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ID PMID Title PublicationDate abstract
22563483 Concordant signaling pathways produced by pesticide exposure in mice correspond to pathway 2012 Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets.
22516932 Flavonoids eupatorin and sinensetin present in Orthosiphon stamineus leaves inhibit inflam 2012 May Cytokines and other inflammatory mediators, such as prostaglandin E₂ (PGE₂) and nitric oxide (NO) produced by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), respectively, activate and drive inflammation and therefore serve as targets for anti-inflammatory drug development. Orthosiphon stamineus is an indigenous medicinal plant of Southeast Asia that has been traditionally used in the treatment of rheumatoid arthritis, gout, and other inflammatory disorders. The present study investigated the anti-inflammatory properties of Orthosiphon stamineus leaf chloroform extract (CE), its flavonoid-containing CE fraction 2 (CF2), and the flavonoids eupatorin, eupatorin-5-methyl ether (TMF), and sinensetin, identified from the CF2. It was found that CE (20 and 50 µg/mL) and CF2 (20 and 50 µg/mL) inhibited iNOS expression and NO production, as well as PGE₂ production. Eupatorin and sinensetin inhibited iNOS and COX-2 expression and the production of NO (IC₅₀ 5.2 µM and 9.2 µM for eupatorin and sinensetin, respectively) and PGE₂ (IC₅₀ 5.0 µM and 2.7 µM for eupatorin and sinensetin, respectively) in a dose-dependent manner. The extracts and the compounds also inhibited tumor necrosis factor α (TNF-α) production (IC₅₀ 5.0 µM and 2.7 µM for eupatorin and sinensetin, respectively). Eupatorin and sinensetin inhibited lipopolysaccharide (LPS)-induced activation of transcription factor signal transducers and activators of transcription 1α (STAT1α). Furthermore, eupatorin (50 mg/kg i. p.) and sinensetin (50 mg/kg i. p.) inhibited carrageenan-induced paw inflammation in mice. The results suggest that CE and CF2, as well as the known constituents of CF2, i.e., eupatorin and sinensetin, have meaningful anti-inflammatory properties which may be utilized in the development of novel anti-inflammatory treatments.
22500977 De novo peptide design with C3a receptor agonist and antagonist activities: theoretical pr 2012 May 10 Targeting the complement component 3a receptor (C3aR) with selective agonists or antagonists is believed to be a viable therapeutic option for several diseases such as stroke, heart attack, reperfusion injuries, and rheumatoid arthritis. We designed a number of agonists, partial agonists, and antagonists of C3aR using our two-stage de novo protein design framework. Of the peptides tested using a degranulation assay in C3aR-transfected rat basophilic leukemia cells, two were prominent agonists (EC(50) values of 25.3 and 66.2 nM) and two others were partial agonists (IC(50) values of 15.4 and 26.1 nM). Further testing of these lead compounds in a calcium flux assay in U937 cells yielded similar results although with reduced potencies compared to transfected cells. The partial agonists also displayed full antagonist activity when tested in a C3aR inhibition assay. In addition, the electrostatic potential profile was shown to potentially discriminate between full agonists and partial agonists.
22493476 Risk of invasive pneumococcal disease in people admitted to hospital with selected immune- 2012 Dec BACKGROUND: Invasive pneumococcal disease is a serious infection, and it is an important cause of morbidity and mortality in certain groups of 'at-risk' people. Those considered 'at-risk' in the UK include very young children, people aged 65 years and older and people with certain serious chronic diseases, asplenia or immunosuppression. There is little evidence about whether people with immune-mediated diseases are at increased risk of pneumococcal disease and therefore may benefit from pneumococcal vaccination. METHODS: Retrospective cohort studies, using linked hospital data, from the longstanding Oxford Record Linkage Study (1963-2008) and from recent English national linked Hospital Episode Statistics (1999-2008); analysis of whether people with immune-mediated diseases are more likely than others to be admitted to hospital for pneumococcal disease; calculation of rate ratio for pneumococcal disease in cohorts with immune-mediated disease compared with control cohorts. RESULTS: There were elevated rate ratios for many of the immune-mediated diseases, for example, Addison's disease in England 3.8 (95% CI 3.4 to 4.2), autoimmune haemolytic anaemia 4.9 (4.4 to 5.3), Crohn's disease 2.2 (2.1 to 2.3), diabetes mellitus 3.7 (3.4 to 4.1), multiple sclerosis 3.7 (3.5 to 3.8), myxoedema 1.60 (1.58 to 1.63), pernicious anaemia 1.74 (1.66 to 1.83), primary biliary cirrhosis 3.3 (2.9 to 3.7), polyarteritis nodosa 5.0 (4.0 to 6.0), rheumatoid arthritis 2.47 (2.41 to 2.52), scleroderma 4.2 (3.8 to 4.7), Sjogren's syndrome 3.2 (2.9 to 3.5) and systemic lupus erythematosus 5.0 (4.6 to 5.4). Findings in the Oxford and all England data sets were similar. CONCLUSIONS: People admitted to hospital with immune-mediated diseases are at higher risk than those with invasive pneumococcal disease. Vaccination should be considered in this group of patients.
