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ID PMID Title PublicationDate abstract
32915975 Fractures are common within 18 months following first-line R-CHOP in older patients with d 2020 Sep 22 Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if <18 months; or at progression or death. Of 877 patients identified, 148 were excluded: 121 had progression or died before 6 months; 23 had follow-up <6 months. Across 729 remaining patients, the median age was 77 years, and 68% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Eighty-one fractures occurred within 18 months of follow-up; 42 were symptomatic, including 30 requiring hospital attendance or admission. The cumulative fracture incidence was 6.2% (95% confidence interval [CI], 4.7-8.2) at 6 months; 9.7% (95% CI, 7.8-12.1) at 12 months; and 11.4% (95% CI, 9.3-14.0) at 18 months. Multivariate analysis identified a predisposing history (osteoporosis, osteopenia, prior fracture, and rheumatoid arthritis [RhA]), DLBCL bone involvement at baseline, and receipt of prephase steroids as independent risk factors for fracture. There is a clinically relevant fracture risk and significant associated morbidity in older patients receiving R-CHOP. Careful attention to bone health is warranted in older patients receiving R-CHOP. Randomized studies are required to better define the most effective strategies to reduce fracture risk.
32717961 Acyclic Triterpenoid Isolated from Alpinia katsumadai Alleviates Formalin-Induced Chronic 2020 Jul 23 Chronic and excessive inflammation can destroy host organs and cause inflammatory diseases such as inflammatory bowel disease, asthma, and rheumatoid arthritis. In this study, we investigated the anti-inflammatory effects of Alpinia katsumadai seed-derived 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (PHT) using lipopolysaccharide (LPS)-stimulated J774 cells and a formalin-induced chronic paw inflammation mouse model. The in vitro results showed that PHT exhibited no cytotoxicity and decreased LPS-induced NO secretion. Additionally, PHT inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. The quantitative real-time PCR results showed that PHT downregulated the gene expression of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). PHT inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB). In a mouse model, oral administration of 50 mg/kg PHT significantly alleviated both mouse paw thickness and volume. These results indicate that PHT has potential anti-inflammatory effects and should be considered a possible functional material.
32524338 Safety and effectiveness of biosimilar of Rituximab CT-P10 in the treatment of cryoglobuli 2021 Jan Rituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. Recently, RTX biosimilar CT-P10 has been approved in Europe for the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of CT-P10 in the treatment of MCV. In this multicenter open-label study, we analyzed the safety of CT-P10 in patients with MCV treated in first-line or after a shift by RTX originator. Fifty-one consecutive MCV patients (females/males 35/16, median age 68 years, median disease duration 42 months, 51% HCV positive) were included in the study between July and December 2018 and were treated with CT-P10 (group 1). Safety and effectiveness of CT-P10 were compared with a retrospective group (group 2) including 75 consecutive patients treated with RTX originator between July 2017 and July 2018. Thirty-six patients were treated with CT-P10 for the first time, while the other 15 switched from RTX originator. RTX was administrated with high or dosage schemes (375 mg/m(2) four times a week apart/1000 mg twice one week apart or 250 mg/m(2) twice one week apart). During a month period after the last infusion, 13/51 adverse events (AE) were observed in group 1 and 17/75 in group 2 (p not significant). Among them, 7/13 and 6/17 (in group 1 and 2, respectively) could be considered immune-mediated AE (p not significant). At univariate analysis patients with IM-AE were more frequently males (p = 0.04) and with a lower disease duration (p = 0.03), but both the parameters were not significant at logistic regression. About clinical response after 6 months by the end of the treatment, no differences were observed between patients treated with originator and CT-P10 regarding the response to the therapy. No differences were observed in safety and effectiveness between patients naïve at RTX or switching from originator. Despite the higher prevalence of immune-mediated AE among patients treated with CT-P10 than originator, we have observed no significant differences between the 2 groups. The use of a low-dosage regimen is more common in group 1 than in group 2, representing a possible bias of the study, possibly influencing the appearance of AE. Considering the cost/efficacy ratio of biosimilars, their use could be helpful to treat a large number of MCV patients with an effectiveness and safety comparable to originator. Multicenter studies including a large number of patients and the new RTX biosimilars could be useful to fully elucidate the possible risk of immune-mediated adverse events with biosimilar drugs. Considering the cost/efficacy ratio of CT-P10, its use could help to treat a large number of MCV patients with an effectiveness and safety comparable to originator.
