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ID PMID Title PublicationDate abstract
20299009 IFNgamma primes macrophages for inflammatory activation by high molecular weight hyalurona 2010 The objective was to assess outcomes of IFNgamma-priming upon macrophage activation by the synovial macromolecule high molecular weight hyaluronan [HMW-HA] in the context of rheumatoid arthritis inflammation. Human macrophages primed by IFNgamma and activated by HMW-HA were evaluated for cytokine secretion by ELISA and Milliplex assay and activation profiles by nuclear transcription factor EIA. IFNgamma-primed, HMW-HA-activated macrophages produced elevated levels of TNF and secreted the TH1 cytokine IL-12p70, while IFNgamma suppressed HMW-HA-induced secretion of the regulatory cytokine IL-10 and activation of the transcription factor c-Jun. IFNgamma modulates the HMW-HA-induced cytokine response profile promoting macrophage activation and inflammatory TH1 cytokine secretion.
20044944 The prevalence and functional impact of musculoskeletal conditions amongst clients of a pr 2010 Jan 4 BACKGROUND: The extent of disease burden of musculoskeletal conditions (MSC) not due to injury has not been well determined in sub-Saharan Africa. The 1999 Global Burden of Disease study estimated the prevalence of osteoarthritis and rheumatoid arthritis to be 150/100,000 compared to 1,500/100,000 in Europe. The objective of the study was to determine the prevalence of MSC and the functional implications in a sample of people attending community health centres in Cape Town, South Africa. METHODS: A cross-sectional, descriptive study was conducted in clinics in two resource poor communities. Phase I consisted of screening and those who screened positive for peripheral or spinal joint pain went on to complete Phase II, which included the Stanford Health Assessment Questionnaire. RESULTS: 1005 people were screened in Phase I. Of these, 362 (36%) reported MSC not due to injury in the past three months. Those with MSC had higher rates of co-morbidities in every category than those without. The mean Disability Index for those with MSC was mild to moderate and moderate to severe in those over 55 years. CONCLUSIONS: Although the sample may not be representative of the general community, the prevalence is considerably greater than those reported elsewhere even when the population of the catchment area is used as a denominator, (367/100 000). The common presentation of MSC with co-morbid diabetes and hypertension requires holistic management by appropriately trained health care practitioners. Any new determination of burden of disease due to MSC should recognise that these disorders may be more prevalent in developing countries than previously estimated.
20026374 Chikungunya fever: CNS infection and pathologies of a re-emerging arbovirus. 2010 Jun Chikungunya virus (CHIKV) is transmitted by Aedes mosquitoes and causes an acute symptomatic illness with fever, skin rash, and incapacitating arthralgia, which can evolve into chronic rheumatoid arthritis in elderly patients. This is a tropical disease originally described in central/east Africa in the 1960s, but its 2004 re-emergence in Africa and rapid spread in lands in and around the Indian Ocean (Reunion island, India, Malaysia) as well as Europe (Italy) led to almost 6 million cases worldwide. The risk of importation and spreading diseases with long-term sequelae is even greater today given the global distribution of the vectors (including in the Americas), increased tourism and the apparent capacity of CHIKV to produce high levels of viremia (10(9)-10(12) virus/ml of blood) and new mutants. CHIKV-associated neuropathology was described early in the 1960s, but it is the unprecedented incidence rate in Indian Ocean areas with efficient clinical facilities that allowed a better description of cases with severe encephalitis, meningoencephalitis, peripheral neuropathies and deaths among newborns (mother-to-child infection), infants and elderly patients. Death rates following CHIKV infection were estimated at 1:1000 cases in la Reunion's outbreak. These clinical observations have been corroborated by experimental infection in several mouse models, leading to CNS pathologies. We further describe in this review the capacity of CHIKV to infect neurons and glial cells, delineate the fundamental innate (intrinsic) immune defence mechanisms to protect from infection and argue about the possible mechanisms involved in the encephalopathy.
