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ID PMID Title PublicationDate abstract
27660198 PD-1/PD-L and autoimmunity: A growing relationship. 2016 Dec Programmed death 1 (PD-1) and its ligands, namely PD-L1 and PD-L2, are one of the key factors responsible for inhibitory T cell signaling, mediating the mechanisms of tolerance and providing immune homeostasis. Mounting evidence demonstrates that impaired PD-1:PD-L function plays an important role in a variety of autoimmune diseases such as Type 1 diabetes (T1D), encephalomyelitis, inflammatory bowel diseases (IBD), Rheumatoid Arthritis (RA), autoimmune hepatitis (AIH), Behcet's disease (BD), myasthenia gravis (MG), autoimmune uveitis (AU), Sjögren's syndrome (SjS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), myocarditis, and ankylosing spondylitis (AS). By investigating the candidate genes, genome-wide association studies, and identification of single nucleotide polymorphisms (SNPs) in PD-1 gene in humans, it has been shown that there is a higher risk in relevant genetic associations with developing autoimmune diseases in certain ethnic groups. In this review we have tried to present a comprehensive role of PD-1:PD-L in all recently studied autoimmune diseases.
27649785 IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activatio 2016 Sep 21 IL-18BP is a natural antagonist of pro-inflammatory IL-18 cytokine linked to autoimmune disorders like rheumatoid arthritis. However, its role in post menopausal osteoporosis is still unknown. In this study, we investigated the role of IL-18BP on murine osteoblasts, its effect on osteoblasts-CD4+ T cells and osteoblasts-CD11b+ macrophage co-culture. mIL-18BPd enhances osteoblast differentiation and inhibits the activation of NLRP3 inflammasome and caspase-1 which process IL-18 to its active form. Using estrogen deficient mice, we also determined the effect of mIL-18BP on various immune and skeletal parameters. Ovariectomized mice treated with mIL-18BPd exhibited decrease in Th17/Treg ratio and pro-inflammatory cytokines. mIL-18BPd treatment restored trabecular microarchitecture, preserved cortical bone parameters likely attributed to an increased number of bone lining cells and reduced osteoclastogenesis. Importantly, these results were corroborated in female osteoporotic subjects where decreased serum IL-18BP levels and enhanced serum IL-18 levels were observed. Our study forms a strong basis for using humanized IL-18BP towards the treatment of postmenopausal osteoporosis.
27279627 Auranofin and N-heterocyclic carbene gold-analogs are potent inhibitors of the bacteria He 2016 Jul Auranofin is an FDA-approved gold-containing compound used for the treatment of rheumatoid arthritis. Recent reports of antimicrobial activity against protozoa and bacteria indicate that auranofin targets the reductive enzyme thioredoxin reductase (TrxR). We evaluated auranofin as well as five auranofin analogs containing N-heterocyclic carbenes (instead of the triethylphosphane present in auranofin) and five gold-carbene controls for their ability to inhibit or kill Helicobacter pylori in vitro Auranofin completely inhibited bacterial growth at 1.2 μM. Purified H. pylori TrxR was inhibited by auranofin in a cell-free assay (IC50 ∼88 nM). The most active gold(I)-N-heterocyclic carbene compounds exhibited MICs comparable to auranofin against H. pylori (2 μM), while also exhibiting lower toxicities for human embryonic kidney cells (HEK-293T cells). Median toxic concentrations (TC50) were 13-20-fold higher compared to auranofin indicating that they were less cytotoxic. The N-heterocyclic carbene analogs maybe well tolerated, but further evaluation is needed in vivo Finally, auranofin was synergistic with the antibiotic amoxicillin, suggesting that targeting both the reductive enzyme TrxR and cell wall synthesis may be effective against H. pylori infections.