32146485 Association of blood pressure with knee cartilage composition and structural knee abnormal 2020 Sep OBJECTIVE: To investigate the associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with changes in knee cartilage composition and joint structure over 48 months, using magnetic resonance imaging (MRI) data from the Osteoarthritis Initiative (OAI). MATERIALS AND METHODS: A total of 1126 participants with right knee Kellgren-Lawrence (KL) score 0-2 at baseline, no history of rheumatoid arthritis, blood pressure measurements at baseline, and cartilage T2 measurements at baseline and 48 months were selected from the OAI. Cartilage composition was assessed using MRI T2 measurements, including laminar and gray-level co-occurrence matrix texture analyses. Structural knee abnormalities were graded using the whole-organ magnetic resonance imaging score (WORMS). We performed linear regression, adjusting for age, sex, body mass index, physical activity, smoking status, alcohol use, KL score, number of anti-hypertensive medications, and number of nonsteroidal anti-inflammatory drugs. RESULTS: Higher baseline DBP was associated with greater increases in global T2 (coefficient 0.22 (95% CI 0.09, 0.34), P = 0.004), global superficial layer T2 (coefficient 0.39 (95% CI 0.20, 0.58), P = 0.001), global contrast (coefficient 15.67 (95% CI 8.81, 22.53), P < 0.001), global entropy (coefficient 0.02 (95% CI 0.01, 0.03) P = 0.011), and global variance (coefficient 9.14 (95% CI 5.18, 13.09), P < 0.001). Compared with DBP, the associations of SBP with change in cartilage T2 parameters and WORMS subscores showed estimates of smaller magnitude. CONCLUSION: Higher baseline DBP was associated with higher and more heterogenous cartilage T2 values over 48 months, indicating increased cartilage matrix degenerative changes.
32066146 Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. 2020 Mar 17 BACKGROUND: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. OBJECTIVE: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. DESIGN: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). SETTING: North America. PARTICIPANTS: Adults with known cardiovascular disease and diabetes or metabolic syndrome. INTERVENTION: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. MEASUREMENTS: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. RESULTS: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). LIMITATION: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. CONCLUSION: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. PRIMARY FUNDING SOURCE: National Institutes of Health.
31341258 Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2. 2020 Jan Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC(50) value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.
33116791 Multisensory Sensitivity is Related to Deep-Tissue but Not Cutaneous Pain Sensitivity in H 2020 PURPOSE: Some individuals with chronic pain find daily life sensations (eg, noise, light, or touch) aversive. This amplification of multisensory sensations has been associated with centrally mediated plasticity; for example, greater multisensory sensitivity (MSS) occurs in patients with fibromyalgia than rheumatoid arthritis. However, whether MSS preferentially relates to pain measures which reflect central influences (eg, dynamic quantitative sensory testing (QST) or referred pain), or whether the MSS-pain relationship requires priming from chronic pain, is unknown. Thus, this cross-sectional study investigated the relationships between MSS assessed in a pain-free state and evoked pain sensitivity. METHODS: Experimental intramuscular infusion pain and multiple static and dynamic QST were assessed in 465 healthy, pain-free adults: pain thresholds using pressure (PPTs) and heat (HPTs), temporal summation of pain (TSP) using pressure, heat or punctate stimuli, and conditioned pain modulation (CPM) using pressure or heat test stimuli. MSS was assessed using 7 items from Barsky's Somatosensory Amplification Scale. Differences in pain and QST between sex-specific MSS quartiles were assessed, adjusting for multiple comparisons. All participants completed at least one intramuscular infusion condition, but not all were asked to complete each QST (n=166-465). RESULTS: Both static and dynamic QST differed between highest and lowest MSS quartiles using pressure stimuli: lower PPTs (adjusted-p<0.01); increased pressure TSP (adjusted-p=0.02); lower pressure CPM (adjusted-p=0.01). However, none of the heat or punctate QST measures (HPTs, TSP, or CPM) differed between MSS quartiles (adjusted-p>0.05). Odds of experiencing TSP or referred pain was not greater, whereas CPM was 8-fold less likely, in those with highest MSS. CONCLUSION: Normal variation in non-noxious MSS is related to both static and dynamic pain sensitivity, without sensitization associated with chronic pain, but is dependent on the QST stimulus. Thus, common influences on MSS and pain sensitivity may involve central mechanisms but are likely more complex than previously recognized.
