Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
30905787 Effects of Periploca forrestii Schltr on wound healing by Src meditated Mek/Erk and PI3K/A 2019 Jun 12 ETHNOPHARMACOLOGICAL RELEVANCE: Periploca forrestii Schltr. (PF) is a traditional folk medicine in China that has been used widely for treating rheumatoid arthritis and traumatic injuries for a long history. Previously, we have roughly demonstrated that the ethanol extract of PF possessed in vitro wound healing potential, and more in depth research deserves to be conducted. AIM OF THE STUDY: The present study is aiming to fully evaluate the wound healing activity of PF in vitro and in vivo, clarify the mechanism of actions and the primary constituents responsible for wound healing. MATERIALS AND METHODS: The total extract of Periploca forrestii Schltr. (EPF) and its fraction (65% ethanol fraction, EPFE65) were obtained and evaluated on in vitro wound healing properties using mouse dermal fibroblasts (L929). Cell proliferation was tested by MTT and EdU assay, confirmed by cell cycle analysis, cell migration was evaluated by scratch and transwell assay and collagen production was also determined. Then EPFE65 was tested on in vivo wound healing activity using the excision rat models. The wounded skin of rats was topically applied with 0.1% EPFE65 once daily for 6 days with hydrogel as the carrier and the recombinant bovine basic fibroblast growth factor hydrogel (rbFGF) as positive control. Histopathology of the wounded skin on day 6 and day 12 was studied via hematoxylin and eosin (HE) staining. The expression of phosphorylation of Src, Akt and Erk1/2 was determined after the treatment with EPFE65 by western blot. In order to figure out whether the activation of Src, Akt and Erk1/2 was directly in conjunction with wound healing process promoted by EPFE65, cell proliferation and migration were tested in the presence of three inhibitors of Src, Akt and Erk1/2. Finally, the chemical composition of the effective fraction EPFE65 was analyzed by HPLC-Q-TOF-MS/MS. RESULTS: In vitro experiments suggested that EPFE65 was comparable to EPF that had potent effect on promoting L929 fibroblasts proliferation, migration and increasing collagen production. 0.1% EPFE65 hydrogel also exhibited significant effect on promoting wound healing in rats. The wound closure was significantly faster in EPFE65 and positive rbFGF group than that in negative control group since the third day post wounding (p < 0.05). Specifically, on day10-12, the wounds in EPFE65 and rbFGF group were almost healed as the wound areas diminished into 13.3-5.3% and 7.7-4.0%, while the wound in control group was still apparent with 36.8-22.1% wound area. HE staining demonstrated that EPFE65 and rbFGF group could advance re-epithelialization in the early days and promote the transition of granulation tissue into complete dermis tissue with more skin appendages resembling those of normal skin in the last days. Western blot results suggested that the active fraction EPFE65 could increase the phosphorylation of Src, Akt and Erk1/2 in both dose-dependent and time-dependent manner, whereas Akt and Erk1/2 phosphorylation caused by EPFE65 could be abolished by Src inhibition. Inhibition experiments confirmed that the activation of Src, Akt and Erk1/2 were involved in cell proliferation and migration. All of these demonstrated that EPFE65 promoted wound healing at least in part via Src mediated Mek/Erk and PI3K/Akt signaling pathways. Analysis of chemical composition of EPFE65 revealed that cardiac glycosides were major components in EPFE65, among which periplocin showed effectiveness on promoting fibroblasts proliferation indicating that cardiac glycosides in EPFE65 maybe the active compounds responsible for wound healing. CONCLUSION: The present study confirmed that EPFE65, ethanol extract of Periploca forrestii Schltr. could accelerate wound healing in vitro and in vivo through Src meditated Mek/Erk and PI3K/Akt signaling pathways.
