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ID PMID Title PublicationDate abstract
19747121 The p38alpha kinase plays a central role in inflammation. 2009 The p38 kinase plays a central role in inflammation, and it has been the subject of extensive efforts in both basic research and drug discovery. This review summarizes the biology of the p38 kinase with a focus on its role in inflammation. The p38 kinase regulates the production of key inflammatory mediators by cells of the innate immune system, including TNFalpha, IL-1beta, and COX-2. In addition, p38 also acts downstream of cytokines such as TNFalpha, mediating some of their effects. Recently p38 has also been found to play a role in responses of T cells, including Th17 and regulatory T cells. Consistent with its important role in inflammation, recent evidence suggests cells may utilize a variety of feedback mechanisms to regulate and maintain p38 signal transduction. The biological processes regulated by p38 kinase suggest both a wide variety of potential indications for inhibitors and a level of complexity that has proven challenging to drug discovery efforts around this target.
18697778 The sensitivity to change for lower disease activity is greater than for higher disease ac 2009 Aug OBJECTIVE: To test whether rheumatoid arthritis (RA) trials treatment efficacy versus control is better detected for patients with lower tender joint counts (TJC) or swollen joint counts (SJC) than for higher counts. METHODS: Using data from six large multicentre trials (N = 2002) and an intent-to-treat approach at 6 months, two subtrials were created within each trial, the lower disease activity group (defined by TJC less than overall median) and the higher disease activity group. The same approach was used for SJC. Active treatment was tested for treatment control differences using several RA trial outcome measures: ACR20, EULAR response, ACRHybrid. Sample sizes needed for higher TJC and SJC RA trials versus lower TJC and SJC trials were compared. RESULTS: Subtrials of subjects with lower TJC were found to have much higher sensitivity to change than those of subjects with higher TJC across all trials and outcome measures. A trial with lower TJC patients would require a smaller sample size than those with higher TJC patients. Results were not consistent for SJC subgroups. Three reasons were found for sensitivity to change of lower TJC: compared with higher TJC, those with lower TJC showed greater response to active treatment. SUBJECTS: with higher TJC on control treatment had greater percentage improvement and more variable responses than those in the lower TJC group. CONCLUSIONS: In RA trials, patients with lower disease activity within the range of current trial eligibility are more likely to show treatment efficacy than patients with higher disease activity. Lowering thresholds especially for TJC in trials may make it easier to detect treatment effects in RA.
20950126 The number needed to treat for second-generation biologics when treating established rheum 2011 Jan OBJECTIVE: To evaluate the number needed to treat (NNT) and the number needed to harm (NNH) of the second-generation biologics abatacept, certolizumab, golimumab, rituximab, and tocilizumab in patients with established rheumatoid arthritis (RA) taking concomitant methotrexate (MTX). METHODS: A systematic literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane Register of Controlled Trials was conducted up to 1 November 2009. We selected any published randomized, double-blind, MTX-controlled study including RA patients with a mean disease duration of at least 5 years before entering a pivotal trial on second-generation biological therapy. Studies eligible for inclusion involved patients, who had previously shown inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) therapy. Pre-specified binary outcomes were extracted with a preference for 1-year data (6-month data were used if no data were available for 1 year). Two reviewers independently extracted the data necessary to estimate the absolute measures in a non-responder intention-to-treat (ITT) analysis. RESULTS: Five randomized controlled trials, one for each of the drugs, were selected and data extracted according to published data at endpoint for American College of Rheumatology 50% (ACR50)-responding patients, and withdrawals due to adverse events. NNT ranged from four to six treated patients to achieve one ACR50 response, while withdrawals due to adverse events were few and non-significant compared to the placebo group, except for rituximab administered as 1000 mg. CONCLUSION: Comparable efficacy was shown by the five biological agents studied, with few adverse events. However, for rituximab, tocilizumab, and golimumab, only 6-month data were available, hampering the external validity with regard to long-term efficacy and tolerability. A low dose (500 mg) of rituximab may be as effective as the recommended dose of 1000 mg.