33076950 Is changing the postoperative pain management in total knee arthroplasty from femoral nerv 2020 Oct 19 PURPOSE: In recent years, there has been an increasing interest in local infiltration analgesia (LIA) as a technique to control postoperative pain. We compared this technique to the gold standard the 3 in 1 femoral nerve block (FNB) in postoperative pain management after total knee arthroplasty (TKA) in a large patient population. This trial analyzes in the early postoperative phase the pain, range of motion, and consumption of pain medications after TKA. METHODS: We conducted a retrospective trial that included all patients who were undergoing primary TKA by one single surgeon in a high-volume arthroplasty center in 2015. Patients who have secondary osteoarthritis due to rheumatoid arthritis or previous knee arthrotomy, as well as revision cases, were excluded. The included patients were divided into 2 groups according to the applied pain management (group 1 FNB, group 2 LIA). Concerning the LIA group, a modified form of composition compared to the first describer without the use of adrenaline was carried out. Post-operative additional pain medications were given on a fixed scheme to the patient. The primary outcome was pain at rest over 7 days after surgery labeled by the numeric pain rating scale (NRS). The secondary outcome measures were the total amount of opioid consumption over the hospital stay and the additional need for non-opioid medication. The conversion of the opiate medications on the morphine preparation was carried out according to the conversion data from the literature. For functional recovery, we compared the range of motion in both groups, which was recorded from the second postoperative day by the attending physiotherapist. RESULTS: In total, 202 patients were assessed for eligibility and included in this clinical trial. Hundred patients were allocated to the continuous FNB group (group 1) and 102 patients to the LIA group (group 2). No statistical difference was found between the two groups regarding demographic data. Primary outcome measurements: The LIA group had a significantly lower NRS score than the continuous FNB group for the measurement in the morning on days 1, 2, and 3 after surgery (day 1, 1.5; day 2, 1.6; day 3, 1.3; p < 0.05). Secondary outcome measurements: The total volume of morphine consumption for the first six postoperative days was significantly lower in the LIA group than the FNB group (FNB 159.8 vs. LIA 96.07). There is also a significant difference between the total morphine consumption of both groups in the direct postoperative course with respect to time and group (two way ANOVA, p < 0.05) On the day of the operation and on the first postoperative day, the intake of additional non-opioids in the LIA group was also significantly reduced compared to the FNB group. No significant difference was observed on the second to sixth postoperative day concerning an additional consumption of non-opioid medications. In terms of range of motion, the LIA group showed a higher active range of motion at the operated extremity than the FNB group during the hospital stay. CONCLUSION: The local intraarticular infiltration therapy (LIA) is a sufficient alternative to regional anesthesia avoiding the known risks of regional procedures. The results of this study reflect the efficiency of this pain management with a lower consumption of analgesics, identical to reduced postoperative pain ratings and an improved ROM in the first postoperative days. LEVEL OF EVIDENCE: Retrospective trial.