21871974 Autoimmune disease: A role for new anti-viral therapies? 2011 Dec Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk.
21807047 Cholera toxin B subunit linked to glutamic acid decarboxylase suppresses dendritic cell ma 2011 Oct 26 Dendritic cells are the largest population of antigen presenting cells in the body. One of their main functions is to regulate the delicate balance between immunity and tolerance responsible for maintenance of immunological homeostasis. Disruption of this delicate balance often results in chronic inflammation responsible for initiation of organ specific autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type I diabetes. The cholera toxin B subunit (CTB) is a weak mucosal adjuvant known for its ability to stimulate immunity to antigenic proteins. However, conjugation of CTB to many autoantigens can induce immunological tolerance resulting in suppression of autoimmunity. In this study, we examined whether linkage of CTB to a 5kDa C-terminal protein fragment of the major diabetes autoantigen glutamic acid decarboxylase (GAD(35)), can block dendritic cell (DC) functions such as biosynthesis of co-stimulatory factor proteins CD86, CD83, CD80 and CD40 and secretion of inflammatory cytokines. The results of human umbilical cord blood monocyte-derived DC-GAD(35) autoantigen incubation experiments showed that inoculation of immature DCs (iDCs), with CTB-GAD(35) protein dramatically suppressed levels of CD86, CD83, CD80 and CD40 co-stimulatory factor protein biosynthesis in comparison with GAD(35) alone inoculated iDCs. Surprisingly, incubation of iDCs in the presence of the CTB-autoantigen and the strong immunostimulatory molecules PMA and Ionomycin revealed that CTB-GAD(35) was capable of arresting PMA+Ionomycin induced DC maturation. Consistent with this finding, CTB-GAD(35) mediated suppression of DC maturation was accompanied by a dramatic decrease in the secretion of the pro-inflammatory cytokines IL-12/23p40 and IL-6 and a significant increase in secretion of the immunosuppressive cytokine IL-10. Taken together, our experimental data suggest that linkage of the weak adjuvant CTB to the dominant type 1 diabetes autoantigen GAD strongly inhibits DC maturation through the down regulation of major co-stimulatory factors and inflammatory cytokine biosynthesis. These results emphasize the possibility that CTB-autoantigen fusion proteins enhance DC priming of naïve Th0 cell development in the direction of immunosuppressive T lymphocytes. The immunological phenomena observed here establish a basis for improvement of adjuvant augmented multi-component subunit vaccine strategies capable of complete suppression of organ-specific autoimmune diseases in vivo.
21485574 [Total hip replacement for the treatment of hip bony fused in non-functional position (17 2011 Mar OBJECTIVE: To explore the key points in the treatment of hip pathological bony fused in non-functional position with total hip replacement, especially to find out the main reasons for improving the joint function and the patients' life quality before and after the operation. And to accumulate more experience for further clinical treatment. METHODS: From May 2001 to May 2005, 12 patients with hip bony fused in non-functional position were treated with total hip replacement. There were 5 males (ranging in age from 32 to 54 years,averaged 43.25 years) and 7 females (ranging in age from 29 to 64 years, averaged 48.80 years). The patients suffered from ankylosing spondylitis (AS, 5 patients), developmental dysplasia of the hip (DDH, 4 patients), and rheumatoid arthritis (RA, 3 patients). The course of the disease ranged from 5.25 to 20 years. All affected hips were bony fused,lost normal function and had rest pain. The X-ray showed there were no joint space left in the affected hips and trabecular bone crossed the femoral head to the acetabulum. The Harris evaluation system was performed before surgery, at 6, 12 and the 36 months after surgery. RESULTS: The Harris evaluation system showed the joint replacement surgery can significantly improve the patients' life quality. The postoperative scores of pain was (40.00 +/- 0.01), joint function was (31.53 +/- 5.36), range of motion was (1.94 +/- 0.05) and the deformity was (4.00 +/- 0.01), which had significantly difference (P < 0.05) from the scores of preoperative ones as the pain (1.18 +/- 3.32), joint function (0.01 +/- 0.01), range of motion (0.01 +/- 0.01) and the deformity (0.01 +/- 0.01). In the three year follow-up study,total scores had gradual improvement (P < 0.05)in the 6, 12 and the 36 months after the operation, which were (77.47 +/- 5.34), (80.95 +/- 4.01) and (82.90 +/- 3.39) respectively. The scores for limp, support, stairs,activities as wearing shoes or socks,and public transportation were (9.59 +/- 1.54), (8.88 +/- 2.69), (3.29 +/- 0.99), (3.75 +/- 0.66) and (6.01 +/- 0.01) respectively, and the former three, which were (10.47 +/- l.18), (10.06 +/- 1.75) and (3.76 +/- 0.66), had continually improved in 12 months after the operation (P < 0.05). Operation also solved the motion problem and made the joint remain stable. All the patients were recovered without complications of nerve injuries. CONCLUSION: By the three year follow-up study, total hip replacement can significantly improve life quality of patients with hip pathological bony fused in non-functional position.
21196597 Validity of the COPCORD core questionnaire as a classification tool for rheumatic diseases 2011 Jan OBJECTIVE: Rheumatic diseases are vastly underdiagnosed and undertreated, particularly among minorities and those of low socioeconomic status. The WHO-ILAR Community Oriented Program in the Rheumatic Diseases (COPCORD) advocates screening of musculoskeletal complaints in the community. The objective of this study was to evaluate the performance of the COPCORD Core Questionnaire (CCQ) as a diagnostic tool for rheumatic diseases. METHODS: We conducted a cross-sectional study designed in parallel with a large COPCORD survey in Mexico. A subsample of 17,566 questionnaires, selected from 4 of the 5 states included in a national COPCORD survey were included in the analysis as a diagnostic test to evaluate sensitivity, specificity, receiver operating characteristics curve (ROC), and positive likelihood ratio (LR+) of the CCQ as a case-detection tool for rheumatic diagnosis and for the most frequent diagnoses identified in the survey, osteoarthritis, regional rheumatic pain syndromes, and rheumatoid arthritis (RA). Logistic regression with the questions with LR+ ≥ 1 was performed to identify the strength of association (OR) for each question. RESULTS: Pain in the last 7 days, high pain score (> 4), and previous diagnosis were the questions with highest LR+ for diagnosis, and for diagnosis of RA treatment with NSAID. The variables that contributed most to the model were pain in the last 7 days (OR 2.0, 95% CI 1.8-2.3), NSAID treatment (OR 3.3, 95% CI 3.0-3.7), a high pain score (OR 1.15, 95% CI 1.13-1.17), and having a previous diagnosis (OR 1.4, 95% CI 1.3-1.6). These 4 questions had R(2) = 0.24, p < 0.01, for detection of any rheumatic diagnosis. The single variable that explains 16% (OR 1.33, 95% CI 1.31-134) of variance was a high pain score in the last 7 days. CONCLUSION: Some variables were identified in the CCQ that could be combined in a brief version for case detection of rheumatic diseases in community surveys. The validity of this proposal has to be tested against the original version.
28520349 Azathioprine Therapy and TPMT and NUDT15 Genotype. 2012 Azathioprine (brand names Imuran, Azasan) is an immunosuppressant that belongs to the drug class of thiopurines. It is used with other drugs to prevent kidney transplant rejection and to manage autoimmune and inflammatory conditions such as systemic lupus erythematosus, inflammatory bowel disease, systemic vasculitis, and rheumatoid arthritis. Azathioprine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. The active metabolites are metabolized and inactivated by the enzyme thiopurine methyltransferase (TPMT) and the enzyme nudix hydrolase 15 (NUDT15). Thus, individuals with reduced activity of either enzyme are exposed to higher levels of thioguanine and have a higher risk of toxicity side effects, including severe bone marrow suppression (myelosuppression). The FDA-approved drug label states that testing for TPMT and NUDT15 deficiency should be considered in individuals who experience severe bone marrow toxicities or repeated episodes of myelosuppression. The FDA recommends considering an alternative therapy for individuals who are known to have homozygous TPMT or NUDT15 deficiency, or both, and to reduce dosages for individuals who have a no function allele, cautioning that a more substantial dose reduction may be required for individuals who are either TPMT or NUDT15 poor metabolizers (Table 1) (1). Dosing recommendations for thioguanine based on TPMT and NUDT15 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC, Table 2, Table 3) and the Dutch Pharmacogenetics Working Group (DPWG). Both the CPIC and DPWG guidelines recommend specific dose reductions for individuals who have low or deficient enzyme activity, including starting dose and more information on how and when to adjust the dose e.g., the time allowed to reach steady state after each dose adjustment (2-4).
23051967 Antibody transfection into neurons as a tool to study disease pathogenesis. 2012 Sep 26 Antibodies provide the ability to gain novel insight into various events taking place in living systems. The ability to produce highly specific antibodies to target proteins has allowed for very precise biological questions to be addressed. Importantly, antibodies have been implicated in the pathogenesis of a number of human diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), paraneoplastic syndromes, multiple sclerosis (MS) and human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP). How antibodies cause disease is an area of ongoing investigation, and data suggests that interactions between antibodies and various intracellular molecules results in inflammation, altered cellular messaging, and apoptosis. It has been shown that patients with MS and HAM/TSP produce autoantibodies to the intracellular RNA binding protein heterogeneous ribonuclear protein A1 (hnRNP A1). Recent data indicate that antibodies to both intra-neuronal and surface antigens are pathogenic. Thus, a procedure that allows for the study of intracellular antibody:protein interactions would lend great insight into disease pathogenesis. Genes are commonly transfected into primary cells and cell lines in culture, however transfection of antibodies into cells has been hindered by alteration of antibody structure or poor transfection efficiency. Other methods of transfection include antibody transfection based on cationic liposomes (consisting of DOTAP/DOPE) and polyethylenimines (PEI); both of which resulted in a ten-fold decrease in antibody transfection compared to controls. The method performed in our study is similar to cationic lipid-mediated methods and uses a lipid-based mechanism to form non-covalent complexes with the antibodies through electrostatic and hydrophobic interactions. We utilized Ab-DeliverIN reagent, which is a lipid formulation capable of capturing antibodies through non-covalent electrostatic and hydrophobic interactions and delivering them inside cells. Thus chemical and genetic couplings are not necessary for delivery of functional antibodies into living cells. This method has enabled us to perform various antibody tracing and protein localization experiments, as well as the analyses of the molecular consequences of intracellular antibody:protein interactions. In this protocol, we will show how to transfect antibodies into neurons rapidly, reproducibly and with a high degree of transfection efficiency. As an example, we will use anti-hnRNP A1 and anti-IgG antibodies. For easy quantification of transfection efficiency we used anti-hnRNP A1 antibodies labelled with Atto-550-NHS and FITC-labeled IgG. Atto550 NHS is a new label with high molecular absorbtion and quantum yield. Excitation source and fluorescent filters for Atto550 are similar to Cy3 (Ex. 556 Em. 578). In addition, Atto550 has high photostability. FITC-labeled IgG were used as a control to show that this method is versatile and not dye dependent. This approach and the data that is generated will assist in understanding of the role that antibodies to intracellular target antigens might play in the pathogenesis of human diseases.
