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ID PMID Title PublicationDate abstract
30961586 Alternative or complementary attitudes toward alternative and complementary medicines. 2019 Apr 8 BACKGROUND: Integrative and complementary health approaches (ICHA) are often pursued by patients facing chronic illnesses. Most of the studies that investigated the factors associated with ICHA consumption have considered that the propensity to use ICHA is a stable or fixed characteristic of an individual. However, people may prefer using ICHA in some situations and not in others, depending on the characteristics of the illness to face. Moreover, the attitude toward ICHA may differ within a single individual and between individuals so that ICHA can be used either in addition to (i.e., complementary attitude) or in place of (i.e., alternative attitude). The present study aimed at examining distinct patterns of attitudes toward ICHA in people hypothetically facing chronic illnesses that differed according to severity and clinical expression. METHODS: We conducted a web-based study including 1807 participants who were asked to imagine that they had a particular chronic illness based on clinical vignettes (mental illnesses: depression, schizophrenia; somatic illnesses: rheumatoid arthritis, multiple sclerosis). Participants were invited to rate their perceived distress and social stigma associated with each illness as well as its perceived treatability. They also rated their belief in treatment effectiveness, and their treatment preference. Four patterns of treatment choice were determined: strictly conventional, weak or strong complementary, and alternative. Bayesian methods were used for statistical analyses. RESULTS: ICHA were selected as complementary treatment option by more than 95% of people who hypothetically faced chronic illness. The complementary attitude towards ICHA (in addition to conventional treatment) was more frequent than the alternative one (in place of conventional treatment). Factors driving this preference included employment status, severity of illness, age and perceived distress, social stigma and treatability of the illness. When the label of illnesses was included in the vignettes, patterns of treatment preference were altered. CONCLUSIONS: This study provides evidence that "medical pluralism" (i.e., the integration of ICHA with conventional treatment) is likely the norm for people facing both mental or somatic illness. However, our result must be interpreted with caution due to the virtual nature of this study. We suggest that taking attitudes toward ICHA into account is crucial for a better understanding of patients' motivation to use ICHA.
30772128 Design, synthesis and biological evaluation of low molecular weight CXCR4 ligands. 2019 Mar 15 The chemokine receptor CXCR4/stromal cell-derived factor-1 (SDF-1: CXCL12) signaling axis represents a crucial drug target due to its relevance to several diseases such as HIV-1 infection, cancer, leukemia, and rheumatoid arthritis. With the aim of enhancing the binding affinity and anti-HIV activity of a potent CXCR4 ligand as a lead, 23 low molecular weight compounds containing dipicolylamine (Dpa) and cyclam cationic moieties with varying spacers and spatial positioning were designed, synthesized and biologically evaluated. All of the synthesized compounds screened at 1.0 μM in the NanoBRET assay system exhibited >70% inhibition of the binding of a competitive probe TAMRA-Ac-TZ14011 (10 nM) to CXCR4 in the presence of zinc (II) ion. Furthermore, selected compounds 3, 8, 9, 19 and 21 with spatial distances between the next carbon to Dpa and the next carbon to cyclam within the range of 6.5-7.5 Å showed potent binding affinity selective for CXCR4 with IC(50) values of 1.6, 7.9, 5.7, 3.5 and 4.5 nM, respectively, with corresponding high anti-HIV activity with EC(50)s of 28, 13, 21, 28 and 61 nM, respectively, in the presence of zinc (II) ion. Some compounds with remarkably more potent CXCR4-binding affinity than that of an initial lead were obtained. These compounds interact with different but overlapping amino acid residues of CXCR4. The present studies have developed new low molecular weight CXCR4 ligands with high CXCR4-binding and anti-HIV activities, which open avenue into the development of more potent CXCR4 ligands.
30692587 Androgen deprivation therapy for prostate cancer and the risk of autoimmune diseases. 2019 Sep BACKGROUND: Androgen deprivation therapy (ADT) has been a mainstay of treatment for advanced prostate cancer (PCa), but limited studies have been performed to investigate the association between ADT and autoimmune diseases. METHODS: We conducted a population-based nationwide cohort study of 17,168 patients newly diagnosed with PCa between 1996 and 2013 using the National Health Insurance Research Database (NHIRD) of Taiwan. Cox proportional hazards models with 1:1 propensity score-matched analysis were used to investigate the association between ADT use and the risk of autoimmune diseases. The autoimmune diseases included Graves' disease, Crohn's disease, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, Guillain-Barre syndrome, Sjogren's syndrome, myasthenia gravis, pernicious anemia, hereditary hemolytic anemia, polyarteritis nodosa, Celiac disease, uveitis, polymyalgia rheumatica, dermatomyositis, Hashimoto's thyroiditis, hypersensitivity vasculitis, Behcet's disease, polymyositis, alopecia areata, Wegener's granulomatosis, ulcerative colitis, autoimmune hemolytic anemia, pemphigus, multiple sclerosis, systemic sclerosis, Goodpasture syndrome, giant cell arteritis, thromboangitis obliterans, arteritis obliterans, and Kawasaki disease. The duration of ADT use as a time-dependent variable was also examined for its association with autoimmune diseases. We also performed six secondary analyses. RESULTS: Of the 17,168 selected PCa patients, 14,444 patients met all the inclusion and exclusion criteria. After propensity score matching, 5590 ADT users and 5590 non-ADT users were included in the study cohort. A propensity score-matched analysis (adjusted hazard ratio (aHR), 0.619, 95% confidence interval (CI), 0.51-0.75, P < 0.001) demonstrated a significantly decreased risk of autoimmune diseases in ADT users. A significant decrease in the risk of autoimmune diseases with increasing ADT duration was also demonstrated (P < 0.001). CONCLUSIONS: We observed that ADT use in patients with PCa was associated with a decreased risk of autoimmune diseases. These novel findings provide a potential role for androgen deprivation therapy in the modification of inflammation and autoimmunity in Asian patients with prostate cancer.
30368738 Risk factors and secondary care utilisation in a primary care population with non-tubercul 2019 Jan Prior research has identified risk factors associated with developing non-tuberculous mycobacterial disease (NTMD); we identified risk factors and secondary care utilisation of NTMD patients in the UK. This was a matched case-control study using electronic healthcare records from Clinical Practice Research Datalink from 2006 to 2016. NTMD was defined using prescription data and Read codes, based on international guidelines. Risk factors for NTMD were investigated using conditional logistic regression within a representative general population. All-cause secondary care utilisation (combined inpatient, outpatient, emergency visits) was investigated for participants with linked Hospital Episode Statistics (HES), using incidence rate ratio (IRR) from 2007 to 2015. We identified 1225 individuals with NTMD. A subset of individuals (426 patients) were eligible for linkage with HES. In the adjusted model, risk factors most strongly associated with an increased likelihood of NTMD included previous tuberculosis (OR 69.0; 47.7-99.8); bronchiectasis (OR 23.3; 12.4-43.9); lung cancer (OR 14.9; 3.98-55.7); oral corticosteroids (OCS; OR 7.28; 4.94-10.7); immunosuppressive (excluding corticosteroids) medication (OR 3.05; 1.15-8.10); being underweight (odds ratio (OR) 2.92; 95% CI 1.95, 4.36); and rheumatoid arthritis (OR 2.12; 1.05-4.27). NTMD patients had significantly higher rates of all-cause secondary care utilisation than non-NTMD patients (IRR 5.80; 5.14-6.46). Using a representative adult population, we identified prior TB, bronchiectasis, lung cancer, immunosuppressive medication, and OCS as the risk factors associated with the highest odds of developing NTMD in the UK. Patients with NTMD experienced nearly six times more all-cause secondary care events following their NTMD diagnosis than patients without NTMD.
31534054 Cadherin-11 blockade reduces inflammation-driven fibrotic remodeling and improves outcomes 2019 Sep 19 Over one million Americans experience myocardial infarction (MI) annually, and the resulting scar and subsequent cardiac fibrosis gives rise to heart failure. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not been studied in myocardium after MI. MI was induced by ligation of the left anterior descending artery in mice with either heterozygous or homozygous knockout of CDH11, wild-type mice receiving bone marrow transplants from Cdh11-deficient animals, and wild-type mice treated with a functional blocking antibody against CDH11 (SYN0012). Flow cytometry revealed significant CDH11 expression in noncardiomyocyte cells after MI. Animals given SYN0012 had improved cardiac function, as measured by echocardiogram, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 reduced bone marrow-derived myeloid cells and increased proangiogenic cells in the heart 3 days after MI. Cardiac fibroblast and macrophage interactions increased IL-6 secretion in vitro. Our findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI and that targeting CDH11 with a blocking antibody improves outcomes by altering recruitment of bone marrow-derived cells, limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.
31405929 Neuronal BC RNA Transport Impairments Caused by Systemic Lupus Erythematosus Autoantibodie 2019 Sep 25 The etiology of the autoimmune disorder systemic lupus erythematosus (SLE) remains poorly understood. In neuropsychiatric SLE (NPSLE), autoimmune responses against neural self-antigens find expression in neurological and cognitive alterations. SLE autoantibodies often target nucleic acids, including RNAs and specifically RNA domains with higher-order structural content. We report that autoantibodies directed against neuronal regulatory brain cytoplasmic (BC) RNAs were generated in a subset of SLE patients. By contrast, anti-BC RNA autoantibodies (anti-BC abs) were not detected in sera from patients with autoimmune diseases other than SLE (e.g., rheumatoid arthritis or multiple sclerosis) or in sera from healthy subjects with no evidence of disease. SLE anti-BC abs belong to the IgG class of immunoglobulins and target both primate BC200 RNA and rodent BC1 RNA. They are specifically directed at architectural motifs in BC RNA 5' stem-loop domains that serve as dendritic targeting elements (DTEs). SLE anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for DTE access and significantly diminish BC RNA delivery to synapto-dendritic sites of function. In vivo experiments with male BALB/c mice indicate that, upon lipopolysaccharide-induced opening of the blood-brain barrier, SLE anti-BC abs are taken up by CNS neurons where they significantly impede localization of endogenous BC1 RNA to synapto-dendritic domains. Lack of BC1 RNA causes phenotypic abnormalities including epileptogenic responses and cognitive dysfunction. The combined data indicate a role for anti-BC RNA autoimmunity in SLE and its neuropsychiatric manifestations.SIGNIFICANCE STATEMENT Although clinical manifestations of neuropsychiatric lupus are well recognized, the underlying molecular-cellular alterations have been difficult to determine. We report that sera of a subset of lupus patients contain autoantibodies directed at regulatory brain cytoplasmic (BC) RNAs. These antibodies, which we call anti-BC abs, target the BC RNA 5' domain noncanonical motif structures that specify dendritic delivery. Lupus anti-BC abs effectively compete with RNA transport factor heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2) for access to BC RNAs. As a result, hnRNP A2 is displaced, and BC RNAs are impaired in their ability to reach synapto-dendritic sites of function. The results reveal an unexpected link between BC RNA autoantibody recognition and dendritic RNA targeting. Cellular RNA dysregulation may thus be a contributing factor in the pathogenesis of neuropsychiatric lupus.
31271819 Optimization of the traditional processing method for precision detoxification of CaoWu th 2019 Oct 5 ETHNOPHARMACOLOGICAL RELEVANCE: CaoWu (Aconiti Kusnezoffii Radix), well known for its high toxicity leading to fatal ventricular arrhythmias, is detoxified by HeZi (Terminalia Chebula Retz) decoction to prepare ZhiCaoWu (Aconiti Kusnezoffii Radix Preparata) as one part of ingredients of NaRu-3 pill which is used for the treatment of rheumatoid arthritis (RA). Aconitine (AC) is a highly toxic alkaloid of CaoWu and it is used as toxic target marker for the quality control (QC) of ZhiCaoWu. In the traditional processing method, the vanish of astringent or spicy feeling in tongue is the important detoxification indicator of ZhiCaoWu. However, how CaoWu is detoxified to ZhiCaoWu and whether the appropriate content of AC in ZhiCaoWu can be efficiently perceived after the empirical detoxification still lack factual basis. AIM OF THE STUDY: The present study aimed to optimize the traditional processing method for precision detoxification of CaoWu through biomimetic linking kinetics and human toxicokinetics (TK) of AC, with a view of providing insights into the changes of toxic target marker. MATERIALS AND METHODS: CaoWu medicinal slices (Mes) and coarse powder (Cop) were processed by blank HeZi decoction through the soaking method for 7 days. High-performance liquid chromatography (HPLC) was used for the analysis of the samples. The acidity of blank HeZi decoction and HeZi processing decoction was directly determined by pH meter. The non-compartment analysis (NCA) was used to have an intuitive appreciation for AC and pH changes in HeZi processing decoction while the compartment model method was used to build the biomimetic linking kinetics model with the covariate. The inter-species scaling of animal TK parameters was conducted to predict human AC TK profiles. The possible uptake ways of AC (rapid-release or extended-release) for humans were attempted to assess the poisoning risk of AC in NaRu-3 pill. Based on the target content of AC in ZhiCaoWu, the biomimetic linking kinetics model was explored to optimize the traditional processing detoxification method of CaoWu. The assays of determining inflammatory cytokines in lipopolysaccharides (LPS)-induced RAW264.7 cells were performed to investigate the inflammatory modulation effects of AC in vitro. RESULTS: ZhiCaoWu was prepared by eliminating redundant AC in CaoWu through the repeatable replacement of HeZi processing decoction in which its acidity (pH) was affected. AC-pH changes in HeZi processing decoction were adequately depicted by a biomimetic linking kinetics model whose predictive power was determined by comparing the predictions of AC in ZhiCaoWu with the reported data. Rapid-release AC at the converted dose of 111.1 and 417.6 μg (0.011 and 0.042% of AC in NaRu-3 pill) reached maximum blood concentrations of 26.1 and 98.1 ng/mL at 0.3 h, in comparison with minimum human lethal concentration (100 ng/mL). Achieving the target content of AC (0.04%) in ZhiCaoWu or AC (0.011%) in NaRu-3 pill to precisely control the poisoning risk, the potential optimized protocols were that the processing time at 0.2-0.8% of AC in CaoWu was 2.0-4.4 days for Cop and 2.7-6.2 days for Mes. Correspondingly, pH values in HeZi processing decoction were 3.95 and 3.77 for Cop and Mes, respectively. Meanwhile, Lipopolysaccharides (LPS)-induced RAW264.7 cells were exposed to 0, 20, and 200 μM of AC for 12 h and AC at 20 μM enhanced the levels of IL-6, IL-10 and TNF-α. CONCLUSIONS: Thus, for the first time, a biomimetic linking kinetics model was built to optimize the traditional detoxification method. Moreover, pH changes could be developed as surrogate endpoint for guiding the processing detoxification of CaoWu. Notably, setting the content limit of AC (0.011%) was very rational to control the poisoning risk of NaRu-3 pill. In addition, it was possible that there existed the more complex mechanisms of AC for inflammatory modulation in vitro.
31137829 Engineering of Nanobodies Recognizing the Human Chemokine Receptor CCR7. 2019 May 27 The chemokine receptor CCR7 plays a pivotal role in health and disease. In particular, CCR7 controls homing of antigen-bearing dendritic cells and T cells to lymph nodes, where adaptive immune responses are initiated. However, CCR7 also guides T cells to inflamed synovium and thereby contributes to rheumatoid arthritis and promotes cancer cell migration and metastasis formation. Nanobodies have recently emerged as versatile tools to study G-protein-coupled receptor functions and are being tested in diagnostics and therapeutics. In this study, we designed a strategy to engineer novel nanobodies recognizing human CCR7. We generated a nanobody library based on a solved crystal structure of the nanobody Nb80 recognizing the β(2)-adrenergic receptor (β(2)AR) and by specifically randomizing two segments within complementarity determining region 1 (CDR1) and CDR3 of Nb80 known to interact with β(2)AR. We fused the nanobody library to one half of split-YFP in order to identify individual nanobody clones interacting with CCR7 fused to the other half of split-YFP using bimolecular fluorescence complementation. We present three novel nanobodies, termed Nb1, Nb5, and Nb38, that recognize human CCR7 without interfering with G-protein-coupling and downstream signaling. Moreover, we were able to follow CCR7 trafficking upon CCL19 triggering using Nb1, Nb5, and Nb38.
31035042 Dry leaf extracts of Tinospora cordifolia (Willd.) Miers attenuate oxidative stress and in 2019 Aug BACKGROUND: Tinospora cordifolia (Willd.) Miers is known for its therapeutic value in Indian traditional medicine for treating diabetes, rheumatoid arthritis, jaundice and cardiac diseases. However, information regarding its protective role against inflammatory diseases at the molecular level is limited. PURPOSE: The objective of the present work is to study the antioxidant and anti-inflammatory effect of alcoholic and water extracts of T. cordifolia (Willd.) Miers leaves in activated human monocytic THP-1 cells. STUDY DESIGN/METHODS: Phytochemical analyses of the dry leaf extracts of T. cordifolia (Willd.) Miers prepared using the solvents alcohol (TCAE) or water (TCWE) are performed employing spectrophotometric methods for estimating total phenolic and flavonoid content, and the plant material was authenticated by detecting T. cordifolia (Willd.) Miers metabolite biomarkers using LC-MS/MS. Arachidonic acid (AA)- and lipopolysaccharide (LPS)-activated human monocytic (THP-1) cells were used as experimental models to investigate the antioxidant and anti-inflammatory activities of the plant extracts. Arachidonic acid (AA)-induced reactive oxygen species (ROS) in THP-1 cells were monitored by confocal microscopy/spectrofluorimetry and transcript of antioxidant enzyme catalase (CAT), by quantitative real time PCR. Lipopolysaccharide (LPS)-induced proinflammatory marker like TNF-α at transcription and protein levels in THP-1 cells were measured by quantitative real-time PCR or ELISA respectively. Further, the effect of T. cordifolia (Willd.) Miers extracts on LPS-induced NF-κB translocation, and IκB and P-IκB protein levels, were studied by immunoblotting and confocal microscopy. RESULTS: T. cordifolia (Willd.) Miers extracts exhibited significant amounts of total phenolic and flavonoid content, and LC-MS/MS analyses detected tinosponone, a TC-specific clerodane-derived diterpene. Both types of extracts attenuated AA-induced ROS generation via enhancing catalase enzyme activity in THP-1 cells. Real time PCR and ELISA experiments revealed that the elevated levels of LPS-induced TNF-α was remarkably attenuated in THP-1 cells pretreated with T. cordifolia (Willd.) Miers extracts. Western blot and confocal microscopy showed that the alcoholic extract's anti-inflammatory activity by attenuating NF-κB translocation into the nucleus in LPS-activated THP-1 cells via the inhibition of IκB degradation in the cytosol. CONCLUSION: Our findings suggest that T. cordifolia (Willd.) Miers dry leaf extracts possess antioxidant and anti-inflammatory properties via upregulation of antioxidant enzymes and attenuation of NF- κB nuclear translocation in activated human monocytic (THP-1) cells, therefore the present study supports our proposed molecular basis for the traditional use of T. cordifolia (Willd.) Miers for treating various inflammatory diseases.
30965649 Peptide Cross-Linked Poly (Ethylene Glycol) Hydrogel Films as Biosensor Coatings for the D 2019 Apr 8 Peptide cross-linked poly(ethylene glycol) hydrogel has been widely used for drug delivery and tissue engineering. However, the use of this material as a biosensor for the detection of collagenase has not been explored. Proteases play a key role in the pathology of diseases such as rheumatoid arthritis and osteoarthritis. The detection of this class of enzyme using the degradable hydrogel film format is promising as a point-of-care device for disease monitoring. In this study, a protease biosensor was developed based on the degradation of a peptide cross-linked poly(ethylene glycol) hydrogel film and demonstrated for the detection of collagenase. The hydrogel was deposited on gold-coated quartz crystals, and their degradation in the presence of collagenase was monitored using a quartz crystal microbalance (QCM). The biosensor was shown to respond to concentrations between 2 and 2000 nM in less than 10 min with a lower detection limit of 2 nM.
30736372 Podoplanin in Inflammation and Cancer. 2019 Feb 6 Podoplanin is a small cell-surface mucin-like glycoprotein that plays a crucial role in the development of the alveoli, heart, and lymphatic vascular system. Emerging evidence indicates that it is also involved in the control of mammary stem-cell activity and biogenesis of platelets in the bone marrow, and exerts an important function in the immune response. Podoplanin expression is upregulated in different cell types, including fibroblasts, macrophages, T helper cells, and epithelial cells, during inflammation and cancer, where it plays important roles. Podoplanin is implicated in chronic inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, promotes inflammation-driven and cancer-associated thrombosis, and stimulates cancer cell invasion and metastasis through a variety of strategies. To accomplish its biological functions, podoplanin must interact with other proteins located in the same cell or in neighbor cells. The binding of podoplanin to its ligands leads to modulation of signaling pathways that regulate proliferation, contractility, migration, epithelial⁻mesenchymal transition, and remodeling of the extracellular matrix. In this review, we describe the diverse roles of podoplanin in inflammation and cancer, depict the protein ligands of podoplanin identified so far, and discuss the mechanistic basis for the involvement of podoplanin in all these processes.
30625176 Primary care management for patients receiving long-term antithrombotic treatment: A clust 2019 PURPOSE: To examine whether applying case management in general practices reduces thromboembolic events requiring hospitalization and major bleeding events (combined primary outcome). Secondary endpoints were mortality, frequency and duration of hospitalization, severe treatment interactions, adverse events, quality of anticoagulation, health-related quality of life and intervention costs, patients' assessment of chronic illness care, self-reported adherence to medication, GP and HCA knowledge, patient knowledge and satisfaction with shared decision-making. METHODS: Cluster-randomized controlled trial undertaken at 52 general practices in Germany with adult patients with a long-term indication for oral anticoagulation. The complex intervention included training for healthcare assistants, information and quality circles for general practitioners and 24 months of case management for patients. Assessment was after 12 and 24 months. The intention-to-treat population included all randomized practices and patients, while the per-protocol analysis included only those that received treatment without major protocol violations. RESULTS: The mean (SD) age of the 736 patients was 73.5 (9.4) years and 597 (81.1%) had atrial fibrillation. After 24 months, the primary endpoint had occurred in 40 (11.0%) intervention and 48 (12.9%) control patients (hazard ratio 0.83, 95% CI 0.55 to 1.25; P = .37). Patients' perceived quality of care, their knowledge, and HCAs' knowledge, had improved significantly at 24 months. The other secondary endpoints did not differ between groups. In the intervention group, hospital admissions were significantly reduced in patients that received treatment without major protocol deviations. CONCLUSIONS: Even though the main outcomes did not differ significantly, the intervention appears to have positively influenced several process parameters under 'real-world conditions'.
30569488 Qualitative and quantitative analysis of Porana sinensis Hemsl by UHPLC-Q-Exactive MS, TLC 2019 May INTRODUCTION: Erycibe obtusifolia and E. schmidtii are widely used in traditional Chinese medicine (TCM) to treat joint pain and rheumatoid arthritis. With the reduction of wild E. obtusifolia and E. schmidtii resources, Porana sinensis has been widely used as a substitute. However, few studies have been conducted on the chemical composition and quality control of P. sinensis. OBJECTIVE: To clarify the chemical composition and improve the quality control of P. sinensis. METHODOLOGY: We developed an ultra-high performance liquid chromatography electrospray ionisation Q-Exactive Focus tandem mass spectrometry (UHPLC-ESI-Q-Exactive Focus-MS/MS) method to characterise the chemical constituents of P. sinensis. A strategy based on a combination of high-performance thin-layer chromatography (HPTLC) and direct analysis in real-time (DART) ion source was proposed for the identification of alkaloid components in P. sinensis. Thin-layer chromatography (TLC) autography for 2,2'-diphenyl-1-picrylhydrazyl free radical (DPPHË™) and TLC bioautography for xanthine oxidase were used to rapidly screen marker compounds for high-performance liquid chromatography (HPLC) determination of P. sinensis. Based on the selected marker compounds, a HPLC method for the quantitative determination of eight marker compounds in P. sinensis was developed. RESULTS: Eighteen compounds in P. sinensis were identified by UHPLC-Q-Exactive MS. Taken together with the results of TLC autography and TLC bioautography, eight compounds were chosen as marker compounds for HPLC determination of P. sinensis. The alkaloid components in P. sinensis were identified as Baogongteng A and Baogongteng C by DART-MS. CONCLUSION: We systematically clarified the chemical composition of P. sinensis for the first time, and potentially improved its quality control. These results should promote the application of P. sinensis as a new resource for Caulis Erycibes.
31822681 Gender differences among Swedish COPD patients: results from the ARCTIC, a real-world retr 2019 Dec 10 The present study aimed to generate real-world evidence regarding gender differences among chronic obstructive pulmonary disease (COPD) patients, especially as regards the diagnosis and outcomes in order to identify areas for improvement and management and optimize the associated healthcare resource allocation. ARCTIC is a large, real-world, retrospective cohort study conducted in Swedish COPD patients and a matched reference population from 52 primary care centers in 2000-2014. The incidence of COPD, prevalence of asthma and other comorbidities, risk of exacerbations, mortality rate, COPD drug prescriptions, and healthcare resource utilization were analyzed. In total, 17,479 patients with COPD were included in the study. During the study period, COPD was more frequent among women (53.8%) and women with COPD experienced more exacerbations vs. men (6.66 vs. 4.66). However, the overall mortality rate was higher in men compared with women (45% vs. 38%), but no difference for mortality due to COPD was seen between genders over the study period. Women seemed to have a greater susceptibility to asthma, fractures, osteoporosis, rheumatoid arthritis, rhinitis, depression, and anxiety, but appeared less likely to have diabetes, kidney diseases, and cardiovascular diseases. Furthermore, women had a greater risk of COPD-related hospitalization and were likely to receive a significantly higher number of COPD drug prescriptions compared with men. These results support the need to reduce disease burden among women with COPD and highlight the role of healthcare professionals in primary care who should consider all these parameters in order to properly diagnose and treat women with COPD.
31349115 Synthesis of new arylhydrazide bearing Schiff bases/thiazolidinone: α-Amylase, urease act 2019 Oct Alpha-amylase and urease enzyme over expression endorses various complications like rheumatoid arthritis, urinary tract infection, colon cancer, metabolic disorder, cardiovascular risk, and chronic kidney disease. To overcome these complications, we have synthesized new arylhydrazide bearing Schiff bases/thiazolidinone analogues as α-amylase and urease inhibitors. The analogues 1a-r were evaluated for α-amylase inhibitory potential. All analogues were found active and show IC(50) value ranging between 0.8 ± 0.05 and 12.50 ± 0.5 μM as compare to standard acarbose (IC(50) = 1.70 ± 0.10 μM). Among the synthesized analogs, compound 1j, 1r, 1k, 1e, 1b and 1f having IC(50) values 0.8 ± 0.05, 0.9 ± 0.05, 1.00 ± 0.05, 1.10 ± 0.10, 1.20 ± 0.10 and 1.30 ± 0.10 μM respectively showed an excellent inhibitory potential. Analogs 2a-o were evaluated against urease activity. All analogues were found active and show IC(50) value ranging between 4.10 ± 0.02 and 38.20 ± 1.10 μM as compare to standard thiourea (IC(50) = 21.40 ± 0.21 μM). Among the synthesized analogs, compound 2k, 2a, 2h, 2j, 2f, 2e, 2g, 2b and 2l having IC(50) values 4.10 ± 0.02, 4.60 ± 0.02, 4.70 ± 0.03, 5.40 ± 0.02, 6.70 ± 0.05, 8.30 ± 0.3, 11.20 ± 0.04, 16.90 ± 0.8 and 19.80 ± 0.60 μM respectively showed an excellent inhibitory potential. All compounds were characterized through (1)H, (13)C NMR and HR-EIMS analysis. Structure activity relationship of the synthesized analogs were recognized and confirmed through molecular docking studies.
31285305 Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases. 2019 Sep A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019.
31171272 Broussonin E suppresses LPS-induced inflammatory response in macrophages via inhibiting MA 2019 May 20 Macrophages play an important role in inflammation, and excessive and chronic activation of macrophages leads to systemic inflammatory diseases, such as atherosclerosis and rheumatoid arthritis. In this paper, we explored the anti-inflammatory effect of broussonin E, a novel phenolic compound isolated from the barks ofBroussonetia kanzinoki, and its underlying molecular mechanisms. We discovered that Broussonin E could suppress the LPS-induced pro-inflammatory production in RAW264.7 cells, involving TNF-α, IL-1β, IL-6, COX-2 and iNOS. And broussonin E enhanced the expressions of anti-inflammatory mediators such as IL-10, CD206 and arginase-1 (Arg-1) in LPS-stimulated RAW264.7 cells. Further, we demonstrated that broussonin E inhibited the LPS-stimulated phosphorylation of ERK and p38 MAPK. Moreover, we found that broussonin E could activate janus kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3. Downregulated pro-inflammatory cytokines and upregulated anti-inflammatory factors by broussonin E were abolished by using the inhibitor of JAK2-STAT3 pathway, WP1066. Taken together, our results showed that broussonin E could suppress inflammation by modulating macrophages activation statevia inhibiting the ERK and p38 MAPK and enhancing JAK2-STAT3 signaling pathway, and can be further developed as a promising drug for the treatment of inflammation-related diseases such as atherosclerosis.
31145263 Aseptic Glenoid Baseplate Loosening After Reverse Total Shoulder Arthroplasty: A Systemati 2019 May BACKGROUND: Aseptic glenoid baseplate loosening can lead to the failure of reverse total shoulder arthroplasty (RTSA). Estimates of the prevalence of aseptic glenoid baseplate loosening after RTSA are required to guide clinical decisions, but published results are variable and lack precision. The goal of this meta-analysis was to determine a precise estimate of the prevalence of aseptic glenoid baseplate loosening after RTSA and to explore variation in the prevalence according to different variables, such as the type of procedure (primary or revision), preoperative diagnosis, the center of rotation of the glenoid component (medialized or lateralized), study size, the definition of aseptic glenoid baseplate loosening, and the duration of follow-up. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. We searched the MEDLINE and Embase databases for English-language articles describing the outcomes after RTSA with a minimum 12-month follow-up in which radiographic findings of aseptic glenoid baseplate loosening were reported. Random-effects meta-analysis was performed, and meta-regression was used to explore the influence of variables on heterogeneity. Subgroup analyses and sensitivity analyses were performed. RESULTS: One hundred and three studies (covering 6,583 RTSAs) performed from 1991 to 2015 met our inclusion criteria. The pooled prevalence of radiographic aseptic glenoid baseplate loosening for all RTSAs was 1.16% (95% confidence interval [CI], 0.80% to 1.69%). The prevalence of aseptic glenoid baseplate loosening was lower among primary RTSAs (0.90%; 95% CI, 0.54% to 1.49%) than among revision RTSAs (3.64%; 95% CI, 1.91% to 6.84%). The pooled prevalence of aseptic glenoid baseplate loosening by diagnosis was 2.69% for osteoarthritis with bone loss, 1.71% for cuff tear arthropathy, 1.20% for rheumatoid arthritis, 1.08% for sequelae of fracture, 0.94% for irreparable massive cuff tear, and 0.25% for acute proximal humeral fracture. The prevalence of aseptic glenoid baseplate loosening was not significantly different for prostheses with a medialized center of rotation (1.15%) versus a lateralized center of rotation (1.84%). CONCLUSIONS: To our knowledge, the present study represents the first meta-analysis investigating only aseptic glenoid baseplate loosening after RTSA. Multiple variables were found to be associated with the prevalence of aseptic glenoid baseplate loosening. The rates reported here are lower than those reported previously because of the inclusion of more recent evidence and more studies that evaluated aseptic glenoid baseplate loosening. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
31131659 Autoimmune disease in patients with diffuse large B-cell lymphoma: occurrence and impact o 2019 Aug Background: Patients with certain autoimmune diseases (AID) have an increased risk of developing diffuse large B-cell lymphoma (DLBCL). However, the occurrence of AID in patients with DLBCL as well as the impact of AID on outcome has not been extensively studied. The main purpose of this study was to establish the occurrence of AIDs in a population-based cohort of DLBCL patients and to compare outcomes in patients with or without AID treated with rituximab(R)-CHOP/CHOP-like treatment. We also aimed to analyse gender differences and the potential role of different AIDs on outcome and the frequency of treatment-associated neutropenic fever. Patients and methods: All adult patients treated 2000-2013 with R-CHOP/CHOP-like treatment for DLBCL in four counties of Sweden were included (n = 612). Lymphoma characteristics, outcome and the presence of AID were obtained through medical records. Results: The number of patients with AID was 106 (17.3%). Thyroid disease dominated (n = 33, 31.1%) followed by rheumatoid arthritis (RA) (n = 24, 22.6%). The proportion of AID was significantly higher in females (59/254, 23.2%) vs. in males (47/358, 13.1%) (p = .001). In the whole cohort there was no difference in event free survival (EFS) or overall survival (OS) between patients with or without AID. However, patients with an AID primarily mediated by B-cell responses (thyroid disorders excluded) had a worse OS (p = .037), which seemed to affect only women. The AID group more often had neutropenic fever after first treatment (16.0% vs 8.7%, p = .034) and those with neutropenic fever had a worse OS (p = .026) in Kaplan-Meier analyses. Conclusion: There is a high prevalence of AID among patients with DLBCL. AIDs categorized as primarily B-cell mediated (in this study mainly RA, systemic lupus erythematosus and Sjögren's syndrome) may be associated with inferior OS. AID patients may be more prone to neutropenic fever compared to patients without concomitant AID.
30910980 A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history i 2019 Apr 9 Parkinson's disease (PD) is a neurodegenerative disease in which genetic risk has been mapped to HLA, but precise allelic associations have been difficult to infer due to limitations in genotyping methodology. Mapping PD risk at highest possible resolution, we performed sequencing of 11 HLA genes in 1,597 PD cases and 1,606 controls. We found that susceptibility to PD can be explained by a specific combination of amino acids at positions 70-74 on the HLA-DRB1 molecule. Previously identified as the primary risk factor in rheumatoid arthritis and referred to as the "shared epitope" (SE), the residues Q/R-K/R-R-A-A at positions 70-74 in combination with valine at position 11 (11-V) is highly protective in PD, while risk is attributable to the identical epitope in the absence of 11-V. Notably, these effects are modified by history of cigarette smoking, with a strong protective effect mediated by a positive history of smoking in combination with the SE and 11-V (P = 10(-4); odds ratio, 0.51; 95% confidence interval, 0.36-0.72) and risk attributable to never smoking in combination with the SE without 11-V (P = 0.01; odds ratio, 1.51; 95% confidence interval, 1.08-2.12). The association of specific combinations of amino acids that participate in critical peptide-binding pockets of the HLA class II molecule implicates antigen presentation in PD pathogenesis and provides further support for genetic control of neuroinflammation in disease. The interaction of HLA-DRB1 with smoking history in disease predisposition, along with predicted patterns of peptide binding to HLA, provide a molecular model that explains the unique epidemiology of smoking in PD.