32584681 Evaluation of a Pharmacist-Managed Nonsteroidal Anti-Inflammatory Drugs Deprescribing Prog 2020 Jul BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat symptoms of chronic inflammatory diseases such as osteoarthritis and rheumatoid arthritis; however, they are also associated with various adverse effects, including gastrointestinal (GI) bleeding and renal harm. As patients get older, some medications may no longer be beneficial or may even cause harm. Deprescribing is defined as the planned and supervised process of dose reduction or discontinuation of medications. While there are studies showing that deprescribing strategies with several classes of medications positively affects outcomes in elderly patients, there is a lack of strong evidence and guidance to deprescribe NSAIDs. OBJECTIVE: To evaluate the effectiveness, safety, and economic impact of pharmacists deprescribing NSAIDs under the guidance of a standardized deprescribing program compared with usual care within an integrated health care system. METHODS: This retrospective, propensity score-matched cohort study included patients aged ≥ 65 years who were eligible for the NSAID deprescribing program from July 2016 to June 2018. Those patients in the deprescribing group were assessed by pharmacists and had their medications deprescribed. Patients who were eligible for the deprescribing program but did not receive any interventions were matched to the deprescribed group using propensity score matching at a 4:1 ratio and became the usual care group. Patients were followed for 6 months, until end of membership, or until death, whichever occurred first. The effectiveness and safety outcomes included rates of 3 adverse events: GI bleeds, acute kidney injuries (AKI), and exacerbation of pain triggering a hospitalization or emergency room visit. The economic outcome was the change in monthly NSAID cost. Descriptive statistics, t-tests, chi-square tests, and conditional logistic regression models were used for analysis. RESULTS: There were 431 patients in the deprescribed group and 1,724 patients in the usual care group, with similar baseline characteristics after propensity score matching. The adjusted results showed no significant difference between the deprescribed and usual care groups for GI bleed events (OR = 0.65, 95% CI = 0.36-1.16, P = 0.15) and AKI (OR = 0.53, 95% CI = 0.24-1.16, P = 0.11). The deprescribed group experienced a significant 2-fold decrease in the odds of exacerbation of pain versus the deprescribed group (OR = 0.50, 95% CI = 0.33-0.77, P < 0.01). Finally, there was no significant difference in the change in monthly NSAIDs costs between the 2 groups (median change, IQR: -$0.29, -$2.37 to -$0.11 for deprescribed group; -$0.23, -2.59 to 0.00 for usual care group, P = 0.054). CONCLUSIONS: Although this study did not find any difference in the rate of GI bleed or AKI, we found a significant decrease in the rate of exacerbation of pain in the deprescribed group versus the usual care group. This result suggests that deprescribing NSAIDs did not cause harm during the 6-month follow-up. Further long-term studies are necessary to validate these outcomes. DISCLOSURES: No funding was provided to support this research study. The authors of this study have no actual or potential conflicts of interest to report. Parts of this study were presented in a nonreviewed resident poster at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; March 25-28, 2019; San Diego, CA.
32497778 A pharmacological interactome between COVID-19 patient samples and human sensory neurons r 2020 Oct The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.