22886402 Smoking is a predictor of worse trabecular mechanical performance in hip fragility fractur 2012 Nov Clinical risk factors (CRFs) are established predictors of fracture events. However, the influence of individual CRFs on trabecular mechanical fragility is still a subject of debate. In this study, we aimed to assess differences, adjusted for CRFs, between bone macrostructural parameters measured in ex-vivo specimens from hip fragility fracture patients and osteoarthritis patients, and to determine whether individual CRFs could predict trabecular bone mechanical behavior in hip fragility fractures. Additionally, we also looked for associations between the 10-year risk of major and hip fracture calculated by FRAX and trabecular bone mechanical performance. In this case-control study, a group of fragility fracture patients were compared with a group of osteoarthritis patients, both having undergone hip replacement surgery. A clinical protocol was applied in order to collect CRFs [body mass index (BMI), prior fragility fracture, parental history of hip fracture, long-term use of oral glucocorticoids, rheumatoid arthritis, current smoking, alcohol consumption, age and gender]. The 10-year probability of fracture was calculated. Serum bone turnover markers were determined and dual X-ray absorptiometry performed. Femoral head diameter was evaluated and trabecular bone cylinders were drilled for mechanical testing to determine bone strength, stiffness and toughness. We evaluated 40 hip fragility fracture and 52 osteoarthritis patients. Trabecular bone stiffness was significantly lower (p = 0.042) in hip fragility fracture patients when compared to osteoarthritic individuals, adjusted for age, gender and BMI. No other macrostructural parameter was statistically different between the groups. In hip fragility fracture patients, smoking habits (β = -0.403; p = 0.018) and female gender (β = -0.416; p = 0.008) were independently associated with lower stiffness. In addition, smoking was also independently associated with worse trabecular strength (β = -0.323; p = 0.045), and toughness (β = -0.403; p = 0.018). In these patients, the 10-year risk of major (r = -0.550; p = 0.012) and hip fracture (r = -0.513; p = 0.021) calculated using only CRFs was strongly correlated with femoral neck bone mineral density but not with mechanical performance. Our data showed that among fragility fracture patients active smoking is a predictor of worse intrinsic trabecular mechanical performance, and female gender is also independently associated with lower stiffness. In this population, the 10-year risk of fracture using CRFs with different weights only reflects bone mass loss but not trabecular mechanical properties.
22359781 (64)Cu-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclo(Arg-Gly-Asp-d-Ph 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (IC(50)), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidomimetics have been found to have high accumulation in tumors in mice (12, 13). From these developments, [(18)F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-18). Knetsch et al. (19) reported the development of (68)Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys) ((68)Ga-NODAGA-c(RGDfK)) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing melanoma tumors. 1-(1-Carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)(3)) was used to prepare (68)Ga-NODAGA-c(RGDfK). Dumont et al. (20) chelated NODAGA-c(RGDfK) with (64)Cu to form (64)Cu-NODAGA-c(RGDfK) for PET imaging of α(v)β(3) receptors in nude mice bearing human glioblastoma tumors. For evaluation as a PET imaging agent for α(v)β(3), (64)Cu has been attached to c(RGDfK) via bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) to form (64)Cu-CB-TE2A-c(RGDfK). The CB-TE2A chelating agent is thought to be a more stable chelate for Cu.
22147909 Association between bisphosphonate use and implant survival after primary total arthroplas 2011 Dec 6 OBJECTIVES: To test whether bisphosphonate use is related to improved implant survival after total arthroplasty of the knee or hip. DESIGN: Population based retrospective cohort study. SETTING: Primary care data from the United Kingdom. PARTICIPANTS: All patients undergoing primary total arthroplasty of the knee (n = 18,726) or hip (n = 23,269) in 1986-2006 within the United Kingdom's General Practice Research Database. We excluded patients with a history of hip fracture before surgery or rheumatoid arthritis, and individuals younger than 40 years at surgery. INTERVENTION: Bisphosphonate users were classified as patients with at least six prescriptions of bisphosphonates or at least six months of prescribed bisphosphonate treatment with more than 80% adherence before revision surgery. OUTCOME MEASURES: Revision arthroplasties occurring after surgery, identified by READ and OXMIS codes. Parametric survival models were used to determine effects on implant survival with propensity score adjustment to account for confounding by indication. Results Of 41 995 patients undergoing primary hip or knee arthroplasty, we identified 1912 bisphosphonate users, who had a lower rate of revision at five years than non-users (0.93% (95% confidence interval 0.52% to 1.68%) v 1.96% (1.80% to 2.14%)). Implant survival was significantly longer in bisphosphonate users than in non-users in propensity adjusted models (hazard ratio 0.54 (0.29 to 0.99); P = 0.047) and had an almost twofold increase in time to revision after hip or knee arthroplasty (time ratio 1.96 (1.01 to 3.82)). Assuming 2% failure over five years, we estimated that the number to treat to avoid one revision was 107 for oral bisphosphonates. Conclusions In patients undergoing lower limb arthroplasty, bisphosphonate use was associated with an almost twofold increase in implant survival time. These findings require replication and testing in experimental studies for confirmation.