30832306 Evaluation of the Liver Toxicity of Pterocephalus hookeri Extract via Triggering Necrosis. 2019 Mar 2 Pterocephalus hookeri (C. B. Clarke) Höeck, recorded in the Chinese Pharmacopoeia (2015 version) as a Tibetan medicine for the treatment of various diseases, especially rheumatoid arthritis, was believed to possess a slight toxicity. However, hardly any research has been carried out about it. The present study aimed to evaluate the toxicity in vivo and in vitro. Toxicity was observed by the evaluation of mice weight loss and histopathological changes in the liver. Then, the comparison research between ethyl acetate extract (EAE) and n-butanol extract (BUE) suggested that liver toxicity was mainly induced by BUE. The mechanical study suggested that BUE-induced liver toxicity was closely associated with necrosis detected by MTT and propidium iodide (PI) staining, via releasing lactate dehydrogenase (LDH), reducing the fluidity, and increasing the permeability of the cell membrane. Western blot analysis confirmed that the necrosis occurred molecularly by the up-regulation of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3), as well as the activation of the nuclear factor-kappa-gene binding (NF-κB) signaling pathway in vivo and in vitro. This finding indicated that the liver toxicity induced by BUE from P. hookeri was mainly caused by necrosis, which provides an important theoretical support for further evaluation of the safety of this folk medicine.
31861667 Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channe 2019 Dec 19 Previous studies have reported the up-regulation of the two-pore domain K(+) channel K(2P)5.1 in the CD4(+) T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K(2P)5.1 in the splenic CD4(+) T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4(+) T cells of the IBD model. In the activated splenic CD4(+) T cells, hypoxia (1.5% O(2)) increased K(2P)5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K(2P)5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K(2P)5.1 transcription in activated CD4(+) T cells, and we found no significant effects on the K(2P)5.1 transcription. No acute compensatory responses of K(2P)3.1-K(2P)5.1 up-regulation were found in the CD4(+) T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K(2P)5.1 up-regulation via HIF-1 in the CD4(+) T cells of the IBD model.
31622745 Dendrobium officinale polysaccharide ameliorates diabetic hepatic glucose metabolism via g 2020 Feb 10 ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium officinale polysaccharide (DOP) is the main active ingredient of Dendrobium officinale Kimura & Migo, which is a precious traditional Chinese medicine and often used in treatment of hepatitis, diabetes, obesity and rheumatoid arthritis. AIM OF THE STUDY: DOP exhibits significant hypoglycemic activity, while its mechanism remains unclear. The present study aims to investigate the hypoglycemic mechanisms of DOP based on the glucagon-mediated signaling pathways and the liver glycogen structure, which catalyze hepatic glucose metabolism, and provide new knowledge about the antidiabetic mechanism of DOP and further evidence for its clinical use for diabetes. MATERIALS AND METHODS: DOP were obtained from the dry stems of Dendrobium officinale by water extraction and alcohol precipitation method. T2DM mice model was established by high-fat diet combined with streptozotocin. Liver histopathological changes were observed by H&E and PAS straining. Pancreatic histology was studied by H&E staining and immunofluorescence analysis. The levels of glucagon and insulin were detected by Elisa Kit and the hepatic glycogen content was detected by GOPOD. The expressions of the hepatic glycogen-related metabolism enzymes, hepatic gluconeogenesis enzymes, and the related protein in cAMP-PKA and Akt/FoxO1 signaling pathways were detected by western blots. Liver glycogen was extracted from the liver tissues by sucrose density gradient centrifugation, and size exclusion chromatography (SEC) was used to analyze the structure of liver glycogen. RESULTS: DOP could significantly affect the glucagon-mediated signaling pathways, cAMP-PKA and Akt/FoxO1, to further promote hepatic glycogen synthesis, inhibit hepatic glycogen degradation and hepatic gluconeogenesis. Moreover, DOP could reverse the instability of the liver glycogen structure and thus probably suppressed glycogen degradation. Thus, DOP finally would ameliorate hepatic glucose metabolism via glucagon-mediated signaling pathways and modifying liver-glycogen structure in diabetic mice. CONCLUSIONS: The hypoglycemic mechanism of DOP might be associated with the regulation of glucagon-mediated hepatic glycogen metabolism and gluconeogenesis, and of liver glycogen structure, contributing to improved hepatic glucose metabolism in diabetic mice.
31461149 Opioid Prescription Patterns and Risk Factors Associated With Opioid Use in the Netherland 2019 Aug 2 IMPORTANCE: An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted. OBJECTIVES: To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081 507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019. EXPOSURE: Opioid prescription. MAIN OUTCOMES AND MEASURES: The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription. RESULTS: In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1 027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription. CONCLUSIONS AND RELEVANCE: This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription.
31119895 Predictive clinical-genetic model of long-term non-response to tumor necrosis factor-alpha 2019 Aug AIM: Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society (ASAS) criteria. METHOD: From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. RESULTS: The clinical factors that significantly increased the non-response rate were: global visual analog scale (VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. CONCLUSION: We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy.
30472651 Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases 2019 Feb OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.
30345821 Comparison of Radiographic and Clinical Results After Extended Distal Chevron Osteotomy Wi 2019 Mar BACKGROUND: We compared the radiographic and clinical outcomes of moderate and severe hallux valgus treated by extended distal chevron osteotomy (EDCO) and distal soft tissue release (DSTR). METHODS: We performed a retrospective analysis comparing the utility of EDCO for the treatment of moderate (36 patients, 46 feet) and severe (36 patients, 42 feet) hallux valgus. The radiologic outcomes were evaluated based on the preoperative and 3-year follow-up x-rays. The clinical results were investigated based on the 3-year follow-up Manchester-Oxford Foot Questionnaire (MOXFQ), patient satisfaction, and postoperative complications. RESULTS: The mean postoperative intermetatarsal angle, hallux valgus angle, tibial sesamoid position, and relative metatarsal bone length were significantly different compared with the preoperative values for both the moderate and severe groups ( P < .001). At 3-year follow-up, intergroup differences were observed in the mean postoperative intermetatarsal angle ( P = .001), hallux valgus angle ( P = .003), and tibial sesamoid position ( P = .013); however, mean radiographic results were within the normal range for both groups. There were no intergroup differences for either the first metatarsal bone length ( P = .172) or shortening ( P = .621). No significant difference in MOXFQ ( P = .525) was evident between the groups at 3-year follow-up. In satisfaction analysis, 82.6% of the moderate group reported good to excellent results, as did 81.0% of the severe group ( P = .815). A total of 7 complications were reported in each group ( P = 1.000). CONCLUSION: The present study showed that midterm mean radiographic results of both moderate and severe hallux valgus treated by EDCO with DSTR were favorable, and those values were within the normal range. Clinical outcomes were comparable between the 2 groups, including overall efficacy. Based on these results, we recommend EDCO with DSTR as an efficient and reliable operative option for both moderate and severe hallux valgus. LEVEL OF EVIDENCE: Level III, retrospective comparative study.
30289001 Extended Sinus Tarsi Approach for Treatment of Displaced Intraarticular Calcaneal Fracture 2019 Feb BACKGROUND: We compared the radiographic results and clinical outcomes of patients operated on via the extended sinus tarsi approach (ESTA) and the extended lateral approach (ELA) for treatment of displaced intraarticular calcaneal fractures. METHODS: We retrospectively studied the utility of the ELA (46 patients, 52 feet) and the ESTA (56 patients, 64 feet) in patients operated on between January 2009 and March 2015. We evaluated pre- and postoperative x-rays and computed tomography (CT) data. Pain, patient-reported functional outcomes, satisfaction, and postoperative complications were investigated at the 3-year follow-up. RESULTS: Neither the postoperative nor 3-year follow-up Böhler angles, nor the calcaneal width, differed significantly between the 2 groups (both P > .05). However, the maximum step-off of the posterior facet on the 3-month CT follow-up of the ESTA group was significantly less than that of the ELA group ( P < .05). We found no significant between-group differences in terms of postoperative translation ( P = .232) or angulation ( P = .132) of the sustentacular fragment on the 3-month CT follow-up. At the 3-year follow-up, we found no significant between-group difference in the mean visual analog scale pain score at rest ( P = .641) or during weightbearing ( P = .525). We found no significant between-group difference in the Foot Function Index (FFI) ( P = .712) or self-reported satisfaction ( P = .823). The ELA group experienced significantly more wound complications ( P = .041) and nonunions ( P = .041) than the ESTA group. Four instances of superficial peroneal nerve injury were reported in the ESTA group ( P = .127). CONCLUSION: Compared with the ELA, the ESTA afforded comparable, favorable radiological results and clinical outcomes, associated with fewer wound complications and nonunions. We suggest that the ESTA is an effective operative option when treating displaced, intraarticular calcaneal fractures. LEVEL OF EVIDENCE: Level III, comparative study.
31611218 Antigen-driven selection of antibodies against SSA, SSB and the centromere 'complex', incl 2020 Jan OBJECTIVES: Recent evidences have revealed that anti-SSA/SSB antibodies, the major autoantibodies in Sjögren's syndrome (SS), are produced in salivary glands. This study aims to clarify overall of autoantibody production at lesion site, including anti-centromere antibody (ACA)-positive SS. METHODS: Antibodies of antibody-secreting cells in human salivary glands were produced as recombinant antibodies. The reactivity of these antibodies and their revertants were investigated by ELISA and newly developed antigen-binding beads assay, which can detect conformational epitopes. The target of uncharacterised antibodies was identified by immunoprecipitation and mass spectrometry. Autoantibody-secreting cells in salivary gland tissue were identified by immunohistochemistry using green fluorescent protein-autoantigen fusion proteins. RESULTS: A total of 256 lesion antibodies were generated, and 69 autoantibodies including 24 ACAs were identified among them. Beads assay could detect more autoantibodies than ELISA, suggesting autoantibodies target to antigens with native conformation. After somatic hypermutations were reverted, autoantibodies drastically decreased antigen reactivity. We showed that MIS12 complex, a novel target of ACA, and CENP-C are major targets of ACA produced in salivary glands by examining cloned antibodies and immunohistochemistry, whereas few anti-CENP-B antibodies were detected. The target profiling of serum ACA from 269 patients with SS, systemic sclerosis (SSc), primary biliary cirrhosis (PBC) and healthy controls revealed that ACA-positive patients have antibodies against various sites of centromere complex regardless of disease. CONCLUSION: We showed direct evidences of antigen-driven maturation of anti-SSA/SSB antibody and ACA in SS lesion. ACA recognises centromere 'complex' rather than individual protein, and this feature is common among patients with SS, SSc and PBC.
31022184 Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE sus 2019 Apr Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.
30824481 Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity. 2019 Apr 15 The aim of this study was to test whether autoantibodies against neurologic surface Ags are found in nonneurologic autoimmune diseases, indicating a broader loss of tolerance. Patient and matched healthy donor (HD) sera were derived from four large cohorts: 1) rheumatoid arthritis (RA) (n = 194, HD n = 64), 2) type 1 diabetes (T1D) (n = 200, HD n = 200), 3) systemic lupus erythematosus (SLE) (n = 200, HD n = 67; neuro-SLE n = 49, HD n = 33), and 4) a control cohort of neurologic autoimmunity (relapsing-remitting multiple sclerosis [MS] n = 110, HD n = 110; primary progressive MS n = 9; secondary progressive MS n = 10; neuromyelitis optica spectrum disorders n = 15; and other neurologic disorders n = 26). Screening of 1287 unique serum samples against four neurologic surface Ags (myelin oligodendrocyte glycoprotein, aquaporin 4, acetylcholine receptor, and muscle-specific kinase) was performed with live cell-based immunofluorescence assays using flow cytometry. Positive samples identified in the screening were further validated using autoantibody titer quantification by serial dilutions or radioimmunoassay. Autoantibodies against neurologic surface Ags were not observed in RA and T1D patients, whereas SLE patients harbored such autoantibodies in rare cases (2/200, 1%). Within the CNS autoimmunity control cohort, autoantibodies against aquaporin 4 and high-titer Abs against myelin oligodendrocyte glycoprotein were, as expected, specific for neuromyelitis optica spectrum disorders. We conclude that neurologic autoantibodies do not cross disease barriers in RA and T1D. The finding of mildly increased neurologic autoantibodies in SLE may be consistent with a broader loss of B cell tolerance in this form of systemic autoimmunity.
31601134 Association of Autoimmune Regulator Gene Rs2075876 Variant, but Not Gene Expression with A 2020 Feb Alopecia areata (AA) is a non-scarring hair loss of autoimmune etiology. The autoimmune regulator (AIRE) gene is believed to be an important driver in AA pathogenesis. Genetic variants can alter mRNA expression levels which may provoke an autoimmune response. A total of 337 males (97 AA patients and 240 controls) were enrolled in the current case-control study. On screening of the most frequent variants in the gene, rs2075876 (A/G) polymorphism in intron 5 was selected and genotyped using Real-Time PCR (polymerase chain reaction) technology. Additionally, circulatory AIRE expression levels were quantified by quantitative reverse-transcription PCR (qRT-PCR). Allelic discrimination analysis revealed GG genotype to be more frequent in patients (90.7% in AA compared to 32.5% in controls, p < .001). G variant conferred increased risk to alopecia under homozygote comparison (GG versus AA: OR = 16.1, 95%CI = 5.57-46.3), dominant model (GG+AG versus AA: OR = 7.24, 95%CI = 2.5-20.5), recessive model (GG versus AG+AA: OR = 20.3, 95%CI = 9.7-42.4), and allelic model (G versus A: OR = 11.6, 95%CI = 6.47-21.1). The expression levels of AIRE gene did not differ significantly between patients and controls and were not related to rs2075876 variant. In conclusion, the intronic variant (rs2075876) is suggested to be a potent susceptibility variant for AA development in the studied population.Abbreviations: AA: Alopecia areata; AIRE: Autoimmune Regulator; APECED: Autoimmune, Polyendocrinopathy Candidiasis Ectodermal Dystrophy; DLQI: Dermatology life quality index questionnaire; MIQE: Minimum information for publication of quantitative real-time PCR experiments; mTEC: Medullary thymic epithelial cells; PHD: Plant homeodomain; qRT-PCR: Quantitative reversetranscription-polymerase chain reaction; RA: Rheumatoid arthritis.
31370840 Differences in the quality of oral anticoagulation therapy with vitamin K antagonists in G 2019 Aug 1 BACKGROUND: In Germany, patients receiving oral anticoagulation (OAC) are often treated by general practitioners (GPs), and large proportions of patients receive vitamin K antagonists (VKAs). The quality of OAC in German GP practices, differences between various practices, and improvement potential through implementation of case management, have not yet been investigated satisfactorily. Based on results of a cluster-randomized controlled trial, we aimed to assess whether OAC quality can be improved, any variations between practices exist and determine practice- and patient-level factors. METHODS: The PICANT trial (2012-2015) was performed in 52 GP practices in Hesse, Germany. Adult patients with long-term indication for OAC received best practice case management in the intervention group. International normalized ratio (INR) values were recorded from anticoagulation passes. The Rosendaal method was used to calculate Time in Therapeutic Range (TTR) at patient level, and mean pooling to obtain center-specific TTR (cTTR) at practice level. The quality of OAC was assessed by TTR and cTTR. Linear model analyses were used to investigate associations between practice-/ patient-level factors and TTR. RESULTS: Inclusion of 736 patients (49.6% intervention and 50.4% control patients); 690 (93.8%) received phenprocoumon. Within 24 months, the TTR was 75.1% (SD 17.6) in the intervention versus 74.3% (SD 17.8) in the control group (p = 0.670). The cTTR averaged 75.1% (SD 6.5, range: 60.4 to 86.7%) in the intervention versus 74.3% (SD 7.2, range: 52.7 to 85.7%) in the control group (p = 0.668). At practice level, the TTR was significantly lower in practices with a male physician and certification in quality management. At patient level, the TTR was significantly higher in patients with moderate to high compliance, in men, and in patients that performed self-management. The TTR was significantly lower in patients with certain comorbidities, and who were hospitalized. CONCLUSIONS: The intervention did not effectively improve OAC quality compared to routine care. Quality of INR control was generally good, but considerable variation existed between GP practices. The variability indicates optimization potential in some practices. The demonstrated association between patient-level factors and TTR highlights the importance of considering patient characteristics that may impede achieving high quality therapeutic outcomes. TRIAL REGISTRATION: ISRCTN registry, ISRCTN41847489 , registered 27 February 2012.
31127007 Evidence for the Interaction of A(3) Adenosine Receptor Agonists at the Drug-Binding Site( 2019 Aug P-glycoprotein (P-gp) is a multidrug transporter that is expressed on the luminal surface of epithelial cells in the kidney, intestine, bile-canalicular membrane in the liver, blood-brain barrier, and adrenal gland. This transporter uses energy of ATP hydrolysis to efflux from cells a variety of structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs. In this regard, understanding the interaction with P-gp of drug entities in development is important and highly recommended in current US Food and Drug Administration guidelines. Here we tested the P-gp interaction of some A(3) adenosine receptor agonists that are being developed for the treatment of chronic diseases, including rheumatoid arthritis, psoriasis, chronic pain, and hepatocellular carcinoma. Biochemical assays of the ATPase activity of P-gp and by photolabeling P-gp with its transport substrate [(125)I]-iodoarylazidoprazosin led to the identification of rigidified (N)-methanocarba nucleosides (i.e., compound 3 as a stimulator and compound 8 as a partial inhibitor of P-gp ATPase activity). Compound 8 significantly inhibited boron-dipyrromethene (BODIPY)-verapamil transport mediated by human P-gp (IC(50) 2.4 ± 0.6 µM); however, the BODIPY-conjugated derivative of 8 (compound 24) was not transported by P-gp. In silico docking of compounds 3 and 8 was performed using the recently solved atomic structure of paclitaxel (Taxol)-bound human P-gp. Molecular modeling studies revealed that both compounds 3 and 8 bind in the same region of the drug-binding pocket as Taxol. Thus, this study indicates that nucleoside derivatives can exhibit varied modulatory effects on P-gp activity, depending on structural functionalization. SIGNIFICANCE STATEMENT: Certain A(3) adenosine receptor agonists are being developed for the treatment of chronic diseases. The goal of this study was to test the interaction of these agonists with the human multidrug resistance-linked transporter P-glycoprotein (P-gp). ATPase and photolabeling assays demonstrated that compounds with rigidified (N)-methanocarba nucleosides inhibit the activity of P-gp; however, a fluorescent derivative of one of the compounds was not transported by P-gp. Furthermore, molecular docking studies revealed that the binding site for these compounds overlaps with the site for paclitaxel in the drug-binding pocket. These results suggest that nucleoside derivatives, depending on structural functionalization, can modulate the function of P-gp.
30727020 Cementless 3D Printed Highly Porous Titanium-Coated Baseplate Total Knee Arthroplasty: Sur 2020 Mar Newer generation cementless total knee arthroplasty (TKA) implants continue to develop with demonstrated clinical success in multiple recent reports. The purpose of this study was to investigate (1) survivorship, (2) complications, and (3) clinical outcomes of a newer generation cementless and highly porous titanium-coated base plate manufactured using three-dimensional (3D) printing technology. We reviewed a single-surgeon, longitudinally maintained database of patients who underwent primary TKA using cementless, highly porous titanium-coated base plate implants from July 1, 2013 to December 31, 2016. A total of 523 patients were identified. Of this cohort, 496 patients had a minimum of 2-year follow-up and were included in our final analysis. Among these patients, 72 had bilateral TKA yielding a total of 568 TKAs. There were 133 men and 363 women who had a mean body mass index of 33 kg/m(2) (range, 20-61 kg/m(2)). The mean age was 66 years (range, 33-88 years). Average follow-up was 36 months (range, 24-48 months). Indications for TKA included osteoarthritis in 432 patients (87%), rheumatoid arthritis in 40 patients (8%), and knee osteonecrosis in 24 (5%) patients. Implant survivorship was defined as any revision leading to explantation of the base plate for any reason. Kaplan-Meier analysis was performed to determine all-cause implant survivorship at final follow-up for every patient. Complications were assessed using the Knee Society standardized list of TKA complications. Clinical outcomes were determined using the Knee Society pain and function scores. Range-of-motion values were also collected. There were a total of four failures, all were due to aseptic loosening with a survivorship rate of 99% at mean follow-up of 3 years (95% confidence interval = 0.984-0.999). In addition, there were a total of 12 surgical and 10 medical complications. Surgical complications did not affect the base plate or result in any additional implant revisions. A total of nine patients had thromboembolic disease complications; all received medical treatment and recovered adequately. Radiological evaluation did not show any signs of loosening or failures in other patients at final follow-up. Knee Society Scores for pain and function improved from 55 and 56 points preoperatively to 92 and 84 points at 2 years postoperatively. Our results are in concordance with the excellent clinical outcomes and survivorship demonstrated for the newer generation cementless TKA implants. In our experience, 3D printed titanium base plates demonstrated clinical success and excellent survivorship at minimum follow-up of 2 years.
31614442 Incidence of Cellulitis Following Acupuncture Treatments in Taiwan. 2019 Oct 11 Background: Cellulitis is a complication of acupuncture, but the risk factors and annualized incidence remain unclear. Objective: This study analyzed the incidence and risk factors of cellulitis related to acupuncture in a cohort of one million participants derived from Taiwan's Longitudinal Health Insurance Database. Methods: We tracked this cohort between 1997 and 2012 and recorded all outpatient medical information including diagnosis and treatment. Patients were categorized according to age, gender, comorbidities, residential area, and number of acupuncture treatments. We compared the incidence and risk of cellulitis between different demographics and comorbidities by logistic regression analysis and adjusted odds ratio (aOR) with a 95% confidence interval (95% CI). Results: We included 407,802 patients and 6,207,378 acupuncture treatments. The incidence of cellulitis after acupuncture was 64.4 per 100,000 courses of acupuncture treatment. The most common sites of cellulitis after acupuncture were the legs, feet, and face. Comorbidity was associated with post-acupuncture cellulitis; a multivariate logistic regression analysis showed that chronic kidney disease (aOR, 1.71; 95% CI, 1.55-1.88), rheumatoid arthritis (aOR, 1.86; 95% CI, 1.21-3.60), liver cirrhosis (aOR, 1.23; 95% CI, 1.15-1.32), diabetes mellitus (aOR, 1.69; 95% CI, 1.57-1.82), stroke (aOR, 1.44; 95% CI, 1.31-1.58), varicose veins (aOR, 2.38; 95% CI, 2.17-2.84), or heart failure (aOR, 1.81; 95% CI, 1.65-1.98) significantly increased cellulitis. Repeated exposure to acupuncture treatment was associated with an increased risk of cellulitis. Conclusions: A variety of chronic diseases may increase the risk of cellulitis after acupuncture. Physicians asked about past medical history before acupuncture might help to reduce cellulitis.
31600880 In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots. 2019 Oct 9 NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) activation has been linked to several chronic pathologies, including atherosclerosis, type-II diabetes, fibrosis, rheumatoid arthritis, and Alzheimer's disease. Therefore, NLRP3 represents an appealing target for the development of innovative therapeutic approaches. A few companies are currently working on the discovery of selective modulators of NLRP3 inflammasome. Unfortunately, limited structural data are available for this target. To date, MCC950 represents one of the most promising noncovalent NLRP3 inhibitors. Recently, a possible region for the binding of MCC950 to the NLRP3 protein was described but no details were disclosed regarding the key interactions. In this communication, we present an in silico multiple approach as an insight useful for the design of novel NLRP3 inhibitors. In detail, combining different computational techniques, we propose consensus-retrieved protein residues that seem to be essential for the binding process and for the stabilization of the protein-ligand complex.
31642878 Factors Associated With Complete Remission After Rituximab Therapy for Pemphigus. 2019 Dec 1 IMPORTANCE: Rituximab has emerged as a front-line therapy for pemphigus, but prognostic factors for achieving complete remission off therapy (CROT) with oral systemic agents remain unknown. OBJECTIVES: To describe rates of CROT and relapse and identify prognostic factors for achieving CROT after rituximab therapy for pemphigus. DESIGN, SETTING, AND PARTICIPANTS: A single-center, retrospective, cohort study was conducted at the University of Pennsylvania including 112 patients with pemphigus treated with rituximab with at least 12 months' clinical follow-up after the start of rituximab therapy. Multivariate regression analysis of factors predictive of CROT and Kaplan-Meier analysis of disease relapse were conducted. The study included patients treated with rituximab from March 15, 2005, until December 19, 2016. Data analysis was performed from December 2017 to June 2018. MAIN OUTCOMES AND MEASURES: The primary study outcome was CROT after 1 cycle. Secondary study outcomes included rate of CROT or the composite end point of CROT or complete remission on minimal therapy after 1 or more cycle, and median time to relapse. Multivariate regression analysis for prognostic variables for CROT, including age, sex, pemphigus subtype, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), disease duration, and dosing regimen, was performed. RESULTS: A total of 112 patients with pemphigus with median 37.8 months (range, 12.1-130.7) follow-up after rituximab therapy were identified. Of these, 65 were women (58.0%). At the time of first rituximab infusion, median age was 52.3 years (range, 20.0-89.3). Including patients who received multiple cycles of rituximab, 79 patients (70.5%) achieved CROT after a median time of 10.5 months (range, 2.0-49.8), and 36 of 72 patients (50.0%) subsequently experienced relapse after a median of 23.3 months (interquartile range, 10.8-50.4 months). Considering only the first cycle of rituximab, 54 patients (48.2%) achieved CROT. Controlling for age, sex, pemphigus subtype, BMI, and disease duration, patients who received lymphoma vs rheumatoid arthritis dosing were 2.70-fold more likely to achieve CROT (odds ratio [OR], 2.70; 95% CI, 1.03-7.12; P = .04). Increasing age was associated with significant increases in achieving CROT (Wald test for trend, P = .01), whereas BMI greater than or equal to 35 was associated with a 0.14 OR (95% CI, 0.03-0.63; P = .01) for achieving CROT, regardless of the dosing regimen. In multivariate analysis, there was no significant difference in CROT rates with sex (OR, 1.01; 95% CI, 0.42-2.50; P = .97), pemphigus subtype (OR, 0.37; 95% CI, 0.09-1.51; P = .17), or disease duration (OR, 0.99; 95% CI, 0.98-1.00; P = .09). CONCLUSIONS AND RELEVANCE: Lymphoma dosing and older age may be associated with CROT and BMI greater than or equal to 35 may be a negative prognostic factor for CROT after rituximab therapy for pemphigus. These findings help inform clinical expectations and merit evaluation in future prospective clinical trials.
30936016 15-Deoxy-Δ-12, 14-prostaglandin J2 acts cooperatively with prednisolone to reduce TGF-β- 2019 Jul BACKGROUND/AIMS: Synovial fibrosis is a pathological process that is observed in several musculoskeletal disorders and characterized by the excessive deposition of extracellular matrix, as well as cell migration and proliferation. Despite the fact that glucocorticoids are widely employed in the treatment of rheumatic pathologies such as osteoarthritis (OA) and rheumatoid arthritis, the mechanisms by which glucocorticoids act in the joint and their impacts on pro-fibrotic pathways are still unclear. MATERIALS: Human OA synovial fibroblasts were obtained from knee and hip joints. Cells were treated with prednisolone (1 mM) or transforming growth factor-beta 1 (TGF-β1) (10 ng/ml) for 1 and 7 days for quantification of RNA and protein expression (by real-time quantitative reverse transcription-PCR and western blot, respectively), 72 h for immunocytochemistry analysis, and 48 h for proliferation (by BrdU assay) and migration (by wound assay) studies. In addition, cells were preincubated with prednisolone and/or the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for 6 h before adding TGF-β1. pSmad1/5, pSmad2 and β-catenin levels were analyzed by Western blot. The activin receptor-like kinase-5 (ALK-5) inhibitor (SB-431542) was employed for the mechanistic assays. RESULTS: Prednisolone showed a predominant anti-fibrotic impact on fibroblast-like synoviocytes as it attenuated the spontaneous and TGF-β-induced gene expression of pro-fibrotic markers. Prednisolone also reduced α-sma protein and type III collagen levels, as well as cell proliferation and migration after TGF-β stimulation. However, prednisolone did not downregulate the gene expression of all the pro-fibrotic markers tested and did not restore the reduced PPAR-γ levels after TGF-β stimulation. Interestingly, anti-fibrotic actions of the glucocorticoid were reinforced in the presence of the PPAR-γ agonist 15d-PGJ2. Combined pretreatment modulated Smad2/3 levels and, similar to the ALK-5 inhibitor, blocked β-catenin accumulation elicited by TGF-β. CONCLUSIONS: Prednisolone, along with 15d-PGJ2, modulates pro-fibrotic pathways activated by TGF-β in synovial fibroblasts at least partially through the inhibition of ALK5/Smad2 signaling and subsequent β-catenin accumulation. These findings shed light on the potential therapeutic effects of glucocorticoids treatment combined with a PPAR-γ agonist against synovial fibrosis, although future studies are warranted to further evaluate this concern.