27168850 Chlorogenic acid induces apoptosis to inhibit inflammatory proliferation of IL-6-induced f 2016 May Chlorogenic acid (CGA) is the primary constituent of Caulis Lonicerae, a Chinese herb used for the treatment of rheumatoid arthritis (RA). The present study aimed to investigate whether CGA was able to inhibit the proliferation of the fibroblast-like synoviocyte cell line (RSC-364), stimulated by interleukin (IL)-6, through inducing apoptosis. Following incubation with IL-6 or IL-6 and CGA, the cellular proliferation of RSC-364 cells was detected by MTT assay. The ratio of apoptosed cells were detected by flow cytometry. Western blot analysis was performed to observe protein expression levels of key molecules involved in the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK/STAT) signaling pathway [phosphorylated (p)-STAT3, JAK1 and gp130] and the nuclear factor κB (NF-κB) signaling pathway [phosphorylated (p)-inhibitor of κB kinase subunit α/β and NF-κB p50). It was revealed that CGA was able to inhibit the inflammatory proliferation of RSC-364 cells mediated by IL-6 through inducing apoptosis. CGA was also able to suppress the expression levels of key molecules in the JAK/STAT and NF-κB signaling pathways, and inhibit the activation of these signaling pathways in the inflammatory response through IL-6-mediated signaling, thereby resulting in the inhibition of the inflammatory proliferation of synoviocytes. The present results indicated that CGA may have potential as a novel therapeutic agent for inhibiting inflammatory hyperplasia of the synovium through inducing synoviocyte apoptosis in patients with RA.
27040904 Bee Venom Promotes Hair Growth in Association with Inhibiting 5α-Reductase Expression. 2016 Jun 1 Alopecia is an important issue that can occur in people of all ages. Recent studies show that bee venom can be used to treat certain diseases including rheumatoid arthritis, neuralgia, and multiple sclerosis. In this study, we investigated the preventive effect of bee venom on alopecia, which was measured by applying bee venom (0.001, 0.005, 0.01%) or minoxidil (2%) as a positive control to the dorsal skin of female C57BL/6 mice for 19 d. Growth factors responsible for hair growth were analyzed by quantitative real-time PCR and Western blot analysis using mice skins and human dermal papilla cells (hDPCs). Bee venom promoted hair growth and inhibited transition from the anagen to catagen phase. In both anagen phase mice and dexamethasone-induced catagen phase mice, hair growth was increased dose dependently compared with controls. Bee venom inhibited the expression of SRD5A2, which encodes a type II 5α-reductase that plays a major role in the conversion of testosterone into dihydrotestosterone. Moreover, bee venom stimulated proliferation of hDPCs and several growth factors (insulin-like growth factor 1 receptor (IGF-1R), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)2 and 7) in bee venom-treated hDPCs dose dependently compared with the control group. In conclusion, bee venom is a potentially potent 5α-reductase inhibitor and hair growth promoter.
27023004 Prevalence of musculoskeletal disorders and rheumatic diseases in Cuenca, Ecuador: a WHO-I 2016 Sep The aim of this study was to determine the prevalence of musculoskeletal pain and rheumatic diseases in subjects over 18 years of age from the canton of Cuenca, Ecuador. Cross-sectional analytical community-based study was conducted in subjects over 18 years of age using the validated Community-Oriented Program for the Control of Rheumatic Diseases (COPCORD) questionnaire. Random sampling was used. The questionnaire was administered by standardized health workers. Subjects were visited house by house. Subjects positive for musculoskeletal (MSK) pain in the last 7 days and at some point in life were assessed by rheumatologists to confirm the diagnosis. A total of 4877 subjects participated, with an average age of 42.8 (SD 18.8) years of age; 59.7 % were women; 69.7 % lived in urban areas. 32.5 % reported MSK pain in the last 7 days and 45.7 % at some point in life. The prevalence of knee osteoarthritis was 7.4 %, hand osteoarthritis 5.3 %, low back pain 9.3 %, rheumatoid arthritis 0.8 %, fibromyalgia 2 %, gout 0.4 %, and lupus 0.06 %. Subjects from rural areas reported experiencing more MSK pain in the last 7 days and at some point in life, lower income, poorer health-care coverage, and increased physical activity involving repetitive tasks such as lifting weights or cooking with firewood. MSK pain prevalence was high. Osteoarthritis and low back pain were the most common diseases. Age, sex, physical activity, repetitive tasks, living in a rural area, and lack of health-care coverage were found to be associated with MSK pain.
26940726 5,6-Dehydrokawain from Alpinia zerumbet promotes osteoblastic MC3T3-E1 cell differentiatio 2016 Jul Bone homeostasis is maintained by balancing bone formation and bone resorption, but an imbalance between them is associated with various bone-related diseases such as osteoporosis and rheumatoid arthritis. We found that 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK), which were isolated as promising compounds from Alpinia zerumbet rhizomes, promote differentiation of osteoblastic MC3T3-E1 cells. DK and DDK increased the alkaline phosphatase activity and matrix mineralization of MC3T3-E1 cells. DK exerts larger effects than DDK. The gene expression of runt-related transcription factor 2 and osterix, which are essential transcription factors in the early period of osteoblast differentiation, was significantly increased by DK treatment. The mRNA level of distal-less homeobox 5 was also enhanced by DK treatment, and DK activated the p38 mitogen-activated protein kinase pathway. Therefore, DK may have clinical potential for preventing osteoporosis, and could be considered as a potential anabolic therapeutic agent.