22008538 Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygen 2011 Oct Auranofin, a disease-modifying gold compound, has been empirically applying to the management of rheumatoid arthritis. We investigated a protective effect of auranofin against hepatic injury induced by cocaine. Cocaine (75 mg/kg) markedly increased serum alanine amino transferase (ALT) (4,130 IU/l) and aspartate amino transferase (AST) (1,730 IU/l) activities at 16 hr after treatment, and induced hepatic necrosis surrounding central veins in mice. Concurrently, overexpression of heme oxygenase-1 (HO-1), a rate-limiting enzyme for heme degradation and an oxidative stress marker, was identified at the edges of cocaine-mediated necrotic area. Auranofin (10 mg/ml, i.p.) significantly induced hepatic HO-1 protein in mice from 12 hr after treatment. Interestingly, pretreatment with auranofin resulted in the prevention of the increase of serum ALT and AST activities in a dose-dependent manner. On the other hand, although cocaine increased tumor necrosis factor α (TNFα) gene expression in mouse livers, cocaine-induced liver injury was observed in TNFα deficient mice as well as wild-type mice. Auranofin-inducted HO-1 gene expression was observed in human primary hepatocytes as well as mouse primary hepatocytes. The present findings suggest that auranofin is effective in preventing cocaine-induced hepatic injury, and HO-1 may contribute to protect against chemically-induced cytotoxicity.
21968671 CD70 and Th17 are involved in human contact sensitivity. 2011 Oct CD70 (CD27L) has been shown to be preferentially expressed on Th1, but not Th2, CD4+ lymphocytes in murine contact sensitivity. The CD70-CD27 co-stimulatory pathway as well as the Th17 subset of lymphocytes have also been identified in human contact sensitivity reactions. The authors have previously reported increased expression of CD70 and the Th17-specific transcription factor retinoid orphan receptor gamma T in the elicitation phase of allergic contact dermatitis by reverse transcriptase-polymerase chain reaction. The manipulation of these pathways has potential for ameliorating autoimmune and inflammatory disorders such as allergic contact dermatitis, psoriasis and rheumatoid arthritis. Also, upregulation of the CD70-CD27 and Th17 pathways has been associated with the remarkable ability of topical sensitizers to treat warts and skin cancers including melanoma. As natural killer and natural killer T cells are also involved in contact sensitivity, future studies investigating the function of these cells are necessary to elucidate the transition between innate and acquired immune responses in the context of the Th1/Th2/Th17 and regulatory T cell paradigm.
21966502 Combining antigen-based therapy with GABA treatment synergistically prolongs survival of t 2011 Antigen-based therapies (ABTs) very effectively prevent the development of type 1 diabetes (T1D) when given to young nonobese diabetic (NOD) mice, however, they have little or no ability to reverse hyperglycemia in newly diabetic NOD mice. More importantly, ABTs have not yet demonstrated an ability to effectively preserve residual ß-cells in individuals newly diagnosed with type 1 diabetes (T1D). Accordingly, there is great interest in identifying new treatments that can be combined with ABTs to safely protect ß-cells in diabetic animals. The activation of γ-aminobutyric acid (GABA) receptors (GABA-Rs) on immune cells has been shown to prevent T1D, experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis in mouse models. Based on GABA's ability to inhibit different autoimmune diseases and its safety profile, we tested whether the combination of ABT with GABA treatment could prolong the survival of transplanted ß-cells in newly diabetic NOD mice. Newly diabetic NOD mice were untreated, or given GAD/alum (20 or 100 µg) and placed on plain drinking water, or water containing GABA (2 or 6 mg/ml). Twenty-eight days later, they received syngenic pancreas grafts and were monitored for the recurrence of hyperglycemia. Hyperglycemia reoccurred in the recipients given plain water, GAD monotherapy, GABA monotherapy, GAD (20 µg)+GABA (2 mg/ml), GAD (20 µg)+GABA (6 mg/ml) and GAD (100 µg)+GABA (6 mg/ml) about 1, 2-3, 3, 2-3, 3-8 and 10-11 weeks post-transplantation, respectively. Thus, combined GABA and ABT treatment had a synergistic effect in a dose-dependent fashion. These findings suggest that co-treatment with GABA (or other GABA-R agonists) may provide a new strategy to safely enhance the efficacy of other therapeutics designed to prevent or reverse T1D, as well as other T cell-mediated autoimmune diseases.
21938857 Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys/Cy5.5-Ferritin (64)Cu-loaded nanocages. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low fluorescence background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence (NIRF) imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Integrins are a family of heterodimeric, cell-surface glycoproteins that mediate diverse biological events involving cell–cell and cell–matrix interactions (6). Integrins comprise an α and a β subunit, and they are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class, affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (7-12). The α(v)β(3) integrin is strongly expressed on tumor cells and activated endothelial cells. In contrast, expression of the α(v)β(3) integrin is weak on resting endothelial cells and on most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (11, 13, 14). A tripeptide sequence comprising Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled cyclic RGD peptides have been introduced for tumor imaging and tumor angiogenesis (15). Ferritin is composed of 24 subunits of heavy and light chains that self-assemble to form a cage-like nanoparticle (nanocage) at physiological pH (7.4) with internal and external diameters of 8 nm and 12 nm (16, 17), respectively. The outer surface of ferritin can be chemically or genetically modified with ligands, and the cavity of ferritin can capture metal ions with high affinity (18). Lin et al. (19) genetically grafted an α(v)β(3)-targeted peptide (RDCRGDCFC, RGD4C) onto heavy chain ferritin (RGD4C-Fn) and chemically coupled Cy5.5 onto heavy chain ferritin (Cy5.5-Fn). Hybridization of RGD4C-Fn and Cy5.5-Fn (1:1) in the presence of (64)CuCl(2) resulted in the formation of RGD4C/Cy5.5-ferritin (64)Cu-loaded nanocages (RGD4C/Cy5.5-Fn-(64)Cu nanocages). RGD4C/Cy5.5-Fn-(64)Cu nanocages have been developed for positron emission tomography and NIRF multimodality imaging of tumor vasculature to study in vivo biodistribution of the tracer in tumor-bearing mice. RGD4C/Cy5.5-Fn-(64)Cu nanocages have been shown to have a high accumulation in the tumor vasculature and a predominant liver accumulation.
21843839 Shoulder Pain and Disability Index (SPADI). 2011 The Shoulder Pain and Disability Index (SPADI) was developed to measure current shoulder pain and disability in an outpatient setting. The SPADI contains 13 items that assess two domains; a 5-item subscale that measures pain and an 8-item subscale that measures disability. There are two versions of the SPADI; the original version has each item scored on a visual analogue scale (VAS) and a second version has items scored on a numerical rating scale (NRS). The latter version was developed to make the tool easier to administer and score (Williams et al 1995). Both versions take less than five minutes to complete (Beaton et al 1996, Williams et al 1995). The questionnaire was developed and initially tested in a mixed diagnosis group of male patients presenting to ambulatory care reporting shoulder pain (Roach et al 1991). The SPADI has since been used in both primary care on mixed diagnosis (Beaton et al 1996, MacDermaid et al 2006) and surgical patient populations including rotator cuff disease (Ekeberg et al 2008), osteoarthritis, and rheumatoid arthritis (Christie et al 2010), adhesive capsulitis (Staples et al 2010, Tveita et al 2008), joint replacement surgery (Angst et al 2007), and in a large population-based study of shoulder symptoms (Hill et al 2011). The SPADI is available free of charge at several sites, eg, www.workcover.com/public/download.aspx?id=799. INSTRUCTIONS TO THE CLIENT AND SCORING: In the original version the patient was instructed to place a mark on the VAS for each item that best represented their experience of their shoulder problem over the last week (Roach et al 1991). Each subscale is summed and transformed to a score out of 100. A mean is taken of the two subscales to give a total score out of 100, higher score indicating greater impairment or disability. In the NRS version (Williams et al 1995) the VAS is replaced by a 0-10 scale and the patient is asked to circle the number that best describes the pain or disability. The total score is derived in exactly the same manner as the VAS version. In each subscale patients may mark one item only as not applicable and the item is omitted from the total score. If a patient marks more than two items as non applicable, no score is calculated (Roach et al 1991). RELIABILITY AND VALIDITY: Reproducibility of the SPADI in the original description was poor, with an intraclass correlation coefficient (ICC) of 0.66. A more recent systematic review has found reliability coefficients of ICC ≥ 0.89 in a variety of patient populations (Roy et al 2009). Internal consistency is high with Cronbach α typically exceeding 0.90 (Roy et al 2009, Hill et al 2011). The SPADI demonstrates good construct validity, correlating well with other region-specific shoulder questionnaires (Paul et al 2004, Bot et al 2004, Roy et al 2009). It has been shown to be responsive to change over time, in a variety of patient populations and is able to discriminate adequately between patients with improving and deteriorating conditions (Beaton et al 1996, Williams et al 1995, Roy et al 2009). No large floor or ceiling effects for the SPADI have been observed (Bot et al 2004, Roy et al 2009). The minimal clinically important difference has been reported to be 8 points; this represents the smallest detectable change that is important to the patient (Paul et al 2004). When the SPADI is used more than once on the same subject, eg, at initial consultation and then at discharge, the minimal detectible change (MDC 95%) is 18 points (Angst et al 2008, Schmitt et al 2004). Thus some caution is advised with regard to repeated use of the instrument on the same patient. A change score of less than this value could be attributed to measurement error.
21717722 [Bone mineral density in patients with type 2 diabetes]. 2011 Mar OBJECTIVE: To establish whether type 2 diabetes (T2D) is associated with changes in the bone mineral density (BMD) of femoral neck, total hip and lumbar spine. MATERIAL AND METHODS: Comparative cross-sectional study that included 450 patients aged 30 years or more; 245 with, and 205 without T2D. Groups were matched by age. Degenerative joint disease, rheumatoid arthritis, neoplasia, renal failure, chronic liver disease, alcohol intake, prior treatment with drugs that modulate the BMD, Diabetes Mellitus Type 1 and other endocrinopathies were exclusion criteria. RESULTS: In the overall group, the presence of menopause was associated with osteoporosis in the hip (odds ratio -OR-4.2; CI95% 1.4-6.1), whereas T2D was a protective factor (OR 0.8; CI95% 0.4-0.9). Among premenopausal women, central obesity and total adiposity were associated with osteoporosis in the hip (OR 1.9; CI95% 1.1-3.9 and OR 2.1; CI95% 1.2-8.7) and femoral areas (OR 2.1; CI95% 1.2-4.1 and OR 2.3; CI95% 1.3-7.1); T2D remained as protective factor (OR 0.7; CI95% 0.5-0.9 and OR 0.6; CI95% 0.4-0.9). The adjusted analysis by BMI, waist circumference, and total adiposity showed that T2D remained as a protective factor for osteoporosis in the hip (OR 0.8; CI95% 0.6-0.9) and femoral areas (OR 0.7; CI95% 0.5-0.9). CONCLUSIONS: Our results suggest that T2D is an independent protective factor for osteoporosis.
21333602 Effective sample size: Quick estimation of the effect of related samples in genetic case-c 2011 Feb Affected relatives are essential for pedigree linkage analysis, however, they cause a violation of the independent sample assumption in case-control association studies. To avoid the correlation between samples, a common practice is to take only one affected sample per pedigree in association analysis. Although several methods exist in handling correlated samples, they are still not widely used in part because these are not easily implemented, or because they are not widely known. We advocate the effective sample size method as a simple and accessible approach for case-control association analysis with correlated samples. This method modifies the chi-square test statistic, p-value, and 95% confidence interval of the odds-ratio by replacing the apparent number of allele or genotype counts with the effective ones in the standard formula, without the need for specialized computer programs. We present a simple formula for calculating effective sample size for many types of relative pairs and relative sets. For allele frequency estimation, the effective sample size method captures the variance inflation exactly. For genotype frequency, simulations showed that effective sample size provides a satisfactory approximation. A gene which is previously identified as a type 1 diabetes susceptibility locus, the interferon-induced helicase gene (IFIH1), is shown to be significantly associated with rheumatoid arthritis when the effective sample size method is applied. This significant association is not established if only one affected sib per pedigree were used in the association analysis. Relationship between the effective sample size method and other methods - the generalized estimation equation, variance of eigenvalues for correlation matrices, and genomic controls - are discussed.