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35471956 Accelerated waning of immunity to SARS-CoV-2 mRNA vaccines in patients with immune mediate 2022 Apr 26 BACKGROUND: Limited information is available on the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). METHODS: This observational cohort study examined the immunogenicity of SARS-CoV-2 mRNA vaccines in adult patients with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic disease, with or without maintenance immunosuppressive therapies. Antibody and T cell responses to SARS-COV-2, including neutralization against SARS-CoV-2 variants were determined before and after 1 and 2 vaccine doses. RESULTS: We prospectively followed 150 subjects, 26 healthy controls, 9 IMID patients on no treatment, 44 on anti-TNF, 16 on anti-TNF with methotrexate/azathioprine (MTX/AZA), 10 on anti-IL-23, 28 on anti-IL-12/23, 9 on anti-IL-17, and 8 on MTX/AZA. Antibody and T cell responses to SARS-CoV-2 were detected in all participants, increasing from dose 1 to dose 2 and declining 3 months later, with greater attrition in IMID patients compared to healthy controls. Antibody levels and neutralization efficacy against variants of concern were substantially lower in anti-TNF treated patients than in healthy controls and were undetectable against Omicron by 3 months after dose 2. CONCLUSIONS: Our findings support the need for a third dose of mRNA vaccine and for continued monitoring of immunity in these patient groups. FUNDING: Funded by a donation from Juan and Stefania Speck and by Canadian Institutes of Health (CIHR) /COVID-Immunity Task Force (CITF) grants VR-1 172711 and VS1-175545 (T.H.W. and A.C.G); CIHR FDN-143250 (T.H.W.), GA2- 177716 (V.C., A.C.G., T.H.W.), GA1-177703 (A.C.G.) and the CIHR rapid response network to SARS-CoV-2 variants, CoVaRR-Net (to A.C.G.).
35157365 Development of a natural language processing system for extracting rheumatoid arthritis ou 2022 Feb 14 OBJECTIVE: To accelerate the use of outcome measures in rheumatology, we developed and evaluated a natural language processing (NLP) pipeline for extracting these measures from free-text outpatient rheumatology notes within the ACR's Rheumatology Informatics System for Effectiveness (RISE) registry. METHODS: We included all patients in RISE (2015 to 2018). The NLP pipeline extracted scores corresponding to eight measures of RA disease activity (DA) and functional status (FS) documented in outpatient rheumatology notes. Score extraction performance was evaluated by chart review, and we assessed agreement with scores documented in structured data. We conducted an external validation of our NLP pipeline using data from rheumatology notes from an academic medical center that is not included in the RISE registry. RESULTS: We processed over 34 million notes from 854,628 patients, 158 practices, and 24 EHR systems from RISE. Manual chart review revealed a sensitivity, positive predictive value (PPV), and F1 score of 95%, 87%, and 91%, respectively. Substantial agreement was observed between scores extracted from RISE notes and scores derived from structured data (kappa: 0.43 - 0.68 among DA and 0.86-0.98 among FS measures). In the external validation, we found a sensitivity, PPV, and F1 score of 92%, 69%, and 79%, respectively. CONCLUSIONS: We developed an NLP pipeline to extract RA outcome measures from a national registry of notes from multiple EHR systems and found it to have good internal and external validity. This pipeline can facilitate measurement of clinical and patient reported outcomes for use in research and quality measurement.
34971754 Single cell transcriptomics in human osteoarthritis synovium and in silico deconvoluted bu 2022 Mar OBJECTIVES: To reveal the heterogeneity of different cell types of osteoarthritis (OA) synovial tissues at a single-cell resolution, and determine by novel methodology whether bulk-RNA-seq data could be deconvoluted to create in silico scRNA-seq data for synovial tissue analyses. METHODS: OA scRNA-seq data (102,077 synoviocytes) were provided by 17 patients undergoing total knee arthroplasty; 9 tissues with matched scRNA-seq and bulk RNA-seq data were used to evaluate six in silico gene deconvolution tools. Predicted and observed cell types and proportions were compared to identify the best deconvolution tool for synovium. RESULTS: We identified seven distinct cell types in OA synovial tissues. Gene deconvolution identified three (of six) platforms as suitable for extrapolating cellular gene expression from bulk RNA-seq data. Using paired scRNA-seq and bulk RNA-seq data, an "arthritis" specific signature matrix was created and validated to have a significantly better predictive performance for synoviocytes than a default signature matrix. Use of the machine learning tool, Cell-type Identification By Estimating Relative Subsets of RNA Transcripts x (CIBERSORTx), to analyze rheumatoid arthritis (RA) and OA bulk RNA-seq data yielded proportions of T cells and fibroblasts that were similar to the gold standard observations from RA and OA scRNA-seq data, respectively. CONCLUSION: This novel study revealed heterogeneity of synovial cell types in OA and the feasibility of gene deconvolution for synovial tissue.
34843092 Patient-Reported Nausea and Fatigue Related to Methotrexate: A Prospective, Self-Controlle 2022 Feb INTRODUCTION: The magnitude and frequency of temporally related methotrexate (MTX)-associated side effects in rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients are difficult to quantify using traditional research methods. As proof of concept designed in part to implement digital data collection for remote patient monitoring, we conducted a study implementing self-controlled case series analytic methods to understand MTX-related symptoms in RA or PsA. METHODS: In study phase 1, adults with RA or PsA from the ArthritisPower(®) Registry (past or current oral MTX users) participated in a cross-sectional survey. In phase 2, current MTX users participated in a longitudinal study and completed the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) 1-day nausea/vomiting and fatigue measure. Within-person change in PROMIS scores between risk (6-36 h post-dose) and control (96-144 h post-dose) windows were compared using mixed models. RESULTS: The baseline survey was completed by 671 participants (mean age: 54 years, 88% female, 92% white, 79% with RA). Among current MTX users (353/671 [53%]), most reported MTX-associated side effects (216/353 [61%]), most frequently fatigue (161/353 [46%]). Among phase 2 participants with (n = 39) and without (n = 84) baseline nausea, mean increase in PROMIS nausea was 5.1 units (P < 0.0001) and 0.7 units (P = 0.135), respectively; among those with (n = 51) and without (n = 72) baseline fatigue, mean increase in PROMIS fatigue was 3.9 units (P = 0.0003) and 0.4 units (P = 0.554), respectively. CONCLUSIONS: Digital remote patient monitoring presents an opportunity to detect and address medication tolerability in real time. Using a novel study design to control for between-person confounding, the magnitude of nausea and fatigue experienced by participants with RA and PsA temporally related to weekly MTX use was substantial.
35249153 Pregnant women with immune mediated inflammatory diseases who discontinue biologics have h 2022 Mar 6 BACKGROUND AND AIMS: Biologic agents have revolutionized treatment of immune mediated inflammatory diseases (IMIDs). However, despite the benefits of treatment, there is limited data on its use during pregnancy leading to significant variation in practices. We evaluated maternal, neonatal, and disease-related outcomes in pregnant women with IMIDs, comparing those with biologic exposure during pregnancy to those without exposure. Our hypothesis was that there would be no difference in outcomes between the two groups. METHODS: This is a retrospective cohort study conducted at a single tertiary care center including women with Crohn's disease (CD), ulcerative colitis (UC), ankylosing spondylitis (AS), rheumatoid arthritis (RA), or psoriasis/psoriatic arthritis (PS/PsA) who delivered between 2010 and 2018 at The Ohio State University Wexner Medical Center. Conditions were identified by ICD-9/ICD-10 code and confirmed by chart review. Demographic data, pregnancy outcomes and disease-related data were collected. RESULTS: There were 338 pregnancies including 100 with CD, 74 with UC, 15 with AS, 61 with RA, and 90 with PS/PsA. 23% of IMID patients had biologic exposure (biologic use within 3 months of conception) and 18% continued therapy during pregnancy. Those with biologic exposure had increased risk of post-partum disease flare (OR 3.44; 95% CI 1.29, 9.15) and were less likely to breastfeed (OR 0.44; 95% CI 0.23, 0.87). In subgroup analysis of patients with IBD, those with biologic exposure also had increased risk of post-partum flare (OR 4.55; 95% CI 1.27, 16.35). Maternal and neonatal pregnancy outcomes were similar. CONCLUSION: Among pregnant women with IMIDs, those that continued biologics during pregnancy had increased rates of major infection, disease related hospital admission, glucocorticoid use, and disease flare within 6 months post-partum, without any significant change in maternal or neonatal outcomes.
35297215 Evaluation of autoantibodies as predictors of treatment response and immune-related advers 2022 Mar 16 BACKGROUND: The presence of autoantibodies in the serum of cancer patients has been associated with immune-checkpoint inhibitor (ICI) therapy response and immune-related adverse events (irAEs). A prospective evaluation of different autoantibodies in different cancer entities is missing. MATERIALS AND METHODS: In this prospective cohort study, we included a pan-cancer cohort of patients undergoing ICI treatment and measured a comprehensive panel of autoantibodies at treatment start and at the time point of first response evaluation. The presence and induction of autoantibodies (ANA, ENA, myositis, hepatopathy, rheumatoid arthritis) in different cancer entities were assessed and the association between autoantibodies and disease control rate (DCR), objective response rate (ORR), and progression-free survival (PFS), as well as the development of grade 3 or higher irAEs were evaluated by logistic regression models, cox proportional hazard models, and Kaplan-Meier estimators. RESULTS: Of 44 patients with various cancer entities, neither the presence of any positive autoantibody measurement nor the presence of positive antinuclear antibodies (ANA) [≥1:80] at baseline was associated with the examined clinical endpoints (DCR, ORR, PFS) in univariable and multivariable analyses. After 8-12 weeks of ICI treatment, DCR, ORR, and PFS did not significantly differ between patients with and without any positive autoantibody measurement or positive ANA titers. The frequency of irAEs did not differ depending on autoantibody status of the patients. CONCLUSION: Autoantibodies at treatment initiation or induction after 8-12 weeks of ICI treatment are not associated with treatment efficacy as indicated by DCR, ORR, and PFS or higher grade irAEs.
35654458 Effects of diet on the outcomes of rheumatic and musculoskeletal diseases (RMDs): systemat 2022 Jun BACKGROUND: A EULAR taskforce was convened to develop recommendations for lifestyle behaviours in rheumatic and musculoskeletal diseases (RMDs). In this paper, the literature on the effect of diet on the progression of RMDs is reviewed. METHODS: Systematic reviews and meta-analyses were performed of studies related to diet and disease outcomes in seven RMDs: osteoarthritis (OA), rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis, psoriatic arthritis, systemic sclerosis and gout. In the first phase, existing relevant systematic reviews and meta-analyses, published from 2013 to 2018, were identified. In the second phase, the review was expanded to include published original studies on diet in RMDs, with no restriction on publication date. Systematic reviews or original studies were included if they assessed a dietary exposure in one of the above RMDs, and reported results regarding progression of disease (eg, pain, function, joint damage). RESULTS: In total, 24 systematic reviews and 150 original articles were included. Many dietary exposures have been studied (n=83), although the majority of studies addressed people with OA and RA. Most dietary exposures were assessed by relatively few studies. Exposures that have been assessed by multiple, well conducted studies (eg, OA: vitamin D, chondroitin, glucosamine; RA: omega-3) were classified as moderate evidence of small effects on disease progression. CONCLUSION: The current literature suggests that there is moderate evidence for a small benefit for certain dietary components. High-level evidence of clinically meaningful effect sizes from individual dietary exposures on outcomes in RMDs is missing.
35645413 Association between forkhead box P3 expression level and gender of Iranian juvenile idiopa 2022 OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a childhood autoimmune rheumatoid disease. Past studies have confirmed that JIA is a complex disease, which means that genes and environmental factors affect the aetiology of the disease. In this study, we analysed the expression of interleukin 32, forkhead box P3 (FOXP3), methyl-CpG binding domain protein 1 (MBD1), and methyl-CpG-binding protein 2 (MECP2) in peripheral blood mononuclear cells of children with JIA in comparison with the expression of those in healthy children. Interleukin 32 is an inflammatory factor, FOXP3 is a transcription factor, and MBD1 and MECP2 are binding proteins that bind to the methylated deoxyribonucleic acid (DNA). MATERIAL AND METHODS: We collected blood from JIA patients who had been diagnosed and classified into clinical subtypes by a rheumatologist from the division of paediatric rheumatology. Healthy children, whose clinical and preclinical analysis confirmed they had no disease and just came to the hospital for a check-up or minor surgical procedures were considered as a control group. Age and gender were matched in patients and the control group. Total ribonucleic acid was extracted from blood, and cDNA was synthesized. Eventually, the transcript levels were analysed by quantitative polymerase chain reaction, and statistical analysis was carried out. RESULTS: Statistical analysis of gene expressions in young females affected by JIA demonstrated that MECP2 and FOXP3 were increased significantly (p-value = 0.002 and 0.05, respectively). Interleukin 32 gene expression was also increased (p-value = 0.14), whereas MBD1 gene expression was decreased (p-value = 0.06); however, these changes in the expression of all 4 genes were not significant in young males. CONCLUSIONS: Different expression levels of the mentioned genes between affected young females and males result from hormones in both gender and also methotrexate (MTX) drug. Also, the reason affected young females are more prone to JIA than males can be the lower level of FOXP3 expression in healthy females than healthy males.
35361692 Effects of physical exercise and body weight on disease-specific outcomes of people with r 2022 Mar BACKGROUND: A European League Against Rheumatism (EULAR) taskforce was convened to develop recommendations for lifestyle behaviours in rheumatic and musculoskeletal diseases (RMDs). This paper reviews the literature on the effects of physical exercise and body weight on disease-specific outcomes of people with RMDs. METHODS: Three systematic reviews were conducted to summarise evidence related to exercise and weight in seven RMDs: osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, axial spondyloarthritis (axSpA), psoriatic arthritis, systemic sclerosis and gout. Systematic reviews and original studies were included if they assessed exercise or weight in one of the above RMDs, and reported results regarding disease-specific outcomes (eg, pain, function, joint damage). Systematic reviews were only included if published between 2013-2018. Search strategies were implemented in the Medline, Embase, Cochrane Library of systematic reviews and CENTRAL databases. RESULTS: 236 articles on exercise and 181 articles on weight were included. Exercise interventions resulted in improvements in outcomes such as pain and function across all the RMDs, although the size of the effect varied by RMD and intervention. Disease activity was not influenced by exercise, other than in axSpA. Increased body weight was associated with worse outcomes for the majority of RMDs and outcomes assessed. In general, study quality was moderate for the literature on exercise and body weight in RMDs, although there was large heterogeneity between studies. CONCLUSION: The current literature supports recommending exercise and the maintenance of a healthy body weight for people with RMDs.
35507355 Immunogenicity and Safety of Standard and Third Dose SARS-CoV-2 Vaccination in Patients on 2022 May 4 OBJECTIVE: Immunogenicity and safety following standard SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases (IMID) are poorly characterized, and data on third dose vaccination are lacking. Study aim was to evaluate serological response and adverse events following standard and third dose SARS-CoV-2 vaccination in IMID-patients on immunosuppressive therapy. METHODS: Adult patients on immunosuppressive therapy for rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and healthy controls receiving standard two dose SARS-CoV-2 vaccination, were included in this prospective observational study. Analyses of antibodies to the receptor-binding domain (RBD) of the SARS-COV-2 spike protein were performed prior to, and 2-4 weeks after vaccination. Poorly responding patients were allotted a third vaccine dose. RESULTS: 1505 (91%) patients and 1096 (98%) healthy controls (p<0.001) responded to standard SARS-CoV-2 vaccination. Anti-RBD levels were lower in patients (median 619 AU/ml [IQR 192-4191]) than controls (median 3355 AU/ml [896 -7849]), p<0.001. The proportion of responders was lowest in patients receiving tumor necrosis factor inhibitor combination therapy, janus kinase inhibitors, or abatacept. Lower age and receiving mRNA-1273 vaccine were predictors of response. Of 153 patients with a weak response receiving a third dose, 129 (84%) became responders. Patients and controls had a comparable safety profile. CONCLUSIONS: IMID-patients had an attenuated response to standard vaccination as compared to healthy controls. A third vaccine dose was safe and resulted in serological response in most patients. These data facilitate identification of patient groups at risk of attenuated vaccine response, and support administering a third vaccine dose to poorly-responding IMID-patients.
35270118 A Major Diplotaxis harra-Derived Bioflavonoid Glycoside as a Protective Agent against Chem 2022 Feb 27 Oxidative stress and chronic inflammation have a role in developing neurodegenerative diseases such as Parkinson's disease (PD) and inflammatory movement disorders such as rheumatoid arthritis that affect millions of populations. In searching for antioxidant and anti-inflammatory molecules from natural sources that can counteract neurodegenerative diseases and arthritis, the flavonoid-rich extract of Diplotaxis harra (DHE) was selected based on its in vitro antioxidant and anti-inflammatory activities. DHE could inhibit the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in the lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages from 100% to the level of 28.51 ± 18.67 and 30.19 ± 5.00% at 20 μg/mL, respectively. A TLC bioautography of DHE fractions using 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) led to the isolation of a major antioxidant compound which was identified by X-ray diffraction analysis as isorhamnetin-3-O-β-D-glucoside (IR3G). IR3G also exhibited a potent anti-inflammatory activity, particularly by suppressing the upregulation of iNOS expression, similar to that of dexamethasone (DEX) at 10 μM to the level of 35.96 ± 7.80 and 29.34 ± 6.34%, respectively. Moreover, IR3G displayed a strong neuroprotectivity (>60% at 1.0(-4)-1.0(-3) μM) against 6-hydroxydopamine (6-OHDA)-challenged SHSY5Y neuroblastoma, an in vitro model of dopaminergic neurons for Parkinson's disease (PD) research. Accordingly, the in vivo anti-Parkinson potentiality was evaluated, where it was found that IR3G successfully reversed the 6-OHDA-induced locomotor deficit in a zebrafish model. A study of molecular docking and molecular dynamic (MD) simulation of IR3G and its aglycone isorhamnetin (IR) against human acetylcholine esterase (AChE), monoamine oxidase B (MAO-B), and Polo-like kinase-2 (PLK2) was performed and further outlined a putative mechanism in modulating neurodegenerative diseases such as PD. The free radical scavenging, anti-inflammatory through anti-iNOS and anti-COX-2 expression, and neuroprotective activities assessed in this study would present partial evidence for the potentiality of D. harra-derived IR3G as a promising natural therapeutic agent against neurodegenerative diseases and inflammatory arthritis. Finally, a biphasic HPTLC method was developed to estimate the biomarker IR3G in D. harra quantitatively.
35406905 Design of Experiments-Based Optimization of Flavonoids Extraction from Daphne genkwa Flowe 2022 Mar 29 The flower buds of Daphne genkwa have been reported as a potent resource associated with anti-angiogenic, anti-tumor, anti-rheumatoid arthritis activities, as well as immunoregulation. This paper aimed to establish an optimal extraction method for flavonoids, as active phytochemicals, and to conduct a comparative analysis by profiling the different blooming stages. Optimized shaking extraction conditions from the design of experiments (DoE), such as minutely mixture design, 2(3) full factorial design, and polynomial regression analysis, involved an agitation speed of 150 rpm and temperature of 65 °C for 12 h in 56% (v/v) acetone solvent. After, a comparative analysis was performed on three blooming stages, juvenile bud, mature purple bud, and complete flowering, by ultra-high-performance liquid chromatography-photodiode array-mass spectrometry (UHPLC-PDA-MS). Most flavonoids increased during bud growth and then decreased when the bud opened for blooming. In particular, apigenin 7-O-glucuronide, genkwanin 5-O-primeveroside, and genkwanin strikingly showcased this pattern. Furthermore, the raw spectrometric dataset was subjected to orthogonal projection to latent structures discriminant analysis (OPLS-DA) to find significant differences in the flavonoids from the juvenile bud, mature purple bud, and complete flowering. In conclusion, the present study facilitates an understanding of flavonoid change at different blooming stages and provides a momentous reference in the research of D. genkwa.
35322465 Synergistic enhancement of rat intestinal alkaline phosphatase activity by taurine and sod 2022 Mar 23 The effect of sodium butyrate (SB) and taurine on rat intestinal alkaline phosphatase (RIA) and the effect of the interaction of taurine and/or SB with bacterial lipopolysaccharides on ALP activity were investigated. In vitro analysis of the activity of RIA was carried out using various concentrations of SB and/or taurine. Substrate concentration-dependent kinetic study was performed at 1-10 mM of taurine and SB at 5.17 mM of p-nitrophenyl phosphate (p-NPP). The in vivo effect of lipopolysaccharide (LPS) in the presence and absence of taurine and SB on the activity of RIA was also evaluated. LPS was administered to rats intraperitoneally and 20 min after; this was followed by oral administration of SB and/or taurine. The hydrolysis of p-NPP by RIA was enhanced by taurine and SB at different concentrations. The in vivo kinetic study revealed that RIA activity was greater (588.23 × 10(-3)  μmol/min/ml) when taurine and SB were co-administered with bacterial LPS, yielding a low K(m) (0.12 mM) value. This suggested an increased affinity for the substrate by the enzyme. The degree of activation was highest when SB and taurine were administered together with LPS. The study concluded that SB and taurine are activators of RIA and their positive synergistic interaction in the presence of bacterial LPS may further emphasize the role of both activators in attenuating bacterial LPS-mediated diseases. PRACTICAL APPLICATIONS: The development and progression of a myriad of diseases such as inflammatory bowel disease, atherosclerosis, sepsis, multiple sclerosis, and rheumatoid arthritis have been linked to bacterial endotoxin. Taurine is an amino acid derived from cysteine, while sodium butyrate is a short-chain fatty acid. Consumption of food and food supplement rich in taurine and sodium butyrate can help protect against endotoxemic injury and aid tissue repair in the small intestine, digestibility, growth, and overall health of animals.
35288496 Preoperative Arterial Coil Embolization for Temporomandibular Joint (TMJ) Surgery in Child 2022 Mar 14 Temporomandibular joint (TMJ) ankylosis in children can alter facial development and affect oral hygiene and function. Surgical release of the ankylosis is the mainstay of treatment. The authors hypothesize that preoperative arterial coil embolization is safe and effective in preventing major blood loss during TMJ surgery (loss prompting blood transfusion or hemodynamic instability requiring vasoactive medication administration) in children with TMJ ankylosis. Patients < 16 years who were diagnosed with TMJ ankylosis (<15 maximal interincisal opening) and had embolization before surgery in the last 5 years were included. Out of 9 initial search results, 3 patients were excluded (age > 16). Information gathered were patient demographics, diagnostic imaging, procedural details, complications, and clinical outcomes. Six patients, mean age 11.14 years (range 7-15 years) year and a mean weight of 40.8 ± 19 kg were included. Underlying etiologies for TMJ ankylosis: Pierre Robin Syndrome (n = 2), juvenile rheumatoid arthritis (n = 1), Goldenhar's syndrome (n = 1), trauma (n = 1), and micrognathia (n = 1). Neck computed tomography angiogram before embolization demonstrated an intimate approximation between the internal maxillary artery (IMAX) and/or external carotid artery and ankylotic mass in all patients. Eight successful embolizations were performed without procedural complication. In 1 patient with angiographic evidence of surgical internal maxillary artery ligation, embolization was performed via collaterals. Surgery was performed within 48 hours of embolization. Airway access during surgery was via nasal intubation (n = 4), oral intubation (n = 3). The estimated blood loss (EBL) during surgery was 78.33 ± 47.08 ml. Three patients had subsequent TMJ surgery with a mean estimated blood loss of 73.33 ± 46.18 ml. After a mean follow-up of 17 ± 15 months, patients showed a 13.8 mm mean increment of maximal interincisal opening with 95% CI (5.74-21.9), P < 0.007.
35256842 Matrine Exerts Pharmacological Effects Through Multiple Signaling Pathways: A Comprehensiv 2022 As The main effective monomer of the traditional Chinese medicine Sophora flavescens Ait, matrine has a broad scope of pharmacological activities such as anti-tumor, anti-inflammatory, analgesic, anti-fibrotic, anti-viral, anti-arrhythmia, and improving immune function. These actions explain its therapeutic effects in various types of tumors, cardiopathy, encephalomyelitis, allergic asthma, rheumatoid arthritis (RA), osteoporosis, and central nervous system (CNS) inflammation. Evidence has shown that the mechanism responsible for the pharmacological actions of matrine may be via the activation or inhibition of certain key molecules in several cellular signaling pathways including the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), transforming growth factor-β/mothers against decapentaplegic homolog (TGF-β/Smad), nuclear factor kappa B (NF-κB), Wnt (wingless/ integration 1)/β-catenin, mitogen-activated protein kinases (MAPKs), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. This review comprehensively summarizes recent studies on the pharmacological mechanisms of matrine to provide a theoretical basis for molecular targeted therapies and further development and utilization of matrine.
35196255 Autoimmune disease and interconnections with vitamin D. 2022 Mar 31 Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.
35130193 Acute Quadriceps Tendon Rupture: Presentation, Diagnosis, and Management. 2022 Feb 7 »: The incidence of quadriceps tendon rupture is estimated to be 1.37 cases per 100,000 people/year, with a predilection for these injuries in patients who are ≥40 years of age. »: Quadriceps tendon ruptures are more likely to occur in the presence of preexisting comorbidities such as rheumatoid arthritis, systemic lupus erythematosus, gout, chronic kidney disease, secondary hyperparathyroidism, diabetes mellitus, and peripheral vascular disease. The most common mechanism of injury is a simple fall. »: Magnetic resonance imaging is the gold-standard test for diagnosing quadriceps tendon ruptures, with a reported sensitivity, specificity, and positive predictive value of 1.0. »: Complete tears require prompt surgical intervention; the most common technique is transosseous sutures passed through longitudinal patellar drill holes. Suture anchors have been proposed as an alternative method; they have shown superior biomechanical results in cadaveric models. »: Early functional mobilization with full weight-bearing and progressive range-of-motion exercises is recommended for rehabilitation following injury.
35108369 Carbamylation of β2-GPI generates new autoantigens for Antiphospholipid Syndrome: a new t 2022 Feb 2 OBJECTIVES: Antiphospholipid syndrome (APS) is a prothrombotic condition defined by recurrent thrombosis, pregnancy complications and circulating antiphospholipid antibodies (aPL), including anti-β2-Glycoprotein I (β2-GPI). In clinical practice it is possible to find patients with APS persistently negative for the aPL tests according to Sydney criteria ("seronegative APS", SN-APS). Recently, several autoimmune responses have been described as a consequence of post-translational modifications of their target autoantigens. This study was undertaken to test carbamylated-β2-GPI (Carb-β2-GPI) as a new autoantigen of APS. METHODS: β2-GPI was carbamylated by potassium cyanate and used to investigate its effect on monocyte-derived DC (moDC) phenotype and function. Sera from 114 SN-APS patients, 60 APS, 20 patients with Rheumatoid Arthritis, 20 NON-APS thrombosis and 50 healthy donors were analyzed for anti-Carb-β2-GPI by ELISA. RESULTS: Carb-β2-GPI is able to activate moDCs, inducing up-regulation of CD80, CD86, and CD40, activation of ERK, p38 MAPK and NF-κB and IL-12p70 release.Serological results showed that both 37/114 SN-APS (32.45%) and 23/60 APS patients (38.33%) resulted positive for anti-Carb-β2-GPI. Interestingly, SN-APS patients tested positive for anti-Carb-β2-GPI showed a higher prevalence of thrombocytopenia (p= 0.04, likelihood positive ratio of 3.9). CONCLUSION: Data obtained from both functional tests on moDCs and from immunologic approaches prompted identification of Carb-β2-GPI as a "new" antigenic target in APS. In particular, anti-Carb-β2-GPI revealed a potential usefulness in identification of a significant proportion of SN-APS patients. Moreover, since patients tested positive for anti-Carb-β2-GPI reported a high risk of thrombocytopenia, this test may be considered a suitable approach in the clinical evaluation of SN-APS.
34417338 Repetitive and forceful movements of the hand as predictors of treatment for pain in the d 2022 Jan OBJECTIVE: To investigate repetitive movements and the use of hand force as causes of treatment for distal upper extremities musculoskeletal disorders METHODS: A cohort of 202 747 workers in a pension health scheme from 2005 to 2017 in one of 17 jobs (eg, office work, carpentry, cleaning) was formed. Representative electro-goniometric measurements of wrist angular velocity as a measure for repetition and expert-rated use of hand force were used in a job exposure matrix (JEM). Job titles were retrieved from the Danish registers. Outcome was first treatment in the distal upper extremities. In a Poisson regression model, incidence rate ratios (IRRs) of treatment were adjusted for age, calendar-year, diagnosis of rheumatoid arthritis and arm fractures. In further analyses, wrist velocity or hand force was added. RESULTS: In men, wrist velocity had an IRR of 1.48 (95% CI 1.15 to 1.91) when the highest exposure level was compared with the lowest but with no clear exposure-response pattern. The effect became insignificant when adjusted for hand force. Hand force had an IRR of 2.65 (95% CI 2.13 to 3.29) for the highest versus the lowest exposure with an exposure-response pattern, which remained after adjustment for wrist velocity. Among women, no increased risk was found for hand force, while wrist velocity showed a significantly protective association with treatment. CONCLUSIONS: In men, occupational exposure to hand force more than doubled the risk of seeking treatment. The results for exposure to repetition were less clear. In women, we could not find any indications of an increased risk neither for force nor for repetition.
34391790 The unique function of p130Cas in regulating the bone metabolism. 2022 Feb p130 Crk-associated substrate (Cas) functions as an adapter protein and plays important roles in certain cell functions, such as cell proliferation, spreading, migration, and invasion. Furthermore, it has recently been reported to have a new function as a mechanosensor. Since bone is a tissue that is constantly under gravity, it is exposed to mechanical stress. Mechanical unloading, such as in a microgravity environment in space or during bed rest, leads to a decrease in bone mass because of the suppression of bone formation and the stimulation of bone resorption. Osteoclasts are multinucleated bone-resorbing giant cells that recognize bone and then form a ruffled border in the resorption lacuna. p130Cas is a molecule located downstream of c-Src that is important for the formation of a ruffled border in osteoclasts. Indeed, osteoclast-specific p130Cas-deficient mice exhibit osteopetrosis due to osteoclast dysfunction, similar to c-Src-deficient mice. Osteoblasts subjected to mechanical stress induce both the phosphorylation of p130Cas and osteoblast differentiation. In osteocytes, mechanical stress regulates bone mass by shuttling p130Cas between the cytoplasm and nucleus. Oral squamous cell carcinoma (OSCC) cells express p130Cas more strongly than epithelial cells in normal tissues. The knockdown of p130Cas in OSCC cells suppressed the cell growth, the expression of receptor activator of NF-κB ligand, which induces osteoclast formation, and bone invasion by OSCC. Taken together, these findings suggest that p130Cas might be a novel therapeutic target molecule in bone diseases, such as osteoporosis, rheumatoid arthritis, bone loss due to bed rest, and bone invasion and metastasis of cancer.