19758434 Protective effect of geranylgeranylacetone, an inducer of heat shock protein 70, against d 2009 Sep 16 BACKGROUND: To determine whether oral administration of geranylgeranylacetone (GGA), a nontoxic anti-ulcer drug that is an inducer of heat shock protein (HSP) 70, protects against drug-induced lung injury/fibrosis in vivo. METHODS: We used a bleomycin (BLM)-induced lung fibrosis model in which mice were treated with oral 600 mg/kg of GGA before and after BLM administration. Inflammation and fibrosis were evaluated by histological scoring, hydroxyproline content in the lung and inflammatory cell count, and quantification by ELISA of macrophage inflammatory protein-2 (MIP-2) in bronchoalveolar lavage fluid. Apoptosis was evaluated by the TUNEL method. The induction of HSP70 in the lung was examined with western blot analysis and its localization was determined by immunohistochemistry. RESULTS: We confirmed the presence of inflammation and fibrosis in the BLM-induced lung injury model and induction of HSP70 by oral administration of GGA. GGA prevented apoptosis of cellular constituents of lung tissue, such as epithelial cells, most likely related to the de novo induction of HSP70 in the lungs. GGA-treated mice also showed less fibrosis of the lungs, associated with the findings of suppression of both production of MIP-2 and inflammatory cell accumulation in the injured lung, compared with vehicle-treated mice. CONCLUSION: GGA had a protective effect on drug-induced lung injury/fibrosis. Disease-modifying antirheumatic drugs such as methotrexate, which are indispensable for the treatment of rheumatoid arthritis, often cause interstitial lung diseases, an adverse event that currently cannot be prevented. Clinical use of GGA for drug-induced pulmonary fibrosis might be considered in the future.
19636550 MHC class II polymorphism is associated with a canine SLE-related disease complex. 2009 Aug Nova Scotia duck tolling retrievers are predisposed to a SLE-related disease complex including immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). IMRD involves symptoms that resemble those seen in systemic autoimmune rheumatic diseases, such as systemic lupus erythematosus, SLE, or SLE-related diseases, in humans. This disease complex involves persistent lameness, stiffness, mainly after resting, and palpable pain from several joints of extremities. The majority of affected dogs display antinuclear autoantibody (ANA)-reactivity. SRMA is manifested in young dogs with high fever and neck stiffness and can be treated with corticosteroids. We have investigated the possible role of MHC class II as a genetic risk factor in IMRD and SRMA etiology. We performed sequence-based typing of the DLA-DRB1, -DQA1, and -DQB1 class II loci in a total of 176 dogs including 51 IMRD (33 ANA-positive), 49 SRMA cases, and 78 healthy controls (two dogs were both IMRD- and SRMA-affected). Homozygosity for the risk haplotype DRB1*00601/DQA1*005011/DQB1*02001 increased the risk for IMRD (OR = 4.9; ANA-positive IMRD: OR = 7.2) compared with all other genotypes. There was a general heterozygote advantage, homozygotes had OR = 4.4 (ANA-positive IMRD: OR = 8.9) compared with all heterozygotes. The risk haplotype contains the five amino acid epitope RARAA, known as the shared epitope for rheumatoid arthritis. No association was observed for SRMA. We conclude that DLA class II is a highly significant genetic risk factor for ANA-positive IMRD. The results indicate narrow diversity of DLA II haplotypes and identify an IMRD-related risk haplotype, which becomes highly significant in homozygous dogs.
19545157 Novel autoimmune hepatitis-specific autoantigens identified using protein microarray techn 2010 Jan Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver with a poorly understood etiology. Detection of nonorgan-specific and liver-related autoantibodies using immunoserological approaches has been widely used for diagnosis and prognosis. However, unambiguous and accurate detection of the disease requires the identification and characterization of disease-specific autoantigens. In the present study, we have profiled the autoantigen repertoire of patients with AIH versus those with other liver diseases, identifying and validating three novel and highly specific biomarkers for AIH. In phase I, we fabricated a human protein chip of 5011 nonredundant proteins and used it to quickly identify 11 candidate autoantigens with relative small serum collection. In phase II, we fabricated an AIH-specific protein chip and obtained autoimmunogenic profiles of serum samples from 44 AIH patients, 50 healthy controls, and 184 additional patients suffering from hepatitis B, hepatitis C, systemic lupus erythematosus, primary Sjogren's syndrome, rheumatoid arthritis, or primary biliary cirrhosis. With this two-phase approach, we identified three new antigens, RPS20, Alba-like, and dUTPase, as highly AIH-specific biomarkers, with sensitivities of 47.5% (RPS20), 45.5% (Alba-like), and 22.7% (dUTPase). These potential biomarkers were further validated with additional AIH samples in a double-blind design. Finally, we demonstrated that these new biomarkers could be readily applied to ELISA-based assays for use in clinical diagnosis/prognosis.
19543881 Familial association between type 1 diabetes and other autoimmune and related diseases. 2009 Sep AIMS/HYPOTHESIS: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and success in gene identification. We wanted to estimate associations between type 1 diabetes mellitus and 33 autoimmune and related diseases in parents, offspring, singleton siblings and twins. METHODS: The availability of a Multigeneration Register in Sweden provides reliable access to families throughout the last century. The diseases in individual family members were obtained through linkage to the Hospital Discharge Register. Standardised incidence ratios (SIRs) were calculated as relative risks of contracting type 1 diabetes in family members of affected patients compared with those lacking affected family members. RESULTS: Among a total of 450,899 patients, 21,168 were diagnosed with type 1 diabetes. Familial cases amounted to 10.3% of all type 1 diabetes patients. SIR for type 1 diabetes was 8.23 in offspring of affected parents, 11.92 in singleton siblings, 39.22 in multiplex families and 21.88 in twins; the calculated risk for monozygotic twins was 32.33. Type 1 diabetes in offspring was associated with 13 diseases in parents, including Addison's disease (SIR 2.41), asthma (1.38), coeliac disease (2.73), Graves' disease/hyperthyroidism (1.86), Hashimoto disease/hypothyroidism (2.35), pernicious anaemia (3.09), primary biliary cirrhosis (3.63), rheumatoid arthritis (2.12), sarcoidosis (1.62), systemic lupus erythematosus (2.04), ulcerative colitis (1.23) and Wegener's granulomatosis (2.12). CONCLUSIONS/INTERPRETATION: The concordant familial risks for type 1 diabetes were high and the calculated risk for multiplex families and monozygotic twins may be explained by epistatic gene x gene or gene x environment interactions. Familial associations with several autoimmune and related diseases suggest genetic sharing and challenge to gene identification.
19443147 Anti-inflammatory and analgesic effects of ethanol and aqueous extracts of Pterocephalus h 2009 Jun 25 AIM OF THE STUDY: This study evaluates the anti-inflammatory and analgesic activities of the ethanol and aqueous extracts of a Tibetan herb Pterocephalus hookeri (C.B. Clarke) Höeck to provide experimental evidence for its traditional use such as cold, flu and rheumatoid arthritis. MATERIALS AND METHODS: Investigations on the analgesic effects of P. hookeri (C.B. Clarke) Höeck were carried out, including hot-plate test and acetic acid-induced writhing. The anti-inflammatory activities were observed by utilizing the following models: carrageenin-induced edema of the hind paw of rats, cotton pellet-induced granuloma formation in rats, acetic acid-induced permeability, and xylene-induced ear edema in mice. The effects of the administration of indomethacin were also studied. RESULTS: It has been shown that the ethanol and aqueous extracts significantly increased the hot-plate pain threshold and reduced acetic acid-induced writhing response in mice. The ethanol and aqueous extracts remarkably inhibited the increase in vascular permeability induced by acetic acid and ear edema induced by xylene. The ethanol extract also significantly decreased the carrageenin-induced rat paw edema perimeter and inhibited the increase of granuloma weight. CONCLUSION: The results show that the ethanol and aqueous extracts have both central and peripheral analgesic activities and as anti-inflammatory effects, supporting the traditional application of this herb in treating various diseases associated with inflammation and pain.
19419299 LPS-induced inhibition of osteogenesis is TNF-alpha dependent in a murine tooth extraction 2009 Oct TNF-alpha is a major etiologic factor of inflammatory bone diseases such as periodontitis and rheumatoid arthritis. In addition, patients with metabolic diseases such as chronic heart disease and diabetes have significantly increased plasma levels of TNF-alpha. Several lines of evidence show inhibition of osteoblastogenesis by TNF-alpha in vitro. Therefore, bone formation and osteogenesis in these patients might be inhibited because of TNF-alpha. However, little is known about the inhibitory role of TNF-alpha in bone formation/osteogenesis in vivo. The purpose of this study was to investigate the role of TNF-alpha in osteogenesis using a murine tooth extraction model. Lipopolysaccharide (LPS) was injected subcutaneously into the calvariae of either wildtype (WT) or TNF-alpha-deficient (KO) mice. The left incisor was extracted 4 days after LPS injection. The measuring area was established as the tooth socket under the mesial root of the first molar. A significant increase in serum TNF-alpha levels after LPS injection was observed in WT mice. The BMD of the tooth socket was significantly decreased by LPS injection 21 days after extraction in WT but not in KO mice. Histomorphometric analysis showed a significant decrease in the mineral apposition rate after LPS injection, which appeared at an early stage in WT but not in KO mice. Injection of a peptide that blocked the TNF-alpha signaling pathway by preventing transmission of the NF-kappaB signal recovered the inhibition of osteogenesis observed after LPS injection. In conclusion, TNF-alpha might play a major role in LPS-induced inhibition of osteogenesis under inflammatory conditions.
19364476 Focus on mammalian thioredoxin reductases--important selenoproteins with versatile functio 2009 Jun Thioredoxin systems, involving redox active thioredoxins and thioredoxin reductases, sustain a number of important thioredoxin-dependent pathways. These redox active proteins support several processes crucial for cell function, cell proliferation, antioxidant defense and redox-regulated signaling cascades. Mammalian thioredoxin reductases are selenium-containing flavoprotein oxidoreductases, dependent upon a selenocysteine residue for reduction of the active site disulfide in thioredoxins. Their activity is required for normal thioredoxin function. The mammalian thioredoxin reductases also display surprisingly multifaceted properties and functions beyond thioredoxin reduction. Expressed from three separate genes (in human named TXNRD1, TXNRD2 and TXNRD3), the thioredoxin reductases can each reduce a number of different types of substrates in different cellular compartments. Their expression patterns involve intriguingly complex transcriptional mechanisms resulting in several splice variants, encoding a number of protein variants likely to have specialized functions in a cell- and tissue-type restricted manner. The thioredoxin reductases are also targeted by a number of drugs and compounds having an impact on cell function and promoting oxidative stress, some of which are used in treatment of rheumatoid arthritis, cancer or other diseases. However, potential specific or essential roles for different forms of human or mouse thioredoxin reductases in health or disease are still rather unclear, although it is known that at least the murine Txnrd1 and Txnrd2 genes are essential for normal development during embryogenesis. This review is a survey of current knowledge of mammalian thioredoxin reductase function and expression, with a focus on human and mouse and a discussion of the striking complexity of these proteins. Several yet open questions regarding their regulation and roles in different cells or tissues are emphasized. It is concluded that the intriguingly complex regulation and function of mammalian thioredoxin reductases within the cellular context and in intact mammals strongly suggests that their functions are highly fi ne-tuned with the many pathways involving thioredoxins and thioredoxin-related proteins. These selenoproteins furthermore propagate many functions beyond a reduction of thioredoxins. Aberrant regulation of thioredoxin reductases, or a particular dependence upon these enzymes in diseased cells, may underlie their presumed therapeutic importance as enzymatic targets using electrophilic drugs. These reductases are also likely to mediate several of the effects on health and disease that are linked to different levels of nutritional selenium intake. The thioredoxin reductases and their splice variants may be pivotal components of diverse cellular signaling pathways, having importance in several redox-related aspects of health and disease. Clearly, a detailed understanding of mammalian thioredoxin reductases is necessary for a full comprehension of the thioredoxin system and of selenium dependent processes in mammals.
19327236 Effects of celecoxib on the expression of osteoprotegerin, energy metabolism and cell viab 2009 Jan BACKGROUND AND OBJECTIVE: The selective COX-2 inhibitor celecoxib is widely used to treat pain and inflammation in rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. The drug has well-known important effects on immune cells but its direct and/or indirect influence on osteoblasts has not yet been explored in detail. This study aimed to investigate the dose-dependent effects of celecoxib on cell viability, energy metabolism and bone remodeling processes in cultured human osteoblastic cells. METHODS: Primary human osteoblasts and MG-63 cells were incubated with celecoxib (2, 10, 50microM). Cell viability and apoptosis were determined by trypan blue, 7AAD and Annexin-V staining. Effects on cellular oxygen consumption were measured amperometrically using a Clark electrode. mRNA expression of GLUT-1 and OPG was determined by RT-PCR; OPG protein secretion by ELISA and HIF-1alpha protein expression by immunoblotting. RESULTS: While celecoxib at a concentration of 2 and 10microM showed only marginal effects, a suprapharmacological concentration of 50microM influenced viability and energy metabolism, as well as OPG expression and secretion of osteoblastic cells. Cell viability was significantly reduced by celecoxib treatment. Celecoxib at 50microM stimulated oxygen consumption significantly. Corresponding experiments with the protonophore FCCP suggest that this effect is due to mitochondrial uncoupling. After 24h, GLUT-1 mRNA expression was significantly increased. HIF-1alpha protein was not expressed under any of our experimental conditions. We also showed that celecoxib at 50microM significantly inhibits OPG protein secretion leading to a compensative increase of mRNA expression. CONCLUSION: Pronounced effects of celecoxib on cell viability (reduction), oxygen consumption (stimulation), GLUT-1 mRNA expression (stimulation) and OPG protein secretion (inhibition) in osteoblastic cells were observed only at 50microM-a concentration not reached by therapeutic doses giving plasma concentrations less than 10microM. On the contrary, celecoxib at 2 and 10microM showed only marginal effects, suggesting that celecoxib administration is probably safe with respect to bone metabolism in cases requiring potent treatment of pain and inflammation. However, higher intracellular concentrations, which might occur through accumulation, necessitate investigations with high concentrations.
19275103 [Application of acetabulum reinforcement ring for reconstructing acetabular defects in art 2009 Feb OBJECTIVE: To study the operative methods and therapeutic effects of acetabulum reinforcement ring in the reconstruction of acetabular defects in primary and revisional artificial hip replacement. METHODS: From November 2000 to July 2005, 14 cases (15 hips) of severe acetabular defects in artificial hip replacement were treated with acetabulum reinforcement ring combined autogenous or allogenic bone transplantation, including 7 males and 8 females aged 34-72 years with an average of 55 years. Among them, 9 cases (9 hips) underwent artificial hip joint revision, which was 3-22 years (average 8.9 years) far away from their primary replacement, and 5 cases (6 hips) received primary replacement, including 1 case of rheumatoid arthritis of both hips, 1 osteoarthritis caused by acetabular dysplasia, 1 femoral head resection due to debridement of hip infection, 1 nonunion of acetabulum old fracture with the center dislocation of femoral head and 1 old acetabulum fracture. The disease course was 2-25 years (average 11.6 years). According to the American Academy of Orthopaedic Surgeons (AAOS) classification, the acetabulum defects of 7 hips were categorized into Type II, 6 hips were Type III and 2 hips were Type IV. Harris score was (59.1 +/- 15.4) points preoperatively. RESULTS: All wounds were healed by first intention. The symptom of sciatic nerve simulation was occurred in 1 case and was relieved after taking neuroprotective drug for 5 months. All the cases were followed up for 33-90 months (average 51.3 months). Harris score at the final follow-up was (81.9 +/- 10.4) points, indicating there was a significant difference between before and after operation (P < 0.01). X-ray film demonstrated that the displacement of acetabulum reinforcement ring and acetabular cup was less than 5 mm, the rotation was less than 5 degrees, and there was no progressive radiolucent zone around acetabulum and screw. CONCLUSION: Acetabulum reinforcement ring is beneficial to reconstruct severe acetabular defects, improve hip joints' function and provide primary stability for putting acetabular cup into an ideal biomechanical position.
19122005 Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes. 2009 Apr Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 microg/kg, approximately 100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T(EM) cells and suppresses delayed type hypersensitivity when administered at 10 or 100 microg/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T(EM) cells.
19054818 Association study of a polymorphism of the CTGF gene and susceptibility to systemic sclero 2009 Dec OBJECTIVES: To validate the association of a single nucleotide polymorphism (SNP) of the connective tissue growth factor gene (CTGF) with susceptibility to systemic sclerosis (SSc) in the Japanese population. METHODS: 395 Japanese patients with SSc, 115 patients with rheumatoid arthritis and 269 healthy Japanese volunteers were enrolled in the study. An SNP (rs6918698) at -945 bp from the start codon in the promoter region of the CTGF gene was determined by allelic discrimination with the use of a specific TaqMan probe. RESULTS: The G allele showed a significantly higher frequency in patients with SSc than in controls (p<0.001; odds ratio 1.5; 95% confidence interval 1.2 to 1.9). In particular, the clinical subsets of SSc showed a more significant association between the G allele and diffuse cutaneous SSc (p<0.001) and the presence of interstitial lung disease (p<0.001), the presence of anti-topoisomerase I antibody (p<0.001) and anti-U1RNP antibody (p = 0.010). Association analyses using the genotype of the SNP yielded results similar to those of analyses using the allele. CONCLUSIONS: This study confirms the association between an SNP in the CTGF gene and susceptibility to SSc, especially in the presence of diffuse cutaneous SSc, interstitial lung disease and anti-topoisomerase I antibody. The results strongly suggest that this SNP may be a powerful indicator of severe skin and lung involvement in patients with SSc.
18804988 Altered monocyte CD44 expression in peripheral arterial disease is corrected by fish oil s 2009 May BACKGROUND AND AIMS: CD44 and its splice variants can be expressed on all leukocytes, conferring adhesive properties and enhancing cellular recruitment to the endothelium during inflammation. CD44 expression is increased in inflammatory conditions such as rheumatoid arthritis and CD44 variant 3 (CD44v3) expression may be associated with inflammation. We have examined CD44 and CD44v3 expression on peripheral blood monocytes from patients with peripheral arterial disease (PAD) and healthy controls. We have also examined the effect of fish oil supplementation on these markers. METHODS AND RESULTS: CD44 and CD44v3 were assessed at baseline and following dietary supplementation with fish oil for 12 weeks in both PAD and control groups. Monocytes from PAD patients had higher CD44 expression than those from controls (median intensity fluorescence (MIF): 480+/-278 vs 336+/-251 (mean+/-SD); p<0.001). Following 12 weeks' dietary supplementation with fish oil, CD44 expression was reduced in PAD patients (MIF: 480+/-278 vs 427+/-262; p=0.05) but not in controls (336+/-251 vs 355+/-280; ns). Monocyte CD44v3 expression was lower in cultured monocytes from PAD patients compared to those from controls (0.15+/-0.15 vs 0.22+/-0.14 OD units; p<0.02). This was increased in the PAD group following fish oil supplementation (0.15+/-0.14 to 0.27+/-0.23 OD units; p<0.001). CONCLUSION: Monocyte CD44 and CD44v3 expression are altered in arterial disease but are returned towards levels seen in control subjects by dietary fish oil supplementation.
18524792 Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) 2009 Jun BACKGROUND: Enthesitis is a recommended core domain for assessment of ankylosing spondylitis (AS), but no measurement has yet been validated according to Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) criteria. OBJECTIVE: The purpose of this study was to seek to validate an enthesitis index for patients with AS according to OMERACT criteria. METHODS: An enthesitis index was validated in two AS patient cohorts: (1) a longitudinal cohort (n = 223) and (2) 22 patients from three Canadian sites participating in a 24-week randomised placebo-controlled trial of adalimumab in AS. Construct validity was evaluated by correlation analysis with the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI) and quality of life instruments. Reproducibility was assessed by intraclass correlation coefficient (ICC), and responsiveness was assessed by Guyatt's effect size and standardised response mean. RESULTS: The most frequently affected sites were the greater trochanter and supraspinatus insertion ( approximately 20%). Patients with enthesitis had significantly greater scores for the BASDAI, BASFI, patient global, AS-specific quality of life index (ASQOL) and the Short Form 36 (SF-36) General Health Survey (p<0.001). The enthesitis score contributed significantly to variance in the BASDAI and BASFI. Interobserver ICCs were 0.96 in the longitudinal cohort and 0.89 and 0.77 in the adalimumab clinical trial cohort (for status and change score, respectively). Significant differences in change scores were evident for all patients after 24 weeks of adalimumab treatment, (p = 0.04), this being more significant when a subset of the most commonly affected entheses were analysed (p = 0.01). CONCLUSION: AS patients with enthesitis constitute a more severe subset of disease, and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index is feasible and reliable for measurement of this condition. Discrimination requires further study in larger trials.
21194976 Bone cement penetration pattern and primary stability testing in keeled and pegged glenoid 2011 Jul BACKGROUND: It has been proposed that bone mineral density has an influence on cement penetration in hip and knee arthroplasty. The hypotheses of this study were that: 1) there is a negative correlation between bone mineral density (BMD) and cement penetration in cemented glenoid components; and 2) that implant design has an influence on cement penetration into the glenoid bone. METHODS: BMD of 10 pairs of fresh frozen scapulas was measured. Micro-computed tomography (micro-CT) scans in 3 different sections were analyzed after implantation of keeled and pegged glenoid components using a 3(rd)-generation cementing technique with a vacuum mixing system. Cement penetration was analyzed and correlated with BMD. Pull-out strength testing was performed to analyze primary stability. RESULTS: The overall peak BMD was 0.6 [g/cm(2)] (range, 0.33-0.98). A strong negative correlation between BMD and mean cement penetration was found for the peg (R(2) = -.83; P < .003) and for the keel group (R(2) = -.81; P < .005). Mean cement penetration was 78.4 mm(2) (range, 60.6-94.2) in the keel and 113.9 mm(2) (range, 78.2-143.4) in the peg group (P < .0001). In all cases, the components were pulled out of the cement mantle, whereas the bone-cement interfaces remained intact. The mean pull-out strength was 1093N (764-1343N) for keeled and 884N (650-1264N) for pegged components (P < .05). CONCLUSION: A modern cementing technique, leading to a deep bonding between bone and cement, is crucial to prevent loosening of glenoid components. The findings of this study might help us to better understand the results of follow-up studies of cemented glenoid implants. Our results could be helpful for the choice of implants in patients with poor bone quality like osteoporosis or rheumatoid arthritis.
21085107 Detection of functional matrix metalloproteinases by zymography. 2010 Nov 8 Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases. They degrade proteins by cleavage of peptide bonds. More than twenty MMPs have been identified and are separated into six groups based on their structure and substrate specificity (collagenases, gelatinases, membrane type [MT-MMP], stromelysins, matrilysins, and others). MMPs play a critical role in cell invasion, cartilage degradation, tissue remodeling, wound healing, and embryogenesis. They therefore participate in both normal processes and in the pathogenesis of many diseases, such as rheumatoid arthritis, cancer, or chronic obstructive pulmonary disease. Here, we will focus on MMP-2 (gelatinase A, type IV collagenase), a widely expressed MMP. We will demonstrate how to detect MMP-2 in cell culture supernatants by zymography, a commonly used, simple, and yet very sensitive technique first described in 1980 by C. Heussen and E.B. Dowdle. This technique is semi-quantitative, it can therefore be used to determine MMP levels in test samples when known concentrations of recombinant MMP are loaded on the same gel. Solutions containing MMPs (e.g. cell culture supernatants, urine, or serum) are loaded onto a polyacrylamide gel containing sodium dodecyl sulfate (SDS; to linearize the proteins) and gelatin (substrate for MMP-2). The sample buffer is designed to increase sample viscosity (to facilitate gel loading), provide a tracking dye (bromophenol blue; to monitor sample migration), provide denaturing molecules (to linearize proteins), and control the pH of the sample. Proteins are then allowed to migrate under an electric current in a running buffer designed to provide a constant migration rate. The distance of migration is inversely correlated with the molecular weight of the protein (small proteins move faster through the gel than large proteins do and therefore migrate further down the gel). After migration, the gel is placed in a renaturing buffer to allow proteins to regain their tertiary structure, necessary for enzymatic activity. The gel is then placed in a developing buffer designed to allow the protease to digest its substrate. The developing buffer also contains p-aminophenylmercuric acetate (APMA) to activate the non-proteolytic pro-MMPs into active MMPs. The next step consists of staining the substrate (gelatin in our example). After washing the excess dye off the gel, areas of protease digestion appear as clear bands. The clearer the band, the more concentrated the protease it contains. Band staining intensity can then be determined by densitometry, using a software such as ImageJ, allowing for sample comparison.
20937725 Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys. 2011 Jan Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy.
20933377 Recent findings on genetics of systemic autoimmune diseases. 2010 Dec Association studies of over 1 million SNPs capturing most of the human genome common variation became possible thanks to the information provided by the HapMap International project and the development of high-throughput genotyping technologies at accessible prices. Genome-wide scans analyzing thousands of individuals have now identified most if not all of the