20412703 Nasal carriage of Staphylococcus aureus and endonasal activity in Wegener s granulomatosis 2010 Jan OBJECTIVES: Nasal colonisation with Staphylococcus aureus (S. aureus) has been implicated in Wegener's granulomatosis (WG) disease activity. In this study, the frequency of nasal colonisation with S. aureus in WG was compared to healthy and disease control groups for the first time. Moreover, endonasal activity was correlated to colonisation. PATIENTS AND METHODS: Nasal carriage of S. aureus of a well-defined group of 89 patients with WG was compared to 40 patients with chronic rhinosinusitis with nasal polyps (CRS), 35 patients with rheumatoid arthritis (RA), 50 hospital staff members and 25 subjects without regular hospital contact and correlation analysis of nasal carriage and endonasal activity of WG was performed. RESULTS: WG patients showed significantly higher rates (72%) of nasal colonisation with S. aureus compared to CRS patients (28%) and healthy subjects without regular hospital contact (25%, 95%-CI), but not to RA patients (46%) and hospital staff members (58%). WG patients with nasal carriage of S. aureus had significantly higher endoscopically proven endonasal activity (p=0.01), significantly more often first manifestation of WG in the upper respiratory tract (p=0.02) and higher relapse-rates (p=0.052) than WG patients without such carriage. CONCLUSIONS: Endonasal activity in WG is associated with higher nasal S. aureus colonisation rates and subsequent higher relapse rates. The higher frequency of S. aureus colonisation could be a consequence of a recently shown mucosal barrier defect in WG and facilitate chronic inflammation and granuloma formation in the upper respiratory tract.
20032101 CXCL 9 and CXCL 10 as Sensitive markers of disease activity in patients with rheumatoid ar 2010 Feb OBJECTIVE: To assess whether serum levels of CC and CXC chemokines correlate with disease activity in patients with rheumatoid arthritis (RA), and to determine whether these effects predict clinical response. METHODS: Serum levels of the chemokines CC (CCL2, CCL5) and CXC (CXCL8, CXCL9, CXCL10) were quantified at baseline and after 12 weeks of treatment with disease-modifying antirheumatic drugs or biologic agents in 28 patients using flow cytometry. Serum from 40 healthy individuals was collected for comparison at baseline. Response to treatment was classified according to the European League Against Rheumatism (EULAR) response criteria. Remission of disease was defined as a Disease Activity Score < 2.6. RESULTS: The baseline serum concentrations of CC and CXC chemokines were significantly elevated in patients with active RA compared to healthy controls (p < 0.05) except for CCL2. Significant improvement in all disease activity measurements was observed after 12 weeks of treatment. Seventeen (60.7%) patients achieved good to moderate response based on the EULAR response criteria, and 5 (17.9%) patients achieved remission. The improvement in clinical activity in patients with RA was accompanied by a significant reduction in the serum concentration of CXCL9 and CXCL10 (p < 0.001). A significant reduction in the serum level of CXCL10 was also observed in the group that achieved EULAR response. Serum concentration of CCL5 remained significantly elevated in patients with RA (n = 5) who achieved remission compared to the healthy controls (p < 0.05). CONCLUSION: Serum concentration of CXCL9 and CXCL10 may serve as sensitive biomarkers for disease activity in patients with RA.
20587038 Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. 2010 Jun 29 BACKGROUND: Although the efficacy of standard fish oil has been the subject of research in arthritis, the effect of krill oil in this disease has yet to be investigated. The objective of the present study was to evaluate a standardised preparation of krill oil and fish oil in an animal model for arthritis. METHODS: Collagen-induced arthritis susceptible DBA/1 mice were provided ad libitum access to a control diet or diets supplemented with either krill oil or fish oil throughout the study. There were 14 mice in each of the 3 treatment groups. The level of EPA + DHA was 0.44 g/100 g in the krill oil diet and 0.47 g/100 g in the fish oil diet. Severity of arthritis was determined using a clinical scoring system. Arthritis joints were analysed by histopathology and graded. Serum samples were obtained at the end of the study and the levels of IL-1alpha, IL-1beta, IL-7, IL-10, IL-12p70, IL-13, IL-15, IL-17 and TGF-beta were determined by a Luminex assay system. RESULTS: Consumption of krill oil and supplemented diet significantly reduced the arthritis scores and hind paw swelling when compared to a control diet not supplemented with EPA and DHA. However, the arthritis score during the late phase of the study was only significantly reduced after krill oil administration. Furthermore, mice fed the krill oil diet demonstrated lower infiltration of inflammatory cells into the joint and synovial layer hyperplasia, when compared to control. Inclusion of fish oil and krill oil in the diets led to a significant reduction in hyperplasia and total histology score. Krill oil did not modulate the levels of serum cytokines whereas consumption of fish oil increased the levels of IL-1alpha and IL-13. CONCLUSIONS: The study suggests that krill oil may be a useful intervention strategy against the clinical and histopathological signs of inflammatory arthritis.
19174567 Diffusion tensor anisotropy magnetic resonance imaging: a new tool to assess synovial infl 2009 Apr OBJECTIVE: Diffusion tensor imaging (DTI) has been used to study the structure of ordered biological tissue. DTI-derived metrics correlate with inflammatory cytokines and adhesion molecules, expressed in the brain abscess. We aimed to study the role of DTI-derived metrics in delineating the synovitis and their correlation with inflammatory proteins expressed in the SF of chronic inflammatory arthritis patients. METHODS: DTI was performed on 18 patients and 6 healthy controls. A follow-up DTI at 6 months was performed in 10 patients. Quantification of inflammatory cytokines (TNF-alpha, IL-1beta) and soluble intercellular adhesion molecule-1 (sICAM-1) in SF and their correlation with DTI-derived metrics was performed. RESULTS: DTI-derived metrics, fractional anisotropy (FA), cylindrical isotropy (CL), planar anisotropy (CP) and spherical isotropy (CS), were significantly altered in the inflamed synovium of the patients as compared to the healthy controls. Significant correlation between FA and TNF-alpha (r = 0.68, P = 0.002) and IL-1beta (r = 0.48, P < 0.05) and inverse correlations between mean diffusivity (MD) and TNF-alpha (r = -0.54, P < 0.05) and CS and TNF-alpha (r = -0.53, P < 0.05) and CP and IL-1beta and sICAM (r = 0.48, P < 0.05 and r = 0.49, P < 0.05, respectively) were observed. A significant correlation between post-contrast signal intensity (PCI) and IL-1beta and sICAM-1 (r = 0.61, P = 0.01 and r = 0.46, P = 0.05) and volume and sICAM-1 (r = 0.45, P = 0.05) was observed, respectively. CONCLUSION: Results of this pilot study suggest that the DTI-derived metrics have the potential to delineate synovial inflammation; however, it is not superior to conventional MRI for its detection and assessment of therapeutic response.
19772791 IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus. 2009 Jul OBJECTIVE: IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility. METHODS: IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR. RESULTS: A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level. CONCLUSIONS: Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations.
21081667 Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or 2011 Mar Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.
20645633 Cone beam computed tomographic findings in temporomandibular joint disorders. 2010 Jun Radiographic examination and imaging play an important role in the diagnosis and management of most temporomandibular joint (TMJ) disorders. Several techniques have been used for the examination of the TMJ, including conventional tomography, magnetic resonance imaging (MRI), arthrography, computed tomography (CT), and, recently, cone beam computed tomography (CBCT).
20155839 Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage 2010 May OBJECTIVE: Since fibroblasts in the synovium of patients with rheumatoid arthritis (RA) express the serine proteases fibroblast activation protein (FAP) and dipeptidylpeptidase 4 (DPP-4)/CD26, we undertook the current study to determine the functional role of both enzymes in the invasion of RA synovial fibroblasts (RASFs) into articular cartilage. METHODS: Expression of FAP and DPP-4/CD26 by RASFs was analyzed using fluorescence-activated cell sorting and immunocytochemistry. Serine protease activity was measured by cleavage of fluorogenic substrates and inhibited upon treatment with L-glutamyl L-boroproline. The induction and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in RASFs were detected using real-time polymerase chain reaction. Densitometric measurements of MMPs using immunoblotting confirmed our findings on the messenger RNA level. Stromal cell-derived factor 1 (SDF-1 [CXCL12]), MMP-1, and MMP-3 protein levels were measured using enzyme-linked immunosorbent assay. The impact of FAP and DPP-4/CD26 inhibition on the invasiveness of RASFs was analyzed in the SCID mouse coimplantation model of RA using immunohistochemistry. RESULTS: Inhibition of serine protease activity of FAP and DPP-4/CD26 in vitro led to increased levels of SDF-1 in concert with MMP-1 and MMP-3, which are downstream effectors of SDF-1 signaling. Using the SCID mouse coimplantation model, inhibition of enzymatic activity in vivo significantly promoted invasion of xenotransplanted RASFs into cotransplanted human cartilage. Zones of cartilage resorption were infiltrated by FAP-expressing RASFs and marked by a significantly higher accumulation of MMP-1 and MMP-3, when compared with controls. CONCLUSION: Our results indicate a central role for the serine protease activity of FAP and DPP-4/CD26 in protecting articular cartilage against invasion by synovial fibroblasts in RA.