31970392 Population-based Data at Ages 31 and 46 Show Decreased HRQoL and Life Satisfaction in Wome 2020 Jun 1 CONTEXT: Polycystic ovary syndrome (PCOS) is associated with decreased health-related quality of life (HRQoL), but longitudinal data beyond the reproductive years are lacking, and the impact of isolated PCOS symptoms is unclear. OBJECTIVE: To study generic HRQoL using the 15D questionnaire, life satisfaction, and self-reported health status in women with PCOS symptoms at ages 31 and 46 years. DESIGN: A longitudinal assessment using the Northern Finland Birth Cohort 1966. SETTING: General community. PARTICIPANTS: The 15D data were available for women reporting isolated oligo-amenorrhea (OA; at age 31 years, 214; and 46 years, 211), isolated hirsutism (H; 31 years, 211; and 46 years, 216), OA + H (PCOS; 31 years, 74; and 46 years, 75), or no PCOS symptoms (controls; 31 years, 1382; and 46 years, 1412). Data for life satisfaction and current health status were available for OA (31 years, 329; and 46 years, 247), H (31 years, 323; and 46 years, 238), PCOS (31 years, 125; and 46 years, 86), control (31 years, 2182; and 46 years, 1613) groups. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 15D HRQoL, questionnaires on life satisfaction, and self-reported health status. RESULTS: HRQoL was lower at ages 31 and 46 in women with PCOS or H than in the controls. PCOS was an independent risk factor for low HRQoL, and the decrease in HRQoL in PCOS was similar to that of women with other chronic conditions, such as asthma, migraine, rheumatoid arthritis, and depression. The risk for low HRQoL in PCOS remained significant after adjusting for body mass index, hyperandrogenism, and socioeconomic status. Mental distress was the strongest contributing factor to HRQoL. PCOS was also associated with a risk for low life satisfaction and a 4-fold risk for reporting a poor health status. CONCLUSIONS: Women with PCOS present with low HRQoL, decreased life satisfaction, and a poorer self-reported health status up to their late reproductive years. Assessments and interventions aiming to improve HRQoL in PCOS should be targeted beyond the fertile age.
31958903 Elevated Neutrophil to Lymphocyte Ratio in Older Adults with Cocaine Use Disorder as a Mar 2020 Feb 29 OBJECTIVE: The neutrophil to lymphocyte ratio (NLR) is a non-specific, easy-to-obtain marker of inflammation associated with morbidity and mortality in systemic, psychiatric, and age-related inflammatory conditions. Given the growing trend of substance use disorder (SUD) in older adults, and the relationship between inflammation and SUD elevated NLR may serve as a useful inflammatory biomarker of the combined burden of aging and SUD. The present study focused on cocaine use disorder (CUD) to examine if cocaine adds further inflammatory burden among older adults, by comparing NLR values between older adults with CUD and a non-cocaine using, aged-matched, nationally representative sample. METHODS: The dataset included 107 (86% male) participants (aged 50-65 years) with cocaine use disorder. NLR was derived from complete blood count tests by dividing the absolute value of peripheral neutrophil concentration by lymphocyte concentration. For comparison, we extracted data from age-matched adults without CUD using the National Health and Nutrition Examination Survey. Individuals with immunocompromising conditions were excluded (e.g., rheumatoid arthritis and sexually transmitted infections such as HIV). A doubly-robust inverse probability-weighted regression adjustment (IPWRA) propensity score method was used to estimate group differences on NLR while controlling for potential confounding variables (age, gender, race, income, nicotine, marijuana and alcohol use). RESULTS: The IPWRA model revealed that the CUD sample had significantly elevated NLR in comparison to non-cocaine users, with a moderate effect size (β weight = 0.67). CONCLUSION: Although non-specific, NLR represents a readily obtainable inflammatory marker for SUD research. CUD may add further inflammatory burden to aging cocaine users.
32810792 Porcine soluble CD83 alleviates LPS-induced abortion in mice by promoting Th2 cytokine pro 2020 Nov CD83, either in its membrance-bound form (mCD83) or soluble form (sCD83), is an important immunomodulatory molecule in humans and mice. While mCD83 is immunostimulatory, sCD83 exhibits striking immunosuppressive activities, suggesting that sCD83 may be used to combat inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease and habitual abortion. Although many studies had shed lights on the role of CD83 in humans and mice, little is known about CD83 in other animals. Recently, we showed that porcine CD83 had similar biochemical characteristics and immunoregulatory functions as its human counterpart. However, whether porcine sCD83 (psCD83) is involved in maintaining the immunological tolerance at the maternal-fetal interface and thereby prevents embryo loss and abortion during pregnancy is unclear. In this study, we used LPS-induced animal model to analyze the effect of porcine sCD83 on the mouse abortion. Results showed that psCD83 could significantly alleviate LPS-induced abortion in mice, indicating that the psCD83 had the function of fetal protection. Mechanically, psCD83-mediated fetal protection was related to the promotion on Th2 cytokine production, Treg cell differentiation and trophoblast invasion. This study provides a molecular basis for the fetal protection of psCD83, as well as a potential target for the regulation of maternal-fetal interfacial immune tolerance.
32639693 High tolerance to instrument drifts by differential chemical isotope labeling LC-MS: A cas 2020 Jun 11 Metabolomics study of a biological system often involves the analysis of many comparative samples over a period of several days or weeks. This process of long-term sample runs can encounter unexpected instrument drifts such as small leaks in liquid chromatography-mass spectrometry (LC-MS), degradation of column performance, and MS signal intensity change. A robust analytical method should ideally tolerate these instrumental drifts as much as possible. In this work, we report a case study to demonstrate the high tolerance of differential chemical isotope labeling (CIL) LC-MS method for quantitative metabolome analysis. In a study of using a rat model to examine the metabolome changes during rheumatoid arthritis (RA) disease development and treatment, over 468 samples were analyzed over a period of 15 days in three batches. During the sample runs, a small leak in LC was discovered after a batch of analyses was completed. Reanalysis of these samples was not an option as sample amounts were limited. To overcome the problem caused by the small leak, we applied a method of retention time correction to the LC-MS data to align peak pairs from different runs with different degrees of leak, followed by peak ratio calculation and analysis. Herein, we illustrate that using (12) C-/(13) C-peak pair intensity values in CIL LC-MS as a measurement of concentration changes in different samples could tolerate the signal drifts, while using the absolute intensity values (ie, (12) C-peak as in conventional LC-MS) was not as reliable. We hope that the case study illustrated and the method of overcoming the small-leak-caused signal drifts can be helpful to others who may encounter this kind of situation in long-term sample runs.
32569630 Effects of protein-protein interface disruptors at the ligand of the glucocorticoid-induce 2020 Aug The tumor necrosis factor (TNF) superfamily (TNFSF) includes about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Receptors of the tumor necrosis factor (TNF) superfamily (TNFSFRs) are pharmacological targets for treatment of inflammatory and autoimmune diseases. Currently, drugs targeting TNFSFR signaling are biological drugs (monoclonal antibodies, decoy receptors) aimed at binding and sequestering TNFSFR ligands. The glucocorticoid-induced tumor necrosis factor receptor-related gene (GITR) signaling is involved in a series of inflammatory and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. Our study aimed at repurposing FDA approved small molecules as protein-protein disruptors at the GITR ligand (GITRL) trimer, in order to inhibit the binding of GITRL to its receptor (GITR). A structure based molecular modeling approach was carried out to identify, through high throughput virtual screening, GITRL monomer-monomer disruptors. We used a database of ~8,000 FDA approved drugs, and after virtual screening, we focused on two hit compounds, minocycline and oxytetracycline. These two compounds were tested for their capability to modulate IL-17, IL-21 and RORγT expression in T lymphocytes, isolated from wild-type and GITR knock-out (GITR(-/-)) mice. Minocycline showed immunomodulatory effects specific to GITR activation and could represent a novel pharmacological tool to treat inflammatory diseases.
32439404 Efficacy-directed discrimination of the essential oils of three Juniperus species based on 2020 Sep 15 ETHNOPHARMACOLOGICAL RELEVANCE: Juniperus plants are considered important sources of cedar-wood oil which is used widely in folk medicine as antiseptic and in treatment of inflammatory disorders such as, rheumatoid arthritis but there is not enough scientific evidence to support the claimed uses and there is no specification of a certain Juniperus species as the most active. AIM OF THE STUDY: The aim of this study is volatiles profiling of three Juniperus species; J. communis, J. horizontalis and J. chinensis in addition to efficacy-directed discrimination of the three studied essential oils based on their antimicrobial, and anti-inflammatory activities in LPS (lipopolysaccharide)-stimulated WBCs (White blood cells) to investigate the inter-specific variability effect on the biological activities of each oil. MATERIALS AND METHODS: Volatile components profiling of the three studied plants volatile oils was achieved using GC-FID (Gas chromatography - flame ionization detector) and GC-MS (Gas chromatography - mass spectrometry). The antimicrobial activity of the studied essential oils was investigated and the minimum inhibitory concentration (MIC) was determined for oils. The production of the pro-inflammatory cytokines was evaluated by ELISA (Enzyme linked immunosorbent assay). Identification of the biomarkers responsible for each activity was attempted through construction of orthogonal projection to latent structures model using multivariate statistical analysis. RESULTS: Forty five components were identified in the volatile oils of the three studied plants. J. horizontalis oil displayed the highest activity against E. coli while J. communis showed the highest activity against S. aureus. OPLS model biplot showed the in-between class discrimination of J. chinensis oil sample from J. communis and J. horizontalis. The three oils were found to significantly decrease the production of the pro-inflammatory cytokines tumour necrosis factor (TNF)- α, interleukin (IL)-1β, and gamma interferon (INF- γ) in lipopolysaccharide-activated white blood cells. All studied oils were similar in reduction of TNF-α, and INF-γ, while J. chinensis oil possessed the highest potency against IL-1β. The coefficient plots of TNF-α and INF-γ pro-inflammatory mediators showed that 1-terpineol, 4-terpineol, bornyl acetate, dl-limonene and α-pinene positive contributors to both activities while β-thujone, 3-carene and γ-muurolene were the positive contributors to IL-1β inhibitory activity. CONCLUSION: The differences observed in the volatile profiles among the three studied oils demonstrate the effect of inter-specific variability on the biological activities of the tested oils. It was shown that the tested oils possessed good antibacterial activities against E.coli and S. aureus justifying its folk use as an a topical antiseptic while the observed anti-inflammatory effects in human WBCs is due at least in part to their inhibitory effect on the production of pro-inflammatory cytokines.
33323124 Prevalence of musculoskeletal conditions and related disabilities in Bangladeshi adults: a 2020 Dec 16 BACKGROUND: Nationally representative data on burden of musculoskeletal conditions (MSK) in Bangladesh are not available. The objective of this study was to determine the prevalence of MSK conditions and related disabilities in the adult population of Bangladesh. METHODS: A total of 2000 individuals aged 18 years or older were targeted from 20 primary sampling units (urban and rural) of all former seven divisions of Bangladesh in 2015. Structured interviews were done using the modified Community Oriented Program for Control of Rheumatic Disorders questionnaire to detect positive respondents. Standard criteria were used for diagnosing MSK conditions by rheumatology residents. In case of uncertainty, opinion was taken from senior rheumatologists. A Bangla version of the Health Assessment Questionnaire was used to determine disability. RESULTS: A total of 1843 (92.1%) participated. Among them, 892 men and 951 women participated from rural (n = 716) and urban (n = 1127) areas. Their mean age was 40.5 (standard deviation 14.7) years. Almost a third did not have any formal schooling. Overall, 30.4% (95% confidence interval, 28.3-32.5) had MSK conditions. Low back pain (18.6%, 16.9-20.5), knee osteoarthritis (7.3%, 6.1-8.5) and soft tissue rheumatism 3.8% (2.9-4.7) were the three top-ranking MSK conditions. Rheumatoid arthritis (1.6%, 1.0-2.1), spondyloarthritis (1.2%, 7-1.8) and adhesive capsulitis (1.4%, 0.9-1.9) were relatively uncommon. Among those who had MSK conditions, 24.8% (21.3-28.6) had some degree of disability. Of them, 24.4% (21.0-28.1) had history of work loss during last 12 months. CONCLUSIONS: The high burden of MSK conditions and related disabilities in Bangladesh warrants greater attention of the health system. Further studies are needed to estimate the impact of this group of conditions particularly addressing related disabilities and loss of work.
33179144 Immunometabolic Pathways and Its Therapeutic Implication in Autoimmune Diseases. 2021 Feb Autoimmune diseases (AIDs) are characterized with aberrant immune responses and their respective signaling pathways controlling cell differentiation, death, and survival. Cell metabolism is also an indispensable biochemical process that provides the very fundamental energy and materials. Accumulating evidences implicate that metabolism pathways have critical roles in determining the function of different immune subsets. Mechanisms of how immunometabolism participate in the pathogenesis of AIDs were also under intensive exploration. Here, in this review, we summarize the metabolic features of immune cells in AIDs and also the individual function of immunometabolism pathways, including glucose metabolism and tricarboxylic acid (TCA) cycle, in the setting of AIDs, mainly focusing on the potential targets for intervention. We also review studies that explore the intervention strategies targeting key molecules of metabolic pathways, such as mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1a (HIF1a), in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The highlight of this review is to provide a comprehensive summary of the status quo of immunometabolism studies in AIDs and the potential translatable drug targets.
32877451 Effectiveness of first-line treatment for relapsing-remitting multiple sclerosis in Brazil 2020 BACKGROUND: Relapsing-remitting multiple sclerosis (RRMM) is a chronic, progressive, inflammatory and immune-mediated disease that affects the central nervous system and is characterized by episodes of neurological dysfunction followed by a period of remission. The pharmacological strategy aims to delay the progression of the disease and prevent relapse. Interferon beta and glatiramer are commonly used in the Brazilian public health system and are available to patients who meet the guideline criteria. The scenario of multiple treatments available and in development brings the need for discussion and evaluation of the technologies already available before the incorporation of new drugs. This study analyses the effectiveness of first-line treatment of RRMS measured by real-world evidence data, from the Brazilian National Health System (SUS). METHODS AND FINDINGS: We conducted a non-concurrent national cohort between 2000 and 2015. The study population consisted of 22,722 patients with RRMS using one of the following first-line drugs of interest: glatiramer or one of three presentations of interferon beta. Kaplan-Meier analysis was used to estimate the time to treatment failure. A univariate and multivariate Cox proportional hazard model was used to evaluate factors associated with treatment failure. In addition, patients were propensity score-matched (1:1) in six groups of comparative first-line treatments to evaluate the effectiveness among them. The analysis indicated a higher risk of treatment failure in female patients (HR = 1.08; P = 0,01), those with comorbidities at baseline (HR = 1.20; P<0,0001), in patients who developed comorbidities after starting treatment (i.e., rheumatoid arthritis-HR = 1.65; P<0,0001), those exclusive SUS patients (HR = 1.31; P<0,0001) and among patients using intramuscular interferon beta (IM βINF-1a) (28% to 60% compared to the other three treatments; P<0,0001). Lower risk of treatment failure was found among patients treated with glatiramer. CONCLUSIONS: This retrospective cohort suggests that glatiramer is associated with greater effectiveness compared to the three presentations of interferon beta. When evaluating beta interferons, the results suggest that the intramuscular presentation is not effective in the treatment of multiple sclerosis.
32841699 Ethanol extract of Liriodendron chinense (Hemsl.) Sarg barks attenuates hyperuricemic neph 2021 Jan 10 ETHNOPHARMACOLOGICAL RELEVANCE: Liriodendron chinense (Hemsl.) Sarg, known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects. AIM OF THE STUDY: The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms. MATERIALS AND METHODS: EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis. RESULTS AND DISCUSSION: Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 μmol/L of EELC vs. 238.28 ± 20.97 μmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 μmol/L of EELC vs. 92.08 ± 6.13 μmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins. CONCLUSIONS: EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney.