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ID PMID Title PublicationDate abstract
27643385 RORγt antagonist suppresses M3 muscarinic acetylcholine receptor-induced Sjögren's syndr 2017 Feb We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3(+) T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R(-/-) ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1(-/-) ) mice (M3R(-/-) →Rag-1(-/-) ) with MIS. Immunized M3R(-/-) mice (pretransfer treatment) and M3R(-/-) →Rag-1(-/-) mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4(+) T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4(+) T cells rather than CD11c(+) cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4(+) T cells of immunized M3R(-/-) mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4(+) T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production by M3R-specific T cells.
27388111 Conjunctival lymphoma in right eye: Case report. 2017 Feb CASE REPORT: A 43-year-old woman presented with a salmon-coloured patch of 0.7mm diameter in the right eye that extended into the lower fornix in the bulbar and tarsal conjunctiva, with irregular edges, and highly vascularised. Incisional biopsy was performed, showing it to be a low-grade conjunctival non-Hodgkin B cell lymphoma (or a mucosa associated lymphoid tissue [MALT] lymphoma). DISCUSSION: The lesion remained stable for 24 months of follow-up, when a relapse of the condition occurred, producing an enlargement of the initial lesion. The definitive diagnosis is made by biopsy of the affected tissue and histopathologic study.
31149462 Remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with 2017 Jan Remitting seronegative symmetrical synovitis with pitting edema syndrome has been reported to be associated with malignant tumors. However, few cases occurring with lung cancer have been reported. We here report a case of remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with lung cancer. A 77-year-old man presented with poly arthritis (both shoulders, knees, and hands), swelling of the hands, and an elevated C-reactive protein level. As the patient's rheumatoid factor was negative, he was diagnosed with remitting seronegative symmetrical synovitis with pitting edema syndrome. At the same time, computed tomography revealed a nodule suspicious of lung carcinoma in the right lower lobe. Right lower lobe lobectomy was performed, and the nodule was diagnosed as adenocarcinoma. Pathologically, pleural invasion and visceral pleural dissemination were detected, and the tumor was diagnosed as a primary lung carcinoma, p-T2aN0M1a, stage IV. During the preoperative interval, the remitting seronegative symmetrical synovitis with pitting edema syndrome had been successfully treated with prednisolone 20 mg/day, which was later reduced to 6 mg/day. Eighteen months after surgery, the patient's carcinoembryonic antigen levels increased, and the same symptoms recurred, this time more severely. We performed cranial magnetic resonance imaging and whole body positron emission tomography, but we did not detect any cancer recurrence. To treat the recurred remitting seronegative symmetrical synovitis with pitting edema syndrome, the patient has required not only prednisolone, but also azathioprine; however, the symptoms have not been controlled effectively. In our case, matrix metalloproteinase-3 levels were elevated, as shown in the tumor cells by immunohistochemistry. If higher matrix metalloproteinase-3 levels cause the symptoms, in our case, then remitting seronegative symmetrical synovitis syndrome might be considered a paraneoplastic syndrome. However, we could not conclusively determine if the subsequent reduction in matrix metalloproteinase-3 levels was the result of the surgery or the prednisolone treatment. Furthermore, based on the patient's progress following surgery, it is still not clear if the remitting seronegative symmetrical synovitis with pitting edema syndrome complicated with primary lung cancer in this case may be a paraneoplastic syndrome.
27993633 Davallia bilabiata exhibits anti-angiogenic effect with modified MMP-2/TIMP-2 secretion an 2017 Jan 20 ETHNOPHARMACOLOGICAL RELEVANCE: Davallia bilabiata Hosokawa (D. bilabiata), also called GuSuiBu, is popularly used as a substitute for Drynaria fortunei J. Sm for rheumatoid and degenerative arthritis in traditional Chinese medicine. Little is known about the underlying mechanisms of anti-angiogenesis responsible for arthritis in D. bilabiata which needs to be elucidated. AIM OF THE STUDY: The present study is intended to investigate the anti-angiogenic effect of D. bilabiata associated with the modulation of matrix metalloproteinases (MMPs) and down regulation of vascular endothelial growth factor (VEGF) ligand/receptors both in vivo and in vitro. MATERIALS AND METHODS: We investigated the potential anti-angiogenic effect of D. bilabiata by the in vivo neovascularization of chick chorioallantoic membranes (CAM) assay, and the in vitro migration and matrix-induced tube formation assay using human umbilical vascular endothelial cells (HUVECs). The expressions of MMP-2, TIMP-2, RECK and VEGF/VEGFR were analyzed by real-time RT-PCR or Western blot method. RESULTS: One major compound from water extract of D. bilabiata was identified as Epicatechin 3-O-β-D-allopyranoside. D. bilabiata was confirmed to inhibit in vivo angiogenesis by CAM assay. D. bilabiata also exhibited in vitro anti-angiogenic and anti-regrowth effects as demonstrated by tube formation assay, transwell migration assay and wound healing assay. The mRNA expressions of MMP-2, and MMP-14 were decreased. On the contrary, tissue inhibitor of metalloproteinase-2 (TIMP-2), reversion-inducing cysteine-rich protein with kazal motifs (RECK) were increased by D. bilabiata. The extracellular MMP-2 activity was found to be reduced both in vitro and in vivo by D. bilabiata as determined by gelatin zymography. Results from western blot analysis and ELISA further demonstrated the decrease of MMP-2 and increase of TIMP-2 secretion after D. bilabiata treatment. The gene expressions of VEGF-A, -B, -C, -D and VEGFR-1, -2, -3 were all inhibited by D. bilabiata. CONCLUSION: We concluded that the anti-angiogenic effect of D. bilabiata was associated with the decreased MMP-2 activity mediated by the upregulation of TIMP-2 and RECK, and the suppression of VEGF/VEGFRs expression.
28808942 Primary Care Providers' Opening of Time-Sensitive Alerts Sent to Commercial Electronic Hea 2017 Nov BACKGROUND: Time-sensitive alerts are among the many types of clinical notifications delivered to physicians' secure InBaskets within commercial electronic health records (EHRs). A delayed alert review can impact patient safety and compromise care. OBJECTIVE: To characterize factors associated with opening of non-interruptive time-sensitive alerts delivered into primary care provider (PCP) InBaskets. DESIGN AND PARTICIPANTS: We analyzed data for 799 automated alerts. Alerts highlighted actionable medication concerns for older patients post-hospital discharge (2010-2011). These were study-generated alerts sent 3 days post-discharge to InBaskets for 75 PCPs across a multisite healthcare system, and represent a subset of all urgent InBasket notifications. MAIN MEASURES: Using EHR access and audit logs to track alert opening, we performed bivariate and multivariate analyses calculating associations between patient characteristics, provider characteristics, contextual factors at the time of alert delivery (number of InBasket notifications, weekday), and alert opening within 24 h. KEY RESULTS: At the time of alert delivery, the PCPs had a median of 69 InBasket notifications and had received a median of 379.8 notifications (IQR 295.0, 492.0) over the prior 7 days. Of the 799 alerts, 47.1% were opened within 24 h. Patients with longer hospital stays (>4 days) were marginally more likely to have alerts opened (OR 1.48 [95% CI 1.00-2.19]). Alerts delivered to PCPs whose InBaskets had a higher number of notifications at the time of alert delivery were significantly less likely to be opened within 24 h (top quartile >157 notifications: OR 0.34 [95% CI 0.18-0.61]; reference bottom quartile ≤42). Alerts delivered on Saturdays were also less likely to be opened within 24 h (OR 0.18 [CI 0.08-0.39]). CONCLUSIONS: The number of total InBasket notifications and weekend delivery may impact the opening of time-sensitive EHR alerts. Further study is needed to support safe and effective approaches to care team management of InBasket notifications.
28712941 Rituximab biosimilar and reference rituximab in patients with previously untreated advance 2017 Aug BACKGROUND: GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab-CVP (R-CVP) in patients with follicular lymphoma. METHODS: In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R-CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period. Randomisation was stratified by Follicular Lymphoma International Prognostic Index risk group and geographic region. The primary endpoint was comparability in overall response, with equivalence concluded if the entire 95% CI was within a margin of -12% to 12%. The primary endpoint was analysed using the per-protocol set, which included all patients who received at least one (partial or complete) dose of investigational treatment and who did not have any major protocol deviations. The trial is registered with ClinicalTrials.gov, number NCT01419665, and is ongoing. FINDINGS: Between Dec 1, 2011, and Jan 15, 2015, 858 patients were screened for eligibility. 314 patients were randomly assigned to GP2013, of whom 312 were given GP2013, and 315 were assigned to reference rituximab. Median follow-up was 11·6 months (IQR 5·8-18·2) for the primary analysis. The primary endpoint, equivalence of overall response, was met (271 [87%] of 311 patients with GP2013 and 274 [88%] of 313 patients with reference rituximab achieved an overall response; difference -0·40% [95% CI -5·94 to 5·14]). Occurrence of adverse events and serious adverse events was similar between the treatment groups (289 [93%] of 312 patients in the GP2013-CVP group had an adverse event and 71 [23%] of 312 patients had a serious adverse event; 288 [91%] of 315 patients in the R-CVP group had an adverse event and 63 [20%] had a serious adverse event). The most common adverse event was neutropenia (80 [26%] of 312 patients in the GP2013-CVP group and 93 [30%] of 315 patients in the R-CVP group in the combination phase and 23 [10%] of 231 patients in the GP2013-CVP group and 13 [6%] of 231 patients in the R-CVP group in the maintenance phase). The most common grade 3 or 4 adverse event during the combination and maintenance phase was neutropenia (55 [18%] of 312 patients in the GP2013-CVP group and 65 [21%] of 315 patients in the R-CVP group in the combination phase and 17 [7%] of 231 patients in the GP2013-CVP group and nine [4%] of 231 patients in the R-CVP group in the maintenance phase). The occurrence of anti-drug antibodies was similar in the treatment groups (five [2%] of 268 patients in the GP2013-CVP; three [1%] in the R-CVP group). INTERPRETATION: Our results show that GP2013 represents a viable rituximab biosimilar candidate for patients with previously untreated advanced follicular lymphoma. The introduction of biosimilars provides additional therapeutic options with potential to increase access to effective and life-saving biological therapies such as rituximab. FUNDING: Hexal.
28545809 Macrophage-specific nanotechnology-driven CD163 overexpression in human macrophages result 2017 Aug M1 macrophages release proinflammatory factors during inflammation. They transit to an M2 phenotype and release anti-inflammatory factors to resolve inflammation. An imbalance in the transition from M1 to M2 phenotype in macrophages contributes to the development of persistent inflammation. CD163, a member of the scavenger receptor cysteine-rich family, is an M2 macrophage marker. The functional role of CD163 during the resolution of inflammation is not completely known. We postulate that CD163 contributes to the transition from M1 to M2 phenotype in macrophages. We induced CD163 gene in THP-1 and primary human macrophages using polyethylenimine nanoparticles grafted with a mannose ligand (Man-PEI). This nanoparticle specifically targets cells of monocytic origin via mannose receptors. Cells were challenged with a single or a double stimulation of lipopolysaccharide (LPS). A CD163 or empty plasmid was complexed with Man-PEI nanoparticles for cell transfections. Quantitative RT-PCR, immunocytochemistry, and ELISAs were used for molecular assessments. CD163-overexpressing macrophages displayed reduced levels of tumor necrosis factor-alpha (TNF)-α and monocytes chemoattractant protein (MCP)-1 after a single stimulation with LPS. Following a double stimulation paradigm, CD163-overexpressing macrophages showed an increase of interleukin (IL)-10 and IL-1ra and a reduction of MCP-1. This anti-inflammatory phenotype was partially blocked by an anti-CD163 antibody (effects on IL-10 and IL-1ra). A decrease in the release of TNF-α, IL-1β, and IL-6 was observed in CD163-overexpressing human primary macrophages. The release of IL-6 was blocked by an anti-CD163 antibody in the CD163-overexpressing group. Our data show that the induction of the CD163 gene in human macrophages under inflammatory conditions produces changes in cytokine secretion in favor of an anti-inflammatory phenotype. Targeting macrophages to induce CD163 using cell-directed nanotechnology is an attractive and practical approach for inflammatory conditions that could lead to persistent pain, i.e. major surgeries, burns, rheumatoid arthritis, etc.
28098763 New Abietane and Kaurane Type Diterpenoids from the Stems of Tripterygium regelii. 2017 Jan 13 Eleven new abietane type (1‒11), and one new kaurane (12), diterpenes, together with eleven known compounds (13-23), were isolated and identified from the stems of Tripterygium regelii, which has been used as a traditional folk Chinese medicine for the treatment of rheumatoid arthritis in China. The structures of new compounds were characterized by means of the interpretation of high-resolution electrospray ionization mass spectrometry (HRESIMS), extensive nuclear magnetic resonance (NMR) spectroscopic data and comparisons of their experimental CD spectra with calculated electronic circular dichroism (ECD) spectra. Compound 1 is the first abietane type diterpene with an 18→1 lactone ring. Compound 19 was isolated from the plants of the Tripterygium genus for the first time, and compounds 14-17 were isolated from T. regelii for the first time. Triregelin I (9) showed significant cytotoxicity against A2780 and HepG2 with IC(50) values of 5.88 and 11.74 µM, respectively. It was found that this compound was inactive against MCF-7 cells. The discovery of these twelve new diterpenes not only provided information on chemical substances of T. regelii, but also contributed to the chemical diversity of natural terpenoids.
29326686 Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease. 2017 Meniere's disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case-control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661-2.627); p = 1.39 × 10(-09)]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10(-11)). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.
27896669 Detection of autoantibodies to DSF70/LEDGFp75 in Mexican Hispanics using multiple compleme 2017 Dec PURPOSE: Antinuclear autoantibodies (ANA) targeting the dense fine speckled antigen DFS70, also known as lens epithelium-derived growth factor p75 (LEDGF/p75), are attracting attention due to their low frequency in systemic rheumatic diseases but increased frequency in clinical laboratory referrals and healthy individuals (HI). These ANA specifically recognize the stress protein DFS70/LEDGFp75, implicated in cancer, HIV-AIDS, and inflammation. While their frequency has been investigated in various ethnic populations, there is little information on their frequency among Hispanics/Latinos. In this study, we determined the frequency of anti-DFS70/LEDGFp75 autoantibodies in Mexican Hispanics using multiple detection platforms. METHODS: The frequency of anti-DFS70/LEDGFp75 antibodies was determined in 171 individuals, including 71 dermatomyositis (DM) patients, 47 rheumatoid arthritis (RA) patients, 30 obesity (OB) patients, and 23 HI. Antibody detection was achieved using four complementary assay platforms: indirect immunofluorescence, Western blotting, ELISA, and chemiluminescent immunoassay. RESULTS: We detected relatively low frequencies of anti-DFS70/LEDGFp75 antibodies in patients with DM (1.4%), RA (4.3%), and OB (6.6%), and elevated frequency (17.4%) in HI. A strong concordance between the different antibody detection platforms was observed. CONCLUSIONS: The low frequency of anti-DFS70/LEDGFp75 antibodies in Mexican patients with rheumatic diseases, but relatively higher frequency in HI, is consistent with previous observations with non-Hispanic populations, suggesting that geographic differences or ethnicity do not influence the frequency of these autoantibodies. Our results also highlight the importance of confirmatory assays for the accurate detection of these autoantibodies. Future studies with larger cohorts of healthy Hispanics/Latinos are needed to confirm if their anti-DFS70/LEDGFp75 antibody frequencies are significantly higher than in non-Hispanics.
29105068 Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the lo 2018 Mar Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant, characterized by low oestrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC)-mediated proinflammatory host responses. Expression of Toll-like receptors (TLRs)-7 and -9 and cytokine profiles was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-β-oestradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles also contained another SS-autoantigen, hy1-RNA. These particles were internalized by pDCs in a size-dependent manner and affected TLR-7 and -9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle-stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS.
28494936 Functional Analysis of Dendritic Cells Generated from T-iPSCs from CD4+ T Cell Clones of S 2017 May 9 Although it is important to clarify the pathogenic functions of T cells in human samples, their examination is often limited due to difficulty in obtaining sufficient numbers of dendritic cells (DCs), used as antigen-presenting cells, especially in autoimmune diseases. We describe the generation of DCs from induced pluripotent stem cells derived from T cells (T-iPSCs). We reprogrammed CD4+ T cell clones from a patient with Sjögren's syndrome (SS) into iPSCs, which were differentiated into DCs (T-iPS-DCs). T-iPS-DCs had dendritic cell-like morphology, and expressed CD11c, HLA-DR, CD80, CD86, and also BDCA-3. Compared with monocyte-derived DCs, the capacity for antigen processing was similar, and T-iPS-DCs induced the proliferative response of autoreactive CD4+ T cells. Moreover, we could evaluate T cell functions of the patient with SS. In conclusion, we obtained adequate numbers of DCs from T-iPSCs, which could be used to characterize pathogenic T cells in autoimmune diseases such as SS.
28536104 Development and validation of QRISK3 risk prediction algorithms to estimate future risk of 2017 May 23 Objectives To develop and validate updated QRISK3 prediction algorithms to estimate the 10 year risk of cardiovascular disease in women and men accounting for potential new risk factors.Design Prospective open cohort study.Setting General practices in England providing data for the QResearch database.Participants 1309 QResearch general practices in England: 981 practices were used to develop the scores and a separate set of 328 practices were used to validate the scores. 7.89 million patients aged 25-84 years were in the derivation cohort and 2.67 million patients in the validation cohort. Patients were free of cardiovascular disease and not prescribed statins at baseline.Methods Cox proportional hazards models in the derivation cohort to derive separate risk equations in men and women for evaluation at 10 years. Risk factors considered included those already in QRISK2 (age, ethnicity, deprivation, systolic blood pressure, body mass index, total cholesterol: high density lipoprotein cholesterol ratio, smoking, family history of coronary heart disease in a first degree relative aged less than 60 years, type 1 diabetes, type 2 diabetes, treated hypertension, rheumatoid arthritis, atrial fibrillation, chronic kidney disease (stage 4 or 5)) and new risk factors (chronic kidney disease (stage 3, 4, or 5), a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, systemic lupus erythematosus (SLE), atypical antipsychotics, severe mental illness, and HIV/AIDs). We also considered erectile dysfunction diagnosis or treatment in men. Measures of calibration and discrimination were determined in the validation cohort for men and women separately and for individual subgroups by age group, ethnicity, and baseline disease status.Main outcome measures Incident cardiovascular disease recorded on any of the following three linked data sources: general practice, mortality, or hospital admission records.Results 363 565 incident cases of cardiovascular disease were identified in the derivation cohort during follow-up arising from 50.8 million person years of observation. All new risk factors considered met the model inclusion criteria except for HIV/AIDS, which was not statistically significant. The models had good calibration and high levels of explained variation and discrimination. In women, the algorithm explained 59.6% of the variation in time to diagnosis of cardiovascular disease (R(2), with higher values indicating more variation), and the D statistic was 2.48 and Harrell's C statistic was 0.88 (both measures of discrimination, with higher values indicating better discrimination). The corresponding values for men were 54.8%, 2.26, and 0.86. Overall performance of the updated QRISK3 algorithms was similar to the QRISK2 algorithms.Conclusion Updated QRISK3 risk prediction models were developed and validated. The inclusion of additional clinical variables in QRISK3 (chronic kidney disease, a measure of systolic blood pressure variability (standard deviation of repeated measures), migraine, corticosteroids, SLE, atypical antipsychotics, severe mental illness, and erectile dysfunction) can help enable doctors to identify those at most risk of heart disease and stroke.
28494419 Neuroprotective effects of total flavonoid fraction of the Epimedium koreanum Nakai extrac 2017 Jul Flavonoids, the active components of Epimedii Genus, have been demonstrated to protect against osteoporosis, cardiovascular diseases and rheumatoid arthritis. The present study aimed to investigate the neuroprotective effects of total flavonoid (TF) fraction of Epimedium koreanum Nakai on dopaminergic neurons in the cellular and mice models of Parkinson's disease (PD). TF pretreatment could ameliorate the decrease of striatal dopamine (DA) content and the loss of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). TF treatment could reverse the changes of Bcl-2 and Bax protein expressions in the striatum of PD mice. 1-Methyl-4-phenylpyridinium ion (MPP(+)) significantly decreased the cell viability and mitochondrial membrane potential in MES23.5 cells. These effects could be reversed by TF treatment. In addition, MPP(+)-induced changes of Bcl-2 and Bax mRNA and protein expressions were also reversed by TF pretreatment. These data demonstrated that TF of E. koreanum Nakai could protect against MPTP-induced dopaminergic neuronal death in mice and MPP(+)-induced neurotoxicity in dopaminergic MES23.5 cells. Anti-apoptosis might be involved in this process.
28689585 Rheumatologic Manifestations of Hepatitis C Virus Infection. 2017 Aug Hepatitis C virus (HCV) infection is associated with a morbidity and mortality due to liver complications. HCV infection is also frequently associated with rheumatic disorders, such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome, as well as the production of autoantibodies. The treatment of HCV infection with interferon alpha (IFN) has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders. New oral IFN-free combinations offer an opportunity for HCV-infected patients with extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects.
28924012 Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Sei 2017 Oct 25 Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD.SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1β. Here we show that blocking IL-1β receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1β with clinically available drugs may be beneficial for symptomatic treatment of the disease.
28187197 Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. 2017 Feb The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.
27881629 Risk of fractures after stroke: Results from the Ontario Stroke Registry. 2017 Jan 3 OBJECTIVE: To determine the risk of fractures after stroke. METHODS: Using the Ontario Stroke Registry, we identified a population-based sample of consecutive patients seen in the emergency department or hospitalized with stroke (n = 23,751) or TIA (n = 11,240) at any of 11 stroke centers in Ontario, Canada, and discharged alive between July 1, 2003, and March 31, 2012. We compared the risk of low-trauma fractures in patients with stroke vs those with TIA using propensity score methods to adjust for differences in baseline factors. Secondary analyses compared fracture risk poststroke with that in age-/sex-matched controls without stroke or TIA (n = 23,751) identified from the Ontario Registered Persons Database. RESULTS: The 2-year rate of fracture was 5.7% in those with stroke compared to 4.8% in those with TIA (adjusted cause-specific hazard ratio [aHR] for those with stroke vs TIA 1.32; 95% confidence interval [CI] 1.19-1.46) and 4.1% in age-/sex-matched controls (aHR for those with stroke vs controls 1.47; 95% CI 1.35-1.60). In the cohort with stroke, factors associated with fractures were older age, female sex, moderate stroke severity, prior fractures or falls, and preexisting osteoporosis, rheumatoid arthritis, hyperparathyroidism, and atrial fibrillation. CONCLUSIONS: Stroke is associated with an increased risk of low-trauma fractures. Individuals with stroke and additional risk factors for fractures may benefit from targeted screening for low bone mineral density and initiation of treatment for fracture prevention.
26214170 Survival and prognostic factors in patients with connective tissue disease-associated pulm 2017 Sep OBJECTIVES: Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). The survival rates and mortality-predictive factors of a nationwide registry of Korean patients with CTD-PH measured by echocardiography were determined. METHODS: Patients with CTD-PH were enrolled between April 2008 and December 2012. Hemodynamic parameters and clinical data (WHO-functional class [FC], organ involvement, laboratory tests and treatment agents) were recorded. Survival rates were calculated by using the Kaplan-Meier method. Mortality-associated factors were examined by Cox proportional hazards regression analysis. RESULTS: In total, 174 incident PH cases (61 with systemic lupus erythematosus, 50 with systemic sclerosis, 10 with mixed CTD, 22 with rheumatoid arthritis (RA) and 31 with other CTDs) were diagnosed by Doppler echocardiography. Of these, 25 (14%) died during the 3.8 ± 2.7 year follow-up period after PH diagnosis. The 1- and 3-year survival rates were 90.7% and 87.3%, respectively. Compared to the other CTD-PHs, RA-PH had the lowest survival rates (56% 3 year survival; P = 0.022). Multiple regression analysis revealed that low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were poor prognostic factors (P = 0.008, 0.04 and 0.009, respectively). Anti-UI-RNP (ribonucleoprotein) antibody positivity was protective (P = 0.022). In patients with WHO-FC III/IV, patients who received vasodilators had lower mortality than those who did not (P = 0.038). CONCLUSIONS: In Korean patients with CTD-PH, the 3-year survival rate was 87%. Low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were independent poor prognostic factors. Anti-UI-RNP antibody was protective. Prompt PAH-specific vasodilator therapy may improve the survival of patients with severe CTD-PH.
28705508 Fingerprint analysis of Gelsemium elegans by HPLC followed by the targeted identification 2017 Sep Gelsemium elegans, which is a genus of the family Loganiaease, is commonly used as a traditional medicine for promoting animal growth and treating rheumatoid arthritis pain and neuropathic pain, among others. In this study, we first established a valid high-performance liquid chromatography (HPLC) method for the fingerprint analysis of Gelsemium elegans samples. Then, the comprehensive detection of chemical constituents from the samples was performed using HPLC coupled with quadrupole-time-of-flight mass spectrometry. The similarity evaluation results showed that location and area differences influenced the quality of the samples. An efficient strategy for the rapid targeted identification of chemical components was matching with a developed Gelsemium database. As a result, the accurate elemental compositions and known structures of compounds are found as hits. This process facilitated the structural identification of compounds combined with the accurate mass measurement of product ions and fragmentation behaviors. Consequently, 41 components including six alkaloids and non-alkaloids were systematically identified from Gelsemium elegans. The results showed that at least seven relatively major components existing in Gelsemium elegans may be useful for its quality control. The present analytical method combined with the developed Gelsemium database was shown to be a useful tool for investigating the chemical components of Gelsemium products.