Современное состояние и перспективы развития процесса совместного получения фенола и ацетона. II. Cпособы интенсификации процесса окисления изопропилбензола.

The application of ozone as initiator of cumene oxidation is shown to result in feed conversion increased to 28%, with selectivity closed to 100%, instead of accordingly 21% and 88% in method using cumene hydroperoxide as initiator. Optimal conditions for cumene oxidation are determined.Проведен обзор существующих методов интенсификации процесса получения гидропероксида изопропилбензола. Показано, что использование озона в качестве инициатора окисления кумола приводит к повышению конверсии сырья до 28% при селективности процесса, близкой к 100%, против 21 и 88% соответственно в известном способе окисления с использованием в качестве инициатора гидропероксида изопропилбензола. Определены оптимальные условия окисления кумола озоно-воздушной смесью

Современное состояние и перспективы развития процессов получения фенола I. Обзор рынка и современное состояние процессов получения фенола

The combined preparation of phenol and acetone from cumol is one of the large-scale production processes of general organic synthesis. Accordingly increasing requirements of isopropylbenzene hydroperoxid as the raw material for the preparation of phenol and acetone and as the individual product, leads to constant development of effective methods of improving process with aim to minimize energy expenses and resources costs. The review of consumption market, phenol production, dynamic of the average product cost is described and the main directions and volumes of cargo are performed.Совместное получение фенола и ацетона из кумола – один из крупнотоннажных процессов основного органического синтеза. Этим методом получают более 90% производимого в мире фенола. В связи с этим растущие потребности в гидропероксиде изопропилбензола как в сырье для получения фенола и ацетона, так и в самостоятельном продукте, ведут к постоянной разработке высокоэффективных способов усовершенствования процесса, характеризующихся минимальными затратами энергии и ресурсов. Приведен обзор рынка потребления, производства фенола, показана динамика средних цен на продукт, указаны основные направления и объемы поставок

POS0321 USE OF HYDROXYCHLOROQUINE AND SYSTEMIC SCLEROSIS: RESULTS FROM A PROSPECTIVE OBSERVATIONAL STUDY ON THE EUSTAR COHORT

Background:Hydroxychloroquine (HCQ) is a well-tolerated drug that contributes to downregulating the immune response against autoantigens and it has been used in several autoimmune diseases. In systemic sclerosis (SSc) it is used to treat inflammatory arthritis without proof of efficacy.Objectives:Our aim was to evaluate the use of HCQ and its impact on Health Assessment Questionnaire disability index (HAQ-DI) and the Cochin Hand Function Status (CHFS). in a large SSc cohort compared to a propensity matched group of SSc patients not using HCQ.Methods:SSc patients from the European Scleroderma Trials and Research (EUSTAR) data base treated with HCQ for at least 6 months were evaluated. Demographic and clinical data, concomitant drugs, duration of HCQ treatment and reasons for its discontinuation, HAQ-DI and CHFS (at least 2 evaluation) were recorded and were the outcome variables of interest. Statistical analysis was performed using propensity score matching for age, gender, disease duration, corticosteroids, immunosuppressives, vasoactive drugs, DMARDs in a 3:1 control:HCQ ratio. Standard descriptive statistics and Student's t-test and Chi-square test were used to assess the propensity-matched groups.Results:1,636 of 17,805 SSc patients (9.2%) were treated with HCQ for at least 6 months; out of these 3% (50/1636). had at least a baseline and follow-up HAQ-DI evaluation, (and 44/1636 (2.7%) had at least a baseline and follow-up CHFS evaluation. Propensity matching assured that pts were matched for demographic variables such as gender (mean on HCQ vs no HCQ:femals:92.0 vs 85.3), age(49.8 vs 49.97yrs) disease duration(8.3 vs 9.1 yrs), limited disease(55.3 vs 62.6%) as well as background medications (P>0.1-0.9). We did not find any significant changes in HAQ or CHFS (difference in slope) over 365 days of treatment, comparing the HCQ-treated group to the non-HCQ treated patients (p=0.240 for both (Figure 1).Conclusion:Results from the EUSTAR registry showed that HCQ was used by 9.2% of SSc patients. HCQ use did not improve the HAQ or CHFS, comparing HCQ users to non-HCQ users.Disclosure of Interests:Silvia Bellando Randone: None declared, Holly Wilhalme: None declared, Cosimo Bruni: None declared, Elise Siegert: None declared, Paolo Airò: None declared, Rosaria Irace: None declared, Oliver Distler: None declared, Andrea Doria: None declared, Lidia P. Ananieva: None declared, László Czirják: None declared, Christopher Denton: None declared, Yannick Allanore: None declared, Valeria Riccieri: None declared, ALESSANDRA VACCA: None declared, Ivan Foeldvari Consultant of: Gilead, Novartis, Pfizer, Hexal, BMS, Sanofi, MEDAC, Anna-Maria Hoffmann-Vold Speakers bureau: Actelion, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Lilly and Medscape, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, ARXX, and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli: None declared, Marco Matucci-Cerinic: None declared, Daniel Furst: None declare

Mitogen- and Stress-Activated Kinase 1 (MSK1) Regulates Cigarette Smoke-Induced Histone Modifications on NF-κB-dependent Genes

Cigarette smoke (CS) causes sustained lung inflammation, which is an important event in the pathogenesis of chronic obstructive pulmonary disease (COPD). We have previously reported that IKKα (I kappaB kinase alpha) plays a key role in CS-induced pro-inflammatory gene transcription by chromatin modifications; however, the underlying role of downstream signaling kinase is not known. Mitogen- and stress-activated kinase 1 (MSK1) serves as a specific downstream NF-κB RelA/p65 kinase, mediating transcriptional activation of NF-κB-dependent pro-inflammatory genes. The role of MSK1 in nuclear signaling and chromatin modifications is not known, particularly in response to environmental stimuli. We hypothesized that MSK1 regulates chromatin modifications of pro-inflammatory gene promoters in response to CS. Here, we report that CS extract activates MSK1 in human lung epithelial (H292 and BEAS-2B) cell lines, human primary small airway epithelial cells (SAEC), and in mouse lung, resulting in phosphorylation of nuclear MSK1 (Thr581), phospho-acetylation of RelA/p65 at Ser276 and Lys310 respectively. This event was associated with phospho-acetylation of histone H3 (Ser10/Lys9) and acetylation of histone H4 (Lys12). MSK1 N- and C-terminal kinase-dead mutants, MSK1 siRNA-mediated knock-down in transiently transfected H292 cells, and MSK1 stable knock-down mouse embryonic fibroblasts significantly reduced CS extract-induced MSK1, NF-κB RelA/p65 activation, and posttranslational modifications of histones. CS extract/CS promotes the direct interaction of MSK1 with RelA/p65 and p300 in epithelial cells and in mouse lung. Furthermore, CS-mediated recruitment of MSK1 and its substrates to the promoters of NF-κB-dependent pro-inflammatory genes leads to transcriptional activation, as determined by chromatin immunoprecipitation. Thus, MSK1 is an important downstream kinase involved in CS-induced NF-κB activation and chromatin modifications, which have implications in pathogenesis of COPD

Helicobacter species in cancers of the gallbladder and extrahepatic biliary tract

Helicobacter species have been found in human bile and biliary tract (BT) tissue and are suspected to cause BT diseases, including gallbladder and extrahepatic cancers, collectively referred to in this work as BT cancers. We conducted a literature review of the epidemiological evidence linking the presence of Helicobacter species in bile or BT biopsies to BT cancers and benign diseases. Reports showed great variability with respect to study methods. Nine studies of BT cancers were identified, all with 30 or fewer BT cancers; eight included cancer-free control subjects and used polymerase chain reaction (PCR) as a means of Helicobacter species detection. In four of these studies, Helicobacter species were detected in patients with BT cancer significantly more frequently than in controls, at least when controls without BT diseases were used. In two studies, no Helicobacter species were detected in either cases or controls. Helicobacter species were also often detected in benign BT diseases such as gallstone disease or chronic cholecystitis. As our current knowledge relies on a few small studies that showed substantial differences, larger studies and more standardised protocols for detecting DNA and antibodies against Helicobacter species are needed to investigate a potential association with BT cancer

Update of EULAR recommendations for the treatment of systemic sclerosis

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc

Digital ulcers predict a worse disease course in patients with systemic sclerosis

Objective: Systemic sclerosis (SSc) is a systemic autoimmune disease with high morbidity and significant mortality. There is a great need of predictors that would allow risk stratification of patients with SSc and ultimately initiation of treatment early enough to ensure optimal clinical results. In this study, we evaluated whether a history of digital ulcers (HDU) at presentation may be a predictor of vascular outcomes and of overall clinical worsening and death in patients with SSc. Methods: Patients from the EULAR Scleroderma Trials and Research (EUSTAR) database, satisfying at inclusion the 1980 American College of Rheumatology classification criteria for SSc, who had a follow-up of at least 3 years since baseline or who have died, were included in the analysis. HDU at presentation as a predictor of disease worsening or death was evaluated by Cox proportional hazards regression analysis. Results :3196 patients matched the inclusion criteria (male sex 13.2%, 33.4% diffuse subset). At presentation, 1092/3196 patients had an HDU (34.1%). In multivariable analysis adjusting for age, gender and all parameters considered potentially significant, HDU was predictive for the presence of active digital ulcers (DUs) at prospective visits (HR (95% CI)): 2.41(1.91 to 3.03), p<0.001, for an elevated systolic pulmonary arterial pressure on heart ultrasound (US-PAPs):1.36 (1.03 to 1.80), p=0.032, for any cardiovascular event (new DUs, elevated US-PAPs or LV failure):3.56 (2.26 to 5.62), p<0.001, and for death (1.53 (1.16 to 2.02), p=0.003). Conclusions :In patients with SSc, HDU at presentation predicts the occurrence of DUs at follow-up and is associated with cardiovascular worsening and decreased survival

Vasodilators and low-dose acetylsalicylic acid are associated with a lower incidence of distinct primary myocardial disease manifestations in systemic sclerosis: results of the DeSScipher inception cohort study

OBJECTIVES: To investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc). METHODS: 601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5-4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed. RESULTS: During 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05). CONCLUSIONS: The present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA

The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

Effectiveness and safety of tocilizumab in patients with systemic sclerosis: a propensity score matched controlled observational study of the EUSTAR cohort

Objectives Tocilizumab showed trends for improving skin fibrosis and prevented progression of lung fibrosis in systemic sclerosis (SSc) in randomised controlled clinical trials. We aimed to assess safety and effectiveness of tocilizumab in a real-life setting using the European Scleroderma Trial and Research (EUSTAR) database. Methods Patients with SSc fulfilling the American College of Rheumatology (ACR)/EULAR 2013 classification criteria, with baseline and follow-up visits at 12±3 months, receiving tocilizumab or standard of care as the control group, were selected. Propensity score matching was applied. Primary endpoints were the modified Rodnan skin score (mRSS) and FVC at 12±3 months compared between the groups. Secondary endpoints were the percentage of progressive/regressive patients for skin and lung at 12±3 months. Results Ninety-three patients with SSc treated with tocilizumab and 3180 patients with SSc with standard of care fulfilled the inclusion criteria. Comparison between groups did not show significant differences, but favoured tocilizumab across all predefined primary and secondary endpoints: mRSS was lower in the tocilizumab group (difference −1.0, 95% CI −3.7 to 1.8, p=0.48). Similarly, FVC % predicted was higher in the tocilizumab group (difference 1.5 (−6.1 to 9.1), p=0.70). The percentage of progressive/regressive patients favoured tocilizumab over controls. These results were robust regarding the sensitivity analyses. Safety analysis confirmed previously reported adverse event profiles. Conclusion Although this large, observational, controlled, real-life EUSTAR study did not show significant effectiveness of tocilizumab on skin and lung fibrosis, the consistency of direction of all predefined endpoints generates hypothesis for potential effectiveness in a broader SSc population