19474128 Tenosynovitis of the flexor tendons of the hand detected by MRI: an early indicator of rhe 2009 Aug OBJECTIVE: To evaluate the potential of MRI of finger and wrist joints for diagnosing early RA. MRI was evaluated as a stand-alone tool and in combination with ACR criteria and serum markers such as RF. METHODS: Ninety-nine patients (31 men, 68 women; median age 46 years) with unspecified arthritis or suspected RA and negative X-ray findings were included. MR images of the hand and wrist of these patients were retrospectively evaluated for the presence of synovitis, erosions and tenosynovitis. The clinical diagnosis (early RA or non-RA) was made by a rheumatologist after clinical follow-up for 6-41 months. Clinical and laboratory data were collected from all patients. RESULTS: Fifty-eight patients had a clinical diagnosis of RA and 41 were diagnosed as non-RA. Step-wise logistic regression of all MR parameters evaluated identified tenosynovitis of the flexor tendons to be the most powerful predictor of early RA (sensitivity = 60%, specificity = 73%). Including ACR criteria in the analysis, positive serum RF and tenosynovitis were the strongest predictors of early RA (sensitivity = 83%, specificity = 63%). When serum anti-cyclic citrullinated peptides (CCP), ANA and CRP were included as additional parameters, anti-CCP and flexor tenosynovitis were the strongest predictors of early RA (sensitivity = 79%, specificity = 73%). CONCLUSIONS: Flexor tenosynovitis diagnosed by MRI of the hand is a strong predictor of early RA. Combining flexor tenosynovitis on MRI with positive serum anti-CCP or positive RF is an even stronger predictor of early RA.
18836893 Improvement in diagnosis and management of musculoskeletal conditions with one-stop clinic 2009 We evaluated the impact of clinic-based musculoskeletal ultrasonography (MSUS) on diagnosis and management of cases as seen in day-to-day rheumatology practice. Data were retrieved for demography, background condition, clinical findings, indications, regions scanned, and outcomes of MSUS, and categorised as: new-patients and follow-up. New-patient records were analysed as to whether MSUS had helped to confirm or change clinical diagnosis or was of no additional help. In follow-ups, we determined whether MSUS had helped in disease assessment, detection of co-existing problems or revision of diagnosis. Its impact on treatment decisions was noted. A total of 237 patients (146 women; mean age 55.9+/-17.2 years) had 264 regions scanned; hands,50.7%. In 78/237 (32.9%) there was disagreement between clinical and MSUS findings. Amongst new-patients (72), 13/39 (33.3%) referred with inflammatory arthritis had no MSUS evidence of inflammation in or around joints. In 76.3% it helped in confirming or changing diagnosis. Of the follow-ups (165), in 78.7%, 13.9% and 7.2% it helped in assessment, detection of co-existing problems and revision of diagnosis, respectively. MSUS influenced treatment in 45/165 (27.27%) cases. In 60/67 (89.55%) cases of rheumatoid arthritis (RA), it was done for disease assessment; in 31/60 (51.66%) it influenced treatment. MSUS, as a clinic-based service in rheumatology, has significant impact on the diagnosis and treatment of patients. This has potential to reduce diagnostic uncertainty and follow-up visits and ensure better outcomes.
20544644 Total hip arthroplasty in inflammatory arthritis in patients under 35 years. A 7 to 19 yea 2010 Apr Total hip arthroplasty in patients with inflammatory arthritis is compromised by the young age of patients at presentation, intake of non-steroidal anti-inflammatory drugs, steroid use and autoimmune diseases which negatively affect bone quality. This study evaluates the survival of total hip arthroplasties (THA) in 32 patients with inflammatory hip disease who were under the age of 35 at the index operation and on which 57 primary total hip arthroplasties were performed between 1989 and 2001. Polished straight tapered cemented stems were used in all 57 hips. There were 10 cemented and 47 uncemented cups. The average follow-up was 12.2 years (range 7-19). Forty-seven hips had more than 10 years follow-up. There were 3 revisions of cemented metal-backed cups for aseptic loosening at 11, 13 and 16 years post-operatively. No uncemented cups and no stems needed revision. Heterotopic ossifications occured in 3 hips with Brooker type-I ossification in 1 hip and Brooker type-II in 2 hips. Cemented polished tapered straight stems demonstrate excellent survival in young patients suffering from inflammatory arthritis.
20039409 Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experiment 2010 Jan OBJECTIVE: To delineate the role of neuropilin-1 (NP-1), a vascular endothelial growth factor receptor (VEGFR), in rheumatoid inflammation and to determine whether blockade of NP-1 could suppress synoviocyte survival and angiogenesis. METHODS: VEGF(111-165) peptide, which encompasses the NP-1 binding domain of VEGF(165), was generated by cleaving VEGF(165) with plasmin. The effect of this peptide on the interaction between VEGF(165) and its receptor was determined by (125)I-VEGFR binding assay. Assays to determine synoviocyte apoptosis, adhesion, and migration were performed in the presence of VEGF(165) and/or the peptide. VEGF(165)-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of endothelial cells (ECs). Mice were immunized with type II collagen to induce experimental arthritis. RESULTS: VEGF(111-165) peptide specifically inhibited the binding of (125)I-VEGF(165) to NP-1 on rheumatoid synoviocytes and ECs. The peptide eliminated the VEGF(165)-mediated increase in synoviocyte survival and activation of p-ERK and Bcl-2. The peptide also completely inhibited a VEGF(165)-induced increase in synoviocyte adhesion and migration. In addition, the anti-NP-1 peptide blocked VEGF(165)-stimulated proliferation, capillary tube formation, and wounding migration of ECs in vitro. VEGF(165)-induced neovascularization in a Matrigel plug in mice was also blocked by treatment with the peptide. Finally, subcutaneous injection of anti-NP-1 peptide suppressed arthritis severity and autoantibody formation in mice with experimental arthritis and inhibited synoviocyte hyperplasia and angiogenesis in arthritic joints. CONCLUSION: Anti-NP-1 peptide suppressed VEGF(165)-induced increases in synoviocyte survival and angiogenesis, and thereby blocked experimental arthritis. Our findings suggest that anti-NP-1 peptide could be useful in alleviating chronic arthritis.
19110161 Posterior tibial artery pseudoaneurysm identified subsequent to surgical wound dehiscence. 2009 Jan The development of a pseudoaneurysm of the posterior tibial artery is a rare event. In this article, we describe the case of a 63-year-old female with rheumatoid arthritis, who initially presented with a symptomatic subcutaneous nodule localized to the medial aspect of the right ankle. After excision of the subcutaneous nodule, she failed to heal the surgical wound and, eventually, the pseudoaneurysm of the posterior tibial artery was identified. It was not until after the posterior tibial artery was ligated and the pseudoaneurysm excised, that the wound finally healed. LEVEL OF CLINICAL EVIDENCE: 4.
19513935 Activity of lysosomal exoglycosidases in serum and synovial fluid in patients with chronic 2009 Lysosomal exoglycosidases participate in the destruction of the articular cartilage by cleaving glycoside bonds in glycoproteins and proteoglycans. The aim of the study was to determine the activity of exoglycosidases: hexosaminidase, beta-glucuronidase, beta-galactosidase, alpha-mannosidase and alpha-fucosidase in serum and synovial fluid of patients with Lyme and rheumatoid arthritis. The study group consisted of 10 patients with chronic Lyme arthritis (age 18 - 74 y), 13 with rheumatoid arthritis (age 32 - 70 y) and 10 with juvenile idiopathic arthritis (age 8 - 17 y). The control group consisted of 9 healthy volunteers (age 24 - 62 y). The activity of the exoglycosidases was determined with the p-nitrophenyl derivatives of sugars as substrates. A significant increase of the activity of all the exoglycosidases in serum and in synovial fluid of the patients with different forms of arthritis was found. The ratio of synovial fluid/serum activity of exoglycosidases was above 2.0 in LA but not in JIA and RA patients. As the main source of exoglycosidases in the joint is the synovial membrane, this result supports the appropriateness of therapeutic synovectomy in chronic Lyme arthritis with knee effusion. The serum activity of hexosaminidase may be used in monitoring the course of Lyme arthritis and the efficiency of treatment.
19208597 Circulating leptin and bone mineral density in rheumatoid arthritis. 2009 Mar OBJECTIVE: To evaluate the association between circulating leptin and bone mineral density (BMD) in patients with rheumatoid arthritis (RA). METHODS: One-hundred thirty postmenopausal women with RA were assessed for body mass index (BMI), disease characteristics, history of drug use, rheumatoid factor, and erythrocyte sedimentation rate (ESR). BMD (g/cm(2)) was determined in the hip and spine by DEXA. Serum leptin concentrations were measured by ELISA. Spearman's correlation coefficients (rho) were determined between BMD and leptin and other variables. A multiple regression analysis was used to adjust for confounders. RESULTS: Patients' serum leptin levels varied widely (range 2-128 ng/ml). Thirty-three patients (25%) had osteoporosis. Higher levels of leptin correlated significantly with BMD in the lumbar spine (rho = 0.17, p = 0.04) and total hip (rho = 0.21, p = 0.01). The variables that were negatively correlated with BMD were age, duration of menopause, and ESR. After adjustment for confounders, leptin was no longer associated with BMD. In the multivariate model, factors that remained associated with BMD in the total hip were age (p = 0.021) and BMI (p = 0.003); and the factors that remained associated with BMD in the lumbar spine were BMI (p = 0.03) and ESR (p = 0.01). CONCLUSION: No relevant association was found between circulating leptin levels and BMD in patients with RA in this cross-sectional study. Followup studies are needed to evaluate whether abnormal leptin levels confer a risk for fractures due to osteoporosis.
19195834 Clinical and radiographic results for the Richards Modular Hip System prosthesis in total 2010 Apr The clinical results of total hip arthroplasty using the Richards Modular Hip System prosthesis were evaluated in 41 patients (44 joints). The mean Harris hip score improved from 42 points before surgery to 82 after 1 year, 85 at 5 years, and 79 at the final examination. The average polyethylene wear rate was 0.09 +/- 0.07 mm/y. Forty joints (90.9%) achieved press fit in either of the proximal or the distal stem portion, and only 4 joints (9.1%) failed to achieve press fit in both the proximal and distal stem portions. Although the 10-year survival of the stem was 94.5% and no revisions of the stem were performed, osteolysis was found at high frequency at a distal stem. The high incidence of osteolysis has been the limiting factor in the long-term success of Richards Modular Hip System. Achievement of good canal fill in both the proximal and distal stem portions did not contribute to the good long-term result of the stem.
20807604 GRP78 signaling hub a receptor for targeted tumor therapy. 2010 Glucose-regulated protein 78 (GRP78) is a potential receptor for targeting therapy in cancer and chronic vascular disease due to its overexpression at the cell surface in tumor cells and in atherosclerotic lesions. Presence of the GRP78 autoantibody in cancer patient sera is generally associated with poor prognosis since it signals a prosurvival mechanism in response to cellular stress. Association of GRP78 with various binding partners involves coordination of multiple signaling pathways that result in either cell survival or cell death. Binding of activated alpha2-macroglobulin to cell-surface GRP78 activates Akt to suppress apoptotic pathways through multiple downstream effectors, and concomitantly upregulates NF-kappaBeta and induces the unfolded protein response (UPR) so that cell proliferation prevails. Interaction of GRP78 with cell-surface T-cadherin promotes endothelial cell survival. Association of oncogenic Cripto with GRP78 nullifies TGF-beta superfamily-dependent signaling through Smad2/3 to promote cell proliferation. In contrast, association of GRP78 with the plasminogen kringle 5 domain or extracellular Par-4 promotes apoptosis. Interaction of GRP78 with microplasminogen induces the UPR while association with tissue factor inhibits procoagulant activity. The diverse and multiple binding proteins of GRP78 and their equally diverse functional outcomes reflect the regulatory cellular functions that GRP78 orchestrates. Several GRP78 targeting peptides have been isolated from different tumors and they show remarkable tumor specificity. Conjugation of GRP78-targeting peptides to an apoptosis-inducing peptide suppresses tumor growth in tumor xenografts, thereby demonstrating that GRP78 is a viable target by which clinical cancer therapies can be successfully developed as well as its potential utility in treating vascular disease.