrude

Comparison of ESSDAI and ClinESSDAI in potential optimization of trial outcomes in primary Sjögren’s syndrome: examination of data from the UK Primary Sjögren’s Syndrome Registry

OBJECTIVES: To assess the use of the Clinical EULAR Sjögren’s Syndrome Disease Activity Index (ClinESSDAI), a version of the ESSDAI without the biological domain, for assessing potential eligibility and outcomes for clinical trials in patients with primary Sjögren’s syndrome (pSS), according to the new ACR-EULAR classification criteria, from the UK Primary Sjögren’s Syndrome Registry (UKPSSR). METHODS: A total of 665 patients from the UKPSSR cohort were analysed at their time of inclusion in the registry. ESSDAI and ClinESSDAI were calculated for each patient. RESULTS: For different disease activity index cut-off values, more potentially eligible participants were found when ClinESSDAI was used than with ESSDAI. The distribution of patients according to defined disease activity levels did not differ statistically (chi2 p = 0.57) between ESSDAI and ClinESSDAI for moderate disease activity (score ≥5 and <14; ESSDAI 36.4%; ClinESSDA 36.5%) or high disease activity (score ≥14; ESSDAI 5.4%; ClinESSDAI 6.8%). We did not find significant differences between the indexes in terms of activity levels for individual domains, with the exception of the articular domain. We found a good level of agreement between both indexes, and a positive correlation between lymphadenopathy and glandular domains with the use of either index and with different cut-off values. With the use of ClinESSDAI, the minimal clinically important improvement value was more often achievable with a one grade improvement of a single domain than with ESSDAI. We observed similar results when using the new ACR-EULAR classification criteria or the previously used American-European Consensus Group (AECG) classification criteria for pSS. CONCLUSIONS: In the UKPSSR population, the use of ClinESSDAI instead of ESSDAI did not lead to significant changes in score distribution, potential eligibility or outcome measurement in trials, or in routine care when immunological tests are not available. These results need to be confirmed in other cohorts and with longitudinal data

Subjective and Objective Measures of Dryness Symptoms in Primary Sjögren's Syndrome::Capturing the Discrepancy

Objective: To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity. Methods: Archive data from the UK Primary Sjögren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from −5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease-related factors, and symptoms of pain, fatigue, anxiety, and depression. Results: Patients were on average relatively stoical for both types of dryness symptoms (mean ± SD ocular dryness −0.42 ± 2.2 and −1.24 ± 1.6 oral dryness). Twenty-seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self-reported pain and that of oral dryness sensitivity to be self-reported fatigue. Conclusion: Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjögrenʼs syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies.</p

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Pain and depression are associated with both physical and mental fatigue independently of comorbidities and medications in primary Sjögren's syndrome

Objectives To report on fatigue in patients from the United Kingdom primary Sjögren’s syndrome (pSS) registry identifying factors associated with fatigue and robust to assignable causes such as comorbidities and medications associated with drowsiness. Methods From our cohort (n = 608), we identified those with comorbidities associated with fatigue, and those taking medications associated with drowsiness. We constructed dummy variables, permitting the contribution of these potentially assignable causes of fatigue to be assessed. Using multiple regression analysis, we modelled the relationship between Profile of Fatigue and Discomfort physical and mental fatigue scores and potentially related variables. Results Pain, depression and daytime sleepiness scores were closely associated with both physical and mental fatigue (all p ≤ 0.0001). In addition, dryness was strongly associated with physical fatigue (p ≤ 0.0001). These effects were observed even after adjustment for comorbidities associated with fatigue or medications associated with drowsiness. Conclusions These findings support further research and clinical interventions targeting pain, dryness, depression and sleep to improve fatigue in patients with pSS. This finding is robust to both the effect of other comorbidities associated with fatigue and medications associated with drowsiness

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

A Transcriptional Signature of Fatigue Derived from Patients with Primary Sjögren's Syndrome

BACKGROUND:Fatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjögren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms. METHODS:Whole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjögren's Syndrome Registry, were used for whole genome microarray. The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W). RESULTS:Although no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525 (SE(W) 0.006), respectively. CONCLUSIONS:Systematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS