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ID PMID Title PublicationDate abstract
31669645 The roles and regulation of TBX3 in development and disease. 2020 Feb 5 TBX3, a member of the ancient and evolutionary conserved T-box transcription factor family, is a critical developmental regulator of several structures including the heart, mammary glands, limbs and lungs. Indeed, mutations in the human TBX3 lead to ulnar mammary syndrome which is characterized by several clinical malformations including hypoplasia of the mammary and apocrine glands, defects of the upper limb, areola, dental structures, heart and genitalia. In contrast, TBX3 has no known function in adult tissues but is frequently overexpressed in a wide range of epithelial and mesenchymal derived cancers. This overexpression greatly impacts several hallmarks of cancer including bypass of senescence, apoptosis and anoikis, promotion of proliferation, tumour formation, angiogenesis, invasion and metastatic capabilities as well as cancer stem cell expansion. The debilitating consequences of having too little or too much TBX3 suggest that its expression levels need to be tightly regulated. While we have a reasonable understanding of the mutations that result in low levels of functional TBX3 during development, very little is known about the factors responsible for the overexpression of TBX3 in cancer. Furthermore, given the plethora of oncogenic processes that TBX3 impacts, it must be regulating several target genes but to date only a few have been identified and characterised. Interestingly, while there is compelling evidence to support oncogenic roles for TBX3, a few studies have indicated that it may also have tumour suppressor functions in certain contexts. Together, the diverse functional elasticity of TBX3 in development and cancer is thought to involve, in part, the protein partners that it interacts with and this area of research has recently received some attention. This review provides an insight into the significance of TBX3 in development and cancer and identifies research gaps that need to be explored to shed more light on this transcription factor.
33374841 Transient Receptor Potential Ankyrin 1 (TRPA1) Is Involved in Upregulating Interleukin-6 E 2020 Dec 23 Transient receptor potential ankyrin 1 (TRPA1) is a membrane-bound ion channel found in neurons, where it mediates nociception and neurogenic inflammation. Recently, we have discovered that TRPA1 is also expressed in human osteoarthritic (OA) chondrocytes and downregulated by the anti-inflammatory drugs aurothiomalate and dexamethasone. We have also shown TRPA1 to mediate inflammation, pain, and cartilage degeneration in experimental osteoarthritis. In this study, we investigated the role of TRPA1 in joint inflammation, focusing on the pro-inflammatory cytokine interleukin-6 (IL-6). We utilized cartilage/chondrocytes from wild-type (WT) and TRPA1 knockout (KO) mice, along with primary chondrocytes from OA patients. The results show that TRPA1 regulates the synthesis of the OA-driving inflammatory cytokine IL-6 in chondrocytes. IL-6 was highly expressed in WT chondrocytes, and its expression, along with the expression of IL-6 family cytokines leukemia inhibitory factor (LIF) and IL-11, were significantly downregulated by TRPA1 deficiency. Furthermore, treatment with the TRPA1 antagonist significantly downregulated the expression of IL-6 in chondrocytes from WT mice and OA patients. The results suggest that TRPA1 is involved in the upregulation of IL-6 production in chondrocytes. These findings together with previous results on the expression and functions of TRPA1 in cellular and animal models point to the role of TRPA1 as a potential mediator and novel drug target in osteoarthritis.
33014110 Effect of Moxibustion on the Serum Levels of MMP-1, MMP-3, and VEGF in Patients with Rheum 2020 BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which will eventually lead to joints deformity and functional damage. The aim of this research is to evaluate the effect of moxibustion on the serum indicators related to bone and cartilage metabolism, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 3 (MMP-3), and vascular endothelial growth factor (VEGF) in patients with RA and to explore the mechanism of moxibustion in the treatment of RA. METHODS: We recruited 70 RA patients who met the inclusion criteria, and they were randomly divided into two groups, a treatment group and a control group in equal ratio. The control group took methotrexate, folate, or leflunomide orally, while the treatment group received methotrexate, folate, or leflunomide orally and moxibustion at ST36 (Zusanli), BL23 (Shen shu), and Ashi points. We compared the clinical symptoms, RA serological disease markers and serum contents of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), MMP-1, MMP-3, and VEGF of RA patients before and after treatment. RESULTS: (1) The clinical symptoms and RA serological disease markers of the two groups improved after treatment (P < 0.05), while the clinical symptoms of the treatment group were significantly improved in comparison with the control group (P < 0.05). (2) The levels of IL-1β, TNF-α, and VEGF decreased in both groups after treatment (P < 0.05), but the treatment group was significantly decreased compared with the control group (P < 0.05). (3) There were significant differences in MMP-1 and MMP-3 contents after treatment in the treatment group (P < 0.05, P < 0.05), while there were no significant differences in the control group (P > 0.05, P > 0.05). Above all, the contents of IL-1β, TNF-α, MMP-1, MMP-3, and VEGF in the treatment group decreased more significantly than those in the control group (P < 0.05). CONCLUSION: The improvement effect of moxibustion on the clinical symptoms of RA patients may be related to influence on the contents of IL-1β, TNF-α, MMP-1, MMP-3, and VEGF, and moxibustion may play a potential role in bone protection.
32996698 Evaluation of inflammatory rheumatic diseases from an emergency medicine perspective. 2020 Dec BACKGROUND: Patients with rheumatological complaints may visit an emergency department (ED) because of an acute attack or complication. Because of the recent increased use of immunosuppressant drugs to treat rheumatic diseases, more patients with these conditions visit the ED with a complaint about an infection. However, there are little data on the ED visits of patients with rheumatological complaints. This study evaluated the ED visits of patients with inflammatory rheumatic diseases. MATERIALS AND METHODS: A total of 2715 patients (1753 females, 962 males) who had been diagnosed with an inflammatory rheumatic disease and followed up at the rheumatology clinic of Yıldırım Beyazit University, Ankara Atatürk Training and Research Hospital between April 2014 and April 2018 were included in the study. The demographic, clinical, and laboratory characteristics of the patients were obtained from the hospital patient records. The ED visits of these patients were classified into five triage groups (T1: critical, T2: very urgent, T3: urgent, T4: less urgent, T5: not urgent). RESULTS: Of the 2715 patients, 577 (21.3%) had visited the ED. The three most numerous groups who visited the ED were patients with rheumatoid arthritis (19.8%), ankylosing spondylitis (19.2%), and familial Mediterranean fever (15.9%). Of these 577 patients, 347 (60.1%) were discharged from the ED, 209 (36.2%) were hospitalized in the wards, and 21 (3.6%) were hospitalized in the intensive care unit (ICU). The 3 main reasons for visiting the ED were fever and malaise (n = 152, 26.3%), musculoskeletal complaints (n = 125, 21.7%), and abdominal pain (n = 89, 15.4%). The most numerous group of patients referred by the ED to the wards had vasculitis (n = 38, 17.9%), while the most numerous group of patients referred to the ICU had scleroderma (n = 7, 33.3%). Of the 21 patients who were referred by the ED to the ICU, 16 (76.1%) had respiratory system complaints. Of the 577 patients, 10 (1.7%) died. Eight of the 10 patients (80%) had a rheumatic disease and died after admission to the ICU. The other 2 patients had been diagnosed with pneumonia and myocardial infarction, respectively. CONCLUSIONS: Our study found that visits to the ED by patients with inflammatory rheumatic diseases were classified as urgent or less urgent. Patients with rheumatoid arthritis were the most numerous ED visitors. Vasculitis was the most common cause of hospitalization in the wards and scleroderma was the most common cause of hospitalization in the ICU and death. This suggests that ED physicians should be aware of these patients.
32310151 Needs, Experiences, and Views of People With Rheumatic and Musculoskeletal Diseases on Sel 2020 Apr 20 BACKGROUND: Despite the growing interest and exponential popularity of mobile health (mHealth) apps for long-term conditions such as rheumatic and musculoskeletal diseases (RMDs) and their self-management, patients are rarely directly consulted and involved in the app development process. OBJECTIVE: This study aims to explore the needs, experiences, and views of people diagnosed with RMDs on mHealth apps. METHODS: The study used a mixed methods approach: (1) an initial qualitative phase via a patient focus group in the UK and (2) a survey disseminated through national organizations for patients with RMDs across European countries, the United States, Canada, and Australia. RESULTS: The focus group included six patients with life-long musculoskeletal conditions. Half had used a self-management app at least once. The use of existing apps was reported as time-consuming due to a lack of functionality. The need for bespoke apps was voiced by all participants. Among 424 patients across European countries, the United States, Canada, and Australia, the main age group was 45 to 54 years (122/424, 28.7%), and 86.8% (368/424) were women. Half of the respondents were aware of the existence of apps to support self-management of their RMDs (188/355, 53%), with 42% (79/188) of them currently using such devices. Patients were mostly interested in an app to self-monitor their health parameters (259/346, 74.9%) and disease activity (221/346, 63.9%) or communicate directly with their health care provider (200/346, 57.8%). CONCLUSIONS: Patients considered that using an app could help them to self-manage their RMD condition if it was tailored to their needs and co-developed with health professionals. The development of such apps will require standardization and regular quality control.
31566229 Oral corticosteroid use during pregnancy and risk of preterm birth. 2020 Jun 1 OBJECTIVE: To evaluate the associations between oral corticosteroid (OCS) dose early and late in pregnancy and preterm birth (PTB) among women with RA. METHODS: Pregnant women in the MotherToBaby Pregnancy Studies (2003-2014) with RA (n = 528) were included in the primary analysis. Information was collected by phone interview and from medical records. We estimated risk ratios (RR) for OCS dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after gestational day 139. RESULTS: PTB risk was 15.5% overall. Compared with no OCS, PTB risk was increased in high (adjusted (a)RR: 4.77 (95% CI: 2.76, 8.26)) and medium (aRR: 1.81 (95% CI: 1.10, 2.97)) cumulative OCS dose trajectories during the first 139 gestational days. The low cumulative trajectory group was associated with an increased risk of PTB that was not statistically significant (aRR: 1.38 (95% CI: 0.79, 2.38)), and DMARDs were not associated with PTB (biologic DMARDs aHR: 1.08 (95% CI: 0.70, 1.66); non-biologic DMARDs aHR: 0.87 (95% CI: 0.55, 1.38)). OCS exposure to ⩾10 mg of prednisone equivalent daily dose after gestational day 139 vs none was associated with increased PTB rate (aHR: 2.45 (95% CI: 1.32, 4.56)), whereas <10 mg was associated with a modestly increased rate of PTB that was not statistically significant (aHR: 1.18 (95% CI: 0.60, 2.30)). CONCLUSION: Higher OCS doses vs no OCS use, both earlier and later in pregnancy, were associated with an increase in PTB among women with RA.
33214110 Tele-Rheumatology During the COVID-19 Pandemic. 2020 Oct 29 INTRODUCTION: During the COVID-19 pandemic strategies to prevent transmission of the viral infection obliged our hospital to promote virtual consultations. OBJETIVE: The objective of this study is to describe the results obtained with the previous strategy of transferring activity to teleconsultation during the period of maximum impact of the pandemic. MATERIAL AND METHODS: Between 16/03 and 10/05/2020 all successive consultations in our unit were performed in virtual rheumatology teleconference (RTC) format. The socio-demographic, geo-functional and clinical characteristics of all patients were collected; a numeric verbal scale (NVS) (where 0=very dissatisfied to 10=fully satisfied) was applied to assess the degree of satisfaction of the doctor/patient with the RTC. RESULTS: 469 TC were included. Most patients seen by RTC were women, mean age: 60,83 years. Only 16% had university education. The mean distance travelled for face-to face consultation is 33 Km with a mean total time of 2hours. Most individuals were diagnosed with osteoarthritis/soft tissue rheumatic diseases and/or osteoporosis; 21% had rheumatoid arthritis. The mean length of the TC was 9.64minutes. We find more patient satisfaction with the TC when their level of education is higher (OR=4.12); doctor satisfaction was higher when the individual was better able to manage the Internet (OR=3.01). CONCLUSION: It is possible to transfer rheumatological care activity to TC with a considerable degree of satisfaction for both the patient and the doctor.
32908565 Deciphering the Molecular Targets and Mechanisms of HGWD in the Treatment of Rheumatoid Ar 2020 BACKGROUND: Huangqi Guizhi Wuwu Decoction (HGWD) has been applied in the treatment of joint pain for more than 1000 years in China. Currently, most physicians use HGWD to treat rheumatoid arthritis (RA), and it has proved to have high efficacy. Therefore, it is necessary to explore the potential mechanism of action of HGWD in RA treatment based on network pharmacology and molecular docking methods. METHODS: The active compounds of HGWD were collected, and their targets were identified from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and DrugBank database, respectively. The RA-related targets were retrieved by analyzing the differentially expressed genes between RA patients and healthy individuals. Subsequently, the compound-target network of HGWD was constructed and visualized through Cytoscape 3.8.0 software. Protein-protein interaction (PPI) network was constructed to explore the potential mechanisms of HGWD on RA using the plugin BisoGenet of Cytoscape 3.8.0 software. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed in R software (Bioconductor, clusterProfiler). Afterward, molecular docking was used to analyze the binding force of the top 10 active compounds with target proteins of VCAM1, CTNNB1, and JUN. RESULTS: Cumulatively, 790 active compounds and 1006 targets of HGWD were identified. A total of 4570 differentially expressed genes of RA with a p value <0.05 and |log 2(fold change)| > 0.5 were collected. Moreover, 739 GO entries of HGWD on RA were identified, and 79 pathways were screened based on GO and KEGG analysis. The core target gene of HGWD in RA treatment was JUN. Other key target genes included FOS, CCND1, IL6, E2F2, and ICAM1. It was confirmed that the TNF signaling pathway and IL-17 signaling pathway are important pathways of HGWD in the treatment of RA. The molecular docking results revealed that the top 10 active compounds of HGWD had a strong binding to the target proteins of VCAM1, CTNNB1, and JUN. CONCLUSION: HGWD has important active compounds such as quercetin, kaempferol, and beta-sitosterol, which exert its therapeutic effect on multiple targets and multiple pathways.
32884244 "Mastering a New Life Situation" - Patients' Preferences of Treatment Outcomes in Early Rh 2020 PURPOSE: To explore patients' preferred treatment outcomes during their first two years with rheumatoid arthritis (RA). PATIENTS AND METHODS: A qualitative, longitudinal, multicenter study with interviews at two time points was performed in Sweden. Individual interviews were conducted at time point 1 with 31 patients with RA, defined as disease duration of ≤1 year and treatment for 3-7 months. Seven focus group interviews and five individual interviews were conducted at time point 2 with 22 patients 12-20 months after treatment initiation. The interviews were analyzed using the Qualitative Analysis Guide of Leuven. A core category with four related concepts emerged. RESULTS: The core finding of patient-preferred treatment outcomes was "mastering a new life situation". Patients preferred to experience control of the disease by controlling the symptoms and by experiencing absence of disease. To experience autonomy by regaining former activity level, experiencing independence, and being empowered was another preferred outcome. Patients preferred to regain identity through being able to participate, experience well-being, and regain former self-image. To experience joy in everyday life through vitality and believing in the future was another preferred outcome. Patients' preferences developed over time from the acute phase of controlling the symptoms and wanting to return to the life they lived prior to diagnosis, to a more preventive way of self-management and empowerment to master the new life situation. CONCLUSION: The patients' preferred treatment outcomes during the first two years with RA were to master their new life situation and changed from a preference to return to a life lived prior disease onset, to a preference of living with quality of life, despite RA. This study increases the understanding of patients' preferred treatment outcomes in the early disease course and can be a foundation for tailoring interventions to be more person-centered and to improve long-term treatment outcomes.
32506053 Seasonal and residential clustering at disease onset of anti-MDA5-associated interstitial 2020 Jun OBJECTIVES: To investigate whether the onset of polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung disease (ILD) is influenced by season and residence in the context of myositis-specific autoantibodies. METHODS: For patients with PM/DM-associated ILD enrolled in a multicentre cohort, 365 and 481 patients were eligible for seasonal and geographical analysis, respectively, based on the availability of reliable clinical information. The patients were divided into three groups: (1) anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive patients, (2) anti-aminoacyl tRNA synthetase (anti-ARS) antibody-positive patients and (3) patients negative for those antibodies. Seasonality was assessed by the Rayleigh test. Distance from residence to the nearest waterfront was measured on Google Map and was compared between groups by the exact Wilcoxon rank-sum test. RESULTS: In anti-MDA5-positive patients, the disease developed more frequently in October-March (p=0.03), whereas a seasonal relationship was not found in the remaining two patient groups. Residence at disease onset in anti-MDA5-positive patients was significantly closer to the waterfront, especially to freshwater, compared with that in anti-ARS-positive or anti-MDA5-/ARS-negative patients (p=0.003 and 0.006, respectively). CONCLUSIONS: Anti-MDA5-associated ILD occurred predominantly from October to March in individuals residing near freshwater, suggesting an environmental influence on the onset of this disease subset.
32411250 Efficacy of Vitamin E in Methotrexate-Induced Hepatotoxicity in Rheumatoid Arthritis: An O 2020 OBJECTIVE: To examine the efficacy of vitamin E in methotrexate- (MTX-) induced transaminitis in patients with rheumatoid arthritis (RA). METHODS: A case-control study was conducted at a tertiary rheumatology center for 12 months. Patients with RA on MTX and deranged aminotransferases were included. Patients with previous liver diseases, baseline transaminitis before methotrexate initiation, alcohol intake, muscle diseases, under hepatotoxic drugs, and aminotransferases > 3 times the upper normal limit were excluded. The patients were divided into treatment (vitamin E 400 mg bid for 3 months) and control groups (no vitamin E) using a random number table. The dose of MTX was unaltered. Follow-up was done after 3 and 6 months. Independent t-test was done to compare means of two groups. Paired t-test was done to compare differences in mean. RESULTS: Among 230 patients, 86.5% were female with a mean BMI of 25.9 ± 4.5 kg/m(2). In the treatment group, SGPT and SGOT at baseline were 73.1 ± 20.4 and 60.2 ± 24.5 IU/L, respectively; at 3-month follow-up 44.6 ± 34.2 and 38.3 ± 20.8 IU/L, respectively; and at 6-month follow-up 40.4 ± 35.7 and 34.2 ± 21.9 IU/L, respectively. In the control group, SGPT and SGOT at baseline were 63.4 ± 15.1 and 46.8 ± 13.7 IU/L, respectively, and at 3-month follow-up 55.8 ± 45.9 and 45.5 ± 30.9 IU/L, respectively. Significant decrease in the level of aminotransferases was seen in the treatment group (p value < 0.001) and not in the control group (p values 0.161 and 0.728, respectively). The change in levels of SGPT and SGOT from baseline to 3 months of follow-up was statistically significant in between two study groups (p values 0.007 and <0.001, respectively). From the control group, 29 patients were crossed over to vitamin E for the next 3 months. SGPT and SGOT decreased from 97.6 ± 44.1 to 46.1 ± 40.9 and 69.3 ± 34.9 to 29.1 ± 11.6 IU/L, respectively (p values 0.031 and 0.017, respectively). CONCLUSION: Vitamin E significantly attenuates MTX-induced transaminitis.
32509342 Clinical Review of Microbial Corneal Ulcers Resulting in Enucleation and Evisceration in a 2020 PURPOSE: To analyse the clinical and microbiological characteristics and preexisting ophthalmic and systemic conditions of infectious keratitis resulting in enucleation/evisceration in a large tertiary referral center in a developed country (Hungary) over a period of 12 years. Patients and Methods. A retrospective review of enucleated/eviscerated eyes undergoing surgery between 2007 and 2018 at the Department of Ophthalmology of Semmelweis University, Budapest, Hungary, with infectious keratitis as the primary indication for enucleation or evisceration. For each subject, clinical history, B-scan ultrasound report, and microbiological analyses were reviewed. RESULTS: There were 48 enucleated/eviscerated eyes from 47 patients (29 females (61.7%), age at the time of surgery 66.4 ± 18.5 years). Indication for surgery was hopeless, unmanageable keratitis (62.5%), and keratitis with endophthalmitis (37.5%). The most common preexisting ophthalmic conditions were previous cataract surgery (60.4%), previous therapeutic penetrating keratoplasty (PKP) (56.3%), corneal perforation (52.1%), glaucoma (41.7%), and long-term topical steroid usage (31.3%). In order to treat keratitis, before enucleation or evisceration, 20 eyes (41.7%) underwent PKP, 12 eyes (25.0%) amniotic membrane transplantation, 8 eyes (16.7%) conjunctival autograft transplantation, 6 eyes (12.5%) tarsorrhaphy, and 4 eyes (8.3%) vitrectomy to salvage the eye prior to the final treatment of enucleation or evisceration. The most frequent preexisting systemic diseases were hypertension (62.5%), cardiac disease (20.8%), diabetes mellitus (20.8%), and rheumatoid arthritis (14.6%). Staphylococcus aureus (17.0%) and Propionibacterium acnes (12.8%) were the most commonly isolated gram-positive bacteria, and Pseudomonas aeruginosa was the most frequently isolated gram-negative pathogen bacterium (10.6%). Six globes (12.5%) had positive fungal cultures (1 case of Candida albicans, Candida parapsilosis, Trichosporon inkin, Acremonium sp., Fusarium sp., and Penicillium sp.). CONCLUSIONS: Staphylococcus aureus, Propionibacterium acnes, and Pseudomonas aeruginosa keratitis with or without endophthalmitis represent the most common indication for ocular enucleation/evisceration in patients with microbial keratitis in a tertiary referral center in Hungary. The incidence of enucleation and evisceration related to mycotic keratitis does not seem to have increased within the last decade. Most frequent preexisting systemic diseases in cases of enucleation and evisceration are hypertension, cardiac disease, diabetes mellitus, and rheumatoid arthritis.
32189353 Yunnan Baiyao diminishes lipopolysaccharide-induced inflammation in osteoclasts. 2020 Jun Yunnan Baiyao (YNBY) has been refined for hundreds of years and has become a treasure of proprietary Chinese medicine that has significant curative effects in the field of hemostasis, blood circulation, and callus. In past years, YNBY has been demonstrated to play an anti-inflammatory role in bone-related diseases, such as rheumatoid arthritis and osteoporosis. However, the osteoclasts are multinucleated giant cells that resorb bone and participate in the occurrence, development, and progression of these bone-related diseases. Previous studies have reported that the inflammatory function is closely associated with arachidonic acid (AA) metabolism, as well as some inflammatory-related pathways, including the nuclear factor кB (NF-кB), mitogen-activated protein kinase (MAPK), and Wnt5a pathways. Therefore, we speculated that the anti-inflammatory effect of YNBY might be associated with the NF-кB, MAPK, and Wnt5a pathways. In order to further excavate the anti-inflammatory roles of YNBY, lipopolysaccharide (LPS) with an optimal concentration of 1,000 pg/ml was used to induce inflammation in osteoclasts. Our results showed that YNBY with a time- and dose-dependent method decreased the concentration of pro-inflammatory cytokines and the expression levels of cyclooxygenase-1 (COX-1), COX-2, 5-lipoxygenase, and prostaglandin E2. Moreover, it was found that COX-2 was the target gene regulated by YNBY. Finally, using NF-кB and MAPK pathway inhibitors or miRNA101b (involved in the Wnt5a pathway) in tandem with YNBY and the results exhibited that these groups caused a reduction in COX-1 and COX-2 expression, indicating that the anti-inflammatory function of YNBY might directly affect the NF-кB, MAPK, and Wnt5a pathways. PRACTICAL APPLICATIONS: Yunnan Baiyao (YNBY) is mainly extracted from precious Chinese medicines such as Panax notoginseng, borneol, musk, and yam and has a wide range of clinical applications. It is not only used to treat various types of traumatic injuries, but also used for upper gastrointestinal bleeding and wound ulcers, neonatal umbilitis, recurrent oral ulcers, esophagitis, bacterial dysentery, and so on. Although the detailed mechanism of action is not clear at present, it is believed that this is related to its anti-inflammatory, hemostatic, and immune-enhancing effects. Many bone-related diseases, such as rheumatoid arthritis and osteoporosis, are regarded to be intimately related to the inflammatory reaction. Thus, this study aimed to explore the underlying mechanisms of YNBY at anti-inflammatory roles. And our results suggested that YNBY directly affected the inflammatory cytokines and AA metabolic products which referred to the NF-кB, MAPK, and Wnt5a pathways, as well as AA metabolism, respectively. Hence, the practical applications of YNBY are the anti-inflammatory effects used to treat for bone-related diseases.
31867763 Heart-lung transplantation: A viable option for connective tissue diseases. 2020 Feb BACKGROUND: While lung transplantation (LTx) has been effective for connective tissue disease (CTD) patients with pulmonary involvement, outcomes for heart-lung transplantation (HLTx) are less defined. The aim of this study is to evaluate HLTx in CTD patients utilizing the UNOS database. METHODS: HLTx patients with CTD (HLTx-CTD) were compared to both LTx patients with CTD (LTx-CTD) and HLTx patients with all other indications (HLTx-OI) from 1999 to 2018. Primary outcome was 1- and 5-year graft survival. Secondary outcomes included freedom from first-year rejection and outcomes prior to transplant discharge. RESULTS: 1143/29 323 adults received first-time HLTx or LTx for CTD. Seventeen were HLTx-CTD (3.3% of total HLTx) and 1126 were LTx-CTD (3.9% of total LTx). There were 492 HLTx-OI. Transplant hemodynamic values including cardiac output, pulmonary capillary wedge pressure, and calculated pulmonary vascular resistance were significantly worse for HLTx-CTD vs LTx-CTD (4.2 vs 5.4 L/min, P = .005; 14 vs 10 mm Hg, P = .009; 439 vs 267 dynes, P = .007, respectively). Cardiac status 1 was more common for HLTx-CTD vs HLTx-OI (94% vs 56%, P < .001). HLTx-CTD 1 and 5-year graft survival was similar compared to LTx-CTD and HLTx-OI. CONCLUSION: HLTx-CTD is a valid option for carefully selected patients with CTD cardiac and pulmonary involvement with similar morbidity and mortality compared to LTx-CTD and HLTx-OI.
32869536 Inhibition of Ras GTPases prevents Collagen-Induced Arthritis by Reducing the Generation o 2020 Sep OBJECTIVE: RasGTPases are master regulators of multiple intracellular signaling cascades. Perturbation of this pathway has been implicated in the pathogenesis of rheumatoid arthritis (RA). In this study we aimed to define the therapeutic potential of a novel RasGTPases inhibitor, farnesylthiosalicylate (FTS), in the preclinical mouse model of collagen-induced arthritis (CIA) and better delineate its immunomodulatory effects both ex vivo and in the mouse. METHODS: We analyzed in vitro the immunomodulatory effects of FTS on various CD4(+) T-cell functions such as activation, proliferation, T-helper polarization, and production of proinflammatory cytokines. Using the CIA model, we further determined the efficacy of FTS to inhibit clinical, histopathologic, and diverse immunological outcomes of arthritis. RESULTS: FTS treatment of CD4(+) T cells in vitro effectively targeted distinct kinases (extracellular signal-regulated kinase 1/2, p38, protein kinase B/AKT, and mammalian target of rapamycin), the production of interleukin (IL)-17A, IL-22, and granulocyte-macrophage colony-stimulating factor, and Th17 polarization. FTS therapy in the mouse CIA model significantly reduced clinical disease severity and joint inflammation/damage by histology. Importantly, FTS suppressed the in vivo induction of splenic IL-17(+) IL-22(+) Th17 cells and the secretion of proinflammatory cytokines. The production of pathogenic autoantibodies and their abnormal hyposialylation was significantly attenuated by FTS therapy. Importantly, in vivo generation of collagen type-II specific effector CD4(+) T cells was likewise repressed by FTS therapy. CONCLUSION: The RasGTPases inhibitor FTS attenuates the production of proinflammatory cytokines by in vitro-activated T cells and is a potent immunomodulatory compound in the CIA model, primarily targeting the generation of autoreactive Th17 cells and the production of autoantibodies and their subsequent pathogenic hyposialylation.
32371019 What do we know about bone morphogenetic proteins and osteochondroprogenitors in inflammat 2020 Aug Osteochondroprogenitors are crucial for embryonic bone development and postnatal processes such as bone repair in response to fracture injury, and their dysfunction may contribute to insufficient repair of structural damage in inflammatory arthritides. In the fracture healing, the early inflammatory phase is crucial for normal callus development and new bone formation. This process involves a complex interplay of many molecules and cell types, responsible for recruitment, expansion and differentiation of osteochondroprogenitor populations. In inflammatory arthritides, inflammation induces bone resorption and causes insufficient bone formation, which leads to local and systemic bone loss. While bone loss is a predominant feature in rheumatoid arthritis, inflammation also induces pathologic bone formation at enthesial sites in seronegative spondyloarthropathies. Bone morphogenetic proteins (BMP) are involved in cell proliferation, differentiation and apoptosis, and have fundamental roles in maintenance of postnatal bone homeostasis. They are crucial regulators of the osteochondroprogenitor pool and drive their proliferation, differentiation, and lifespan during bone regeneration. In this review, we summarize the effects of inflammation on osteochondroprogenitor populations during fracture repair and in inflammatory arthritides, with special focus on inflammation-mediated modulation of BMP signaling. We also present data in which we describe a population of murine synovial osteochondroprogenitor cells, which are reduced in arthritis, and characterize their expression of genes involved in regulation of bone homeostasis, emphasizing the up-regulation of BMP pathways in early progenitor subset. Based on the presented data, it may be concluded that during an inflammatory response, innate immune cells induce osteochondroprogenitors by providing signals for their recruitment, by producing BMPs and other osteogenic factors for paracrine effects, and by secreting inflammatory cytokines that may positively regulate osteogenic pathways. On the other hand, inflammatory cells may secrete cytokines that interfere with osteogenic pathways, proapoptotic factors that reduce the pool of osteochondroprogenitor cells, as well as BMP and Wnt antagonists. The net effect is strongly context-dependent and influenced by the local milieu of cells, cytokines, and growth factors. Further elucidation of the interplay between inflammatory signals and BMP-mediated bone formation may provide valuable tools for therapeutic targeting.
33382786 Serological and hematological characteristics of Sjogren's syndrome and dry eye syndrome p 2020 OBJECTIVES: To compare hematologic and serological parameters among patients with Sjogren's syndrome (SS), dry eye syndrome (DES) and controls, and validate a novel multiplex-serology method for identifying auto-antibodies in these populations. METHODS: In a clinic-based case-control study a total of 422 participants were recruited, including 91 with SS, 120 DES, and 211 controls (age and sex frequency-matched). We measured blood counts, anti-nuclear-antibodies (ANA), anti-SSA/SSB, anti-ribonucleoprotein (RNP), anti-double-stranded-DNA (DS-DNA), and rheumatoid factor (RF) using the "Immunodot" qualitative-ELISA assay. Immunoglobulins, C3 and C4 were measured by immune-fluorescence. Autoantibodies were also quantified with a newly-developed method using glutathione-S-transferase fusion proteins of SSA/Ro 52 and 60kD and SSB/La (multiplex-serology), measuring median fluorescence intensity (MFI). RESULTS: Among DES patients, only 2% (95%CI: 0.36-6.3) had positive immune serology. SS patients had lower lymphocyte, hemoglobin and C3 levels but higher prevalence of RF, ANA, anti-SSA/B and higher IgG and MFI levels, compared to DES and controls (P<0.001). Presence of anti-SSA/Ro-52kD was associated with SS [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.46-2.88]. Anti-SSB/La was inversely associated with DES (OR = 0.81, 95%CI: 0.65-1.00) compared to controls. Positivity to RF (adjusted for age, gender and ethnicity OR = 5.03, 95%CI: 1.78-14.21), ANA (OR = 14.75, 95%CI: 4.09-53.17), or combination of anti-SSA/B (OR = 20.97, 95%CI: 4.60-95.54) were more likely in SS compared to DES. The novel multiplex-serology method correctly identified anti-SSA/B autoantibodies by ELISA among SS, DES patients and controls (sensitivity = 1.0, negative-predictive-value = 1.0). CONCLUSIONS: Serologic parameters distinguish SS from DES patients and controls. A newly-developed multiplex-serology technique may be useful to detect autoantibodies in large epidemiologic studies.
32681396 A study of antigen-specific anti-cytomegalovirus antibody reactivity in patients with syst 2020 Oct Anti-Ro52 autoantibody (autoAb), highly prevalent in Sjogren's syndrome (SjS) and systemic lupus erythematosus (SLE), is also frequent in systemic sclerosis (SSc). Viral agents, such as human cytomegalovirus (HCMV), have been considered as a trigger for SSc and SSc-associated autoAbs. To seek for antigen-specific anti-HCMV associations with anti-Ro52, we assessed the dominant anti-HCMV ab responses in anti-Ro52 antibody (ab)-positive and -negative patients with SSc and compared them with those in SLE and SjS. 116 Anti-HCMV ab(+) sera were analyzed, including 70 from anti-Ro52(+) patients (29 SSc, 23 SLE and 18 SjS) and 46 from anti-Ro52(-) patients (29 with SSc, 9 with SLE and 8 with SjS) as negative controls. Abs against specific HCMV pp130/UL57, pp65/UL83, pp55/UL55, pp52/UL44, p38 and pp28/UL99 antigens were tested by immunoblotting. Anti-Ro52(+) SSc patients reacted more frequently against pp52/UL44 and p38 compared to anti-Ro52(-) [(13/29, 44.8%; 95% CI 26.7-62.9% vs. 1/29, 3.4%; 95% CI 0-10%, p < 0.001, and 9/29, 31.0%; 95% CI 14.2-47.8% vs. 2/29, 6.9%; 95% CI 0-16.1%, p = 0.041, respectively]. No such differences were noted between anti-Ro52(+) and anti-Ro52(-) SLE or SjS patients. Also, antibody titres against HCMV pp65/UL83, pp52/UL44 and p38 antigens were higher in anti-Ro52(+) than anti-Ro52(-) SSc patients (p < 0.01). Ab responses against specific HCMV antigens differ among anti-Ro52 ab-positive and -negative patients with SSc (as well as between SSc and SLE or SjS), but whether these differences are epiphenomenal remains to be seen.
32499473 Hypokalemic paralysis as an initial presentation of Sjogren syndrome. 2020 Apr Sjogren syndrome (SS) is a systemic autoimmune disorder with predominant exocrine gland involvement leading to sicca symptoms. Among extraglandular manifestations, renal disease is the most common. Tubular interstitial nephritis and renal tubular acidosis (RTA) are the common presentations. Mild hypokalemia associated with distal RTA is common in SS, however, severe hypokalemia causing paralysis is unusual. We report the case of a 26-year-old female who presented with hypokalemic paralysis. On evaluation, distal RTA was diagnosed. Further evaluation showed positive SS-a/SS-b antibodies in high titer, which confirms the diagnosis of primary SS. Our report illustrates that SS is a rare but important cause of hypokalemic paralysis.
32401033 A Fast and Clean BTK Inhibitor. 2020 May 28 Bruton's tyrosine kinase (BTK) is a major drug target for B-cell related malignancies; however, existing BTK inhibitors approved for cancer treatment have significant off-targets that limit their use for autoimmune and inflammatory diseases. Remibrutinib (LOU064) is a novel covalent BTK inhibitor that binds an inactive BTK conformation, which affords it unprecedented selectivity. Its optimization led to rapid BTK engagement in vivo and fast clearance, further limiting systemic exposure. Remibrutinib is currently in phase 2 clinical trials for treatment of chronic urticaria and Sjoegren's syndrome.