26830903 The high incidence of anti-Ro/SSA and anti-p200 antibodies in female patients with connect 2016 Mar It is known that anti-Ro/SSA positivity leads to higher risk of miscarriage and fetal cardiac malformations. Particularly, anti-p200 antibodies against a finer specificity of the Ro/SSA antigen, have been associated with congenital heart block. The aim of the study was to assess the frequency of anti-p200 among female patients with different connective tissue diseases and, among these, the relevance of anti-p200 values in patients with cutaneous diseases compared to systemic diseases. Anti-p200 were investigated in 110 anti-Ro/SSA positive female sera, sent to our laboratory between 2008 and 2014 with suspect of connective disease, by using ELISA testing. Positivity was found in 40.9 % samples, 34 of them showed a strong positivity (values ≥ 1.0, cut off = 0.7). Patients with systemic diseases were anti-p200 positive in the 45.9 % of cases while patients with cutaneous diseases were positive in the 24.0 % of cases. Positivity for anti-p200 antibodies was revealed in 24.0 % of patients with discoid lupus erythematosus; 100 % of patients with dermatomyositis; 40.0 % of patients with mixed connective tissue disease; 25.0 % of patients with rheumatoid arthritis; 100 % of patients with Sjögren's syndrome; 33.3 % of patients with subacute cutaneous lupus erythematosus; 42.9 % of patients with systemic lupus erythematosus; 80.0 % of patients with systemic sclerosis. No significant difference in anti-p200 prevalence was found between systemic and cutaneous involvement, nevertheless, considering only positive sera, the antibody titer was higher in systemic diseases rather than in cutaneous diseases (2.6 ± 1.7 and 1.7 ± 1.9; p = 0.041). The authors think screenings for anti-Ro/SSA and anti-p200 antibodies should be included in the laboratory checklist for pregnancy.
26830712 Intraductal papillary mucinous neoplasm of the pancreas, one manifestation of a more syste 2016 Mar BACKGROUND: Several studies have demonstrated a high prevalence of extrapancreatic malignancies, and an association with autoimmune pancreatitis in patients with intraductal papillary mucinous neoplasm (IPMN). We hypothesized that IPMNs were associated with an increase rate of systemic diseases. METHODS: From 1996 to 2013, a retrospective analysis of a prospectively collected database was performed and supplemented with electronic medical charts review. RESULTS: Two hundred twenty extrapancreatic malignancies were found in 185 patients (22%) compared with expected 5% in the general population. Colorectal, lung, and renal cell carcinoma had significant observed/expected ratios (P < .0001). One hundred ten synchronous autoimmune diseases were found in 96 patients (11%). Systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease showed statistically significant observed/expected ratios (P < .0001, .01, and <.0001, respectively). There was no impact of immunosuppressive treatment on the IPMN subtype and malignancy rate. CONCLUSIONS: IPMN are associated with surprisingly high rates of autoimmune diseases suggesting that IPMN might be 1 manifestation of a more systemic disease.
26712781 HTLV-1, Immune Response and Autoimmunity. 2015 Dec 24 Human T-lymphotropic virus type-1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATL). Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM) is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Sjögren's Syndrome (SS). The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4⁺ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4⁺ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity.
26449416 Identification of geranylgeranyl diphosphate synthase genes from Tripterygium wilfordii. 2015 Dec We found triptolide synthesis is correlated with the expressions of TwGGPPS1 and TwGGPPS4 . This lays the foundation for future studies of biosynthetic pathways for triptolide and other diterpenoids in T. wilfordii. Tripterygium wilfordii is a traditional Chinese medical plant commonly used to treat rheumatoid arthritis. One of its main bioactive compounds is triptolide, which is identified as an abietane-type diterpenoid natural product. Geranylgeranyl diphosphate synthase (GGPPS) catalyses the synthesis of GGPP (geranylgeranyl diphosphate), the common precursor of diterpenes, and is therefore a crucial enzyme in diterpene biosynthesis. A previous study showed that GGPP could be catalyzed by copalyl diphosphate synthase and kaurene synthase like of Salvia miltiorrhiza (SmCPS, SmKSL) to miltiradiene, a key intermediate in tanshinone biosynthesis. In this paper, five new full-length cDNAs (TwGGPPS) encoding GGPP synthases were cloned from T. wilfordii. Sequence comparisons revealed that all six TwGGPPSs (including TwGGPPS2 cloned previously) exhibit similarities to GGPPSs of other plants. Subsequent functional complement assays demonstrated that TwGGPPS1, TwGGPPS4 and TwGGPPS5 can participate in miltiradiene biosynthesis in the recombinant E. coli. Correlation analysis of gene expressions and secondary metabolite accumulation indicated that TwGGPPS1 and TwGGPPS4 are likely involved in the biosynthesis of triptolide. These findings lay the foundation for future studies of the biosynthetic pathways for triptolide and other diterpenoids in T. wilfordii.
26376209 The miR-30a Negatively Regulates IL-17-Mediated Signal Transduction by Targeting Traf3ip2. 2015 Nov Interleukin-17 (IL-17) has been proved to be involved in the pathogenesis of several autoimmune diseases, including lupus, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. The regulation of IL-17 signal transduction is less studied. miR-30a has been identified to be downregulated in these human autoimmune diseases and their related animal models. However, how it functions in IL-17-mediated inflammation and the pathogenesis of these diseases remain unknown. In this study, we showed that miR-30a inhibits IL-17-mediated NF-κB and MAPK activation, leading to the reduced production of inflammatory cytokines and chemokines. miR-30a also reduced mRNA stability triggered by IL-17 stimulation. These suppressive effects of miR-30a were mediated by directly targeting Traf3ip2 mRNA (coding for Act1). Thus, we concluded that the downregulation of miR-30a in autoimmune diseases may exacerbate IL-17-mediated inflammation, which may serve as a potential target for the therapy of these diseases.
26270649 Predicting Hemagglutinin MHC-II Ligand Analogues in Anti-TNFα Biologics: Implications for 2015 The purpose of this study was to evaluate the extent of overlapping immunogenic peptides between three pharmaceutical biologics and influenza viruses. Clinical studies have shown that subsets of patients with rheumatoid arthritis (RA) develop anti-drug antibodies towards anti-TNFα biologics. We postulate that common infectious pathogens, including influenza viruses, may sensitize RA patients toward recombinant proteins. We hypothesize that embedded within infliximab (IFX), adalimumab (ADA), and etanercept (ETN) are ligands of class II major histocompatibility complex (MHC-II) that mimic T cell epitopes derived from influenza hemagglutinin (HA). The rationale is that repeated administration of the biologics would reactivate HA-primed CD4 T cells, stimulating B cells to produce cross-reactive antibodies. Custom scripts were constructed using MATLAB to compare MHC-II ligands of HA and the biologics; all ligands were predicted using tools in Immune Epitope Database and Resources (IEDB). We analyzed three HLA-DR1 alleles (0101, 0401 and 1001) that are prominent in RA patients, and two alleles (0103 and 1502) that are not associated with RA. The results indicate that 0401 would present more analogues of HA ligands in the three anti-TNFα biologics compared to the other alleles. The approach led to identification of potential ligands in IFX and ADA that shares sequence homology with a known HA-specific CD4 T cell epitope. We also discovered a peptide in the complementarity-determining region 3 (CDR-3) of ADA that encompasses both a potential CD4 T cell epitope and a known B cell epitope in HA. The results may help generate new hypotheses for interrogating patient variability of immunogenicity of the anti-TNFα drugs. The approach would aid development of new recombinant biologics by identifying analogues of CD4 T cell epitopes of common pathogens at the preclinical stage.
26156520 Using gene expression signatures to identify novel treatment strategies in gulf war illnes 2015 Jul 9 BACKGROUND: Gulf War Illness (GWI) is a complex multi-symptom disorder that affects up to one in three veterans of this 1991 conflict and for which no effective treatment has been found. Discovering novel treatment strategies for such a complex chronic illness is extremely expensive, carries a high probability of failure and a lengthy cycle time. Repurposing Food and Drug Administration approved drugs offers a cost-effective solution with a significantly abbreviated timeline. METHODS: Here, we explore drug re-purposing opportunities in GWI by combining systems biology and bioinformatics techniques with pharmacogenomic information to find overlapping elements in gene expression linking GWI to successfully treated diseases. Gene modules were defined based on cellular function and their activation estimated from the differential expression of each module's constituent genes. These gene modules were then cross-referenced with drug atlas and pharmacogenomic databases to identify agents currently used successfully for treatment in other diseases. To explore the clinical use of these drugs in illnesses similar to GWI we compared gene expression patterns in modules that were significantly expressed in GWI with expression patterns in those same modules in other illnesses. RESULTS: We found 19 functional modules with significantly altered gene expression patterns in GWI. Within these modules, 45 genes were documented drug targets. Illnesses with highly correlated gene expression patterns overlapping considerably with GWI were found in 18 of the disease conditions studied. Brain, muscular and autoimmune disorders composed the bulk of these. CONCLUSION: Of the associated drugs, immunosuppressants currently used in treating rheumatoid arthritis, and hormone based therapies were identified as the best available candidates for treating GWI symptoms.
26026695 Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy. 2015 Oct Epigenetics is the study of heritable changes in genome function without underlying modifications in their nucleotide sequence. Disorders of epigenetic processes, which involve DNA methylation, histone modification, non-coding RNA and nucleosome remodeling, may influence chromosomal stability and gene expression, resulting in complicated syndromes. In the past few years, it has been disclosed that identified epigenetic alterations give rise to several typical human autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). These emerging epigenetic studies provide new insights into autoimmune diseases. The identification of specific epigenetic dysregulation may inspire more discoveries of other uncharacterized mechanisms. Further elucidation of the biological functions and clinical significance of these epigenetic alterations may be exploited for diagnostic biomarkers and therapeutic benefits.
25866780 In vivo evaluation of TNF-alpha in the lungs of patients affected by sarcoidosis. 2015 INTRODUCTION: Sarcoidosis is a multisystemic granulomatous disorder characterized by multiple noncaseating granulomas involving intrathoracic lymph nodes and lung parenchyma. Recently, the use of anti-tumor necrosis factor alpha (anti-TNFα) agents has been introduced for therapy of chronic and refractory sarcoidosis with controversial results. Infliximab (Remicade) is a chimeric monoclonal antibody (mAb) that recognizes and binds TNFα, neutralizing its biological effects. In the present study,   (99m)Tc labelled infliximab was used to study the expression of TNFα in sarcoid lesions and to evaluate its role as a predictive marker in response to therapy with Remicade. MATERIAL AND METHODS: A total of 10 patients with newly diagnosed sarcoidosis were enrolled together with 10 control patients affected by rheumatoid arthritis. All patients were studied by planar imaging of the chest with   (99m)Tc-infliximab at 6 h and 24 h and total body [(18)F]-FDG PET/CT. Regions of interest were drawn over the lungs and the right arm and target-to-background ratios were analysed for   (99m)Tc-infliximab. SUV mean and SUV max were calculated over lungs for FDG. RESULTS AND DISCUSSION: Image analysis showed low correlation between T/B ratios and BAL results in patients despite positivity at [(18)F]-FDG PET. CONCLUSION: In conclusion, patients with newly diagnosed pulmonary sarcoidosis, with FDG-PET and BAL positivity, showed a negative   (99m)Tc-infliximab scintigraphy.
25825628 Antithrombotic Utilization Trends after Noncardioembolic Ischemic Stroke or TIA in the Set 2015 Feb BACKGROUND AND PURPOSE: Several large trials published over the last decade have significantly altered recommended guidelines for therapy following a noncardioembolic ischemic stroke or transient ischemic attack (TIA). The impact of these studies on patient usage of alternative antithrombotic agents has hitherto not been evaluated. We examined the usage of these agents in the United States over the last decade, with regard to the publication of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH), European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), and Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) clinical trials, in order to test the hypothesis that resulting recommendations are reflected in usage trends. METHODS: Antithrombotic utilization was prospectively collected as part of the National Ambulatory Medical Care Survey (NAMCS) on a total of 53,608,351 patients in the United States between 2002 and 2009. Patients with a history of ischemic stroke or TIA were included. Patients were excluded if there was a prior history of subarachnoid or intracerebral hemorrhage, or if other indications for antithrombotic treatment were present, including deep venous thrombosis, pulmonary embolism, atrial fibrillation or flutter, mechanical cardiac valve replacement, congestive heart failure, coronary artery disease, peripheral arterial disease, and rheumatoid arthritis. Annual utilization of the following antithrombotic strategies was compared in 53,608,351 patients: 1) aspirin monotherapy, 2) clopidogrel monotherapy, 3) combined clopidogrel and aspirin, 4) combined extended-release dipyridamole (ERDP) and aspirin, and 5) warfarin. Annual utilization was compared before and after publication of MATCH, ESPRIT, and PRoFESS in 2004, 2006, and 2008, respectively. Trend analysis was performed with the Mantel-Haenszel test for trends. Sensitivity analysis of demographic and clinical characteristics stratified by antithrombotic-usage group was performed using the Wald Chi-square test. RESULTS: Utilization of combined clopidogrel and aspirin increased from 3.3% to 6.7% after the MATCH trial (p<0.0001). Following the results of the ESPRIT trial, utilization of combination ERDP and aspirin decreased from 4% to 3% (p<0.0001), utilization of clopidogrel declined from 6.8% to 6% (p<0.0001), and utilization of aspirin remained essentially unchanged. After the PRoFESS trial, utilization of clopidogrel increased from 5% to 9% (p<0.0001), utilization of ERDP-aspirin increased from 3 % to 4.6% (p<0.0001), and utilization of aspirin increased from 15.6% to 17.8% (p<0.0001). The proportion of patients on none of the five antithrombotic secondary prevention strategies steadily declined from a peak of 74% in 2003 to 57% by 2009. CONCLUSIONS: The impact of the MATCH, ESPRIT, and PRoFESS trials on antithrombotic utilization has been variable. These findings highlight the importance of addressing factors that affect the implementation of findings from major clinical trials.
25682861 Determination of risk factors for recurrent methicillin-resistant Staphylococcus aureus ba 2015 May OBJECTIVE: To identify important risk factors for recurrent methicillin-resistant Staphylococcus aureus (MRSA) to assist clinicians in identifying high-risk patients for continued surveillance and follow-up. METHODS: In this retrospective cohort study, we examined patients with MRSA bacteremia at 122 Veterans Affairs medical facilities from January 1, 2003, through December 31, 2010. Recurrent MRSA bacteremia was identified by a positive blood culture result from 2 to 180 days after index hospitalization discharge. Subset analyses were performed to evaluate risk factors for early-onset (2-60 days after discharge) and late-onset (61-180 days after discharge) recurrence. Risk factors were evaluated using Cox proportional hazards regression. RESULTS: Of 18,425 patients, 1,159 (6.3%) had recurrent MRSA bacteremia. The median time to recurrence was 63 days. Longer duration of index bacteremia, increased severity of illness, receipt of only vancomycin, community-acquired infection, and several comorbidities were risk factors for recurrence. Congestive heart failure, hypertension, and rheumatoid arthritis/collagen disease were risk factors for early-onset but not late-onset recurrence. Geographic region and cardiac arrhythmias were risk factors for late-onset but not early-onset recurrence. CONCLUSIONS: Risk factors for recurrent MRSA bacteremia included comorbidities, severity of illness, duration of bacteremia, and receipt of only vancomycin. Awareness of risk factors may be important at patient discharge for implementation of quality improvement initiatives including surveillance, follow-up, and education for high-risk patients.
25387804 The A3 adenosine receptor: history and perspectives. 2015 By general consensus, the omnipresent purine nucleoside adenosine is considered a major regulator of local tissue function, especially when energy supply fails to meet cellular energy demand. Adenosine mediation involves activation of a family of four G protein-coupled adenosine receptors (ARs): A(1), A(2)A, A(2)B, and A(3). The A(3) adenosine receptor (A(3)AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells, thus making it a potential target for therapy. Originally isolated as an orphan receptor, A(3)AR presented a twofold nature under different pathophysiologic conditions: it appeared to be protective/harmful under ischemic conditions, pro/anti-inflammatory, and pro/antitumoral depending on the systems investigated. Until recently, the greatest and most intriguing challenge has been to understand whether, and in which cases, selective A(3) agonists or antagonists would be the best choice. Today, the choice has been made and A(3)AR agonists are now under clinical development for some disorders including rheumatoid arthritis, psoriasis, glaucoma, and hepatocellular carcinoma. More specifically, the interest and relevance of these new agents derives from clinical data demonstrating that A(3)AR agonists are both effective and safe. Thus, it will become apparent in the present review that purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health.
25149823 Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical re 2015 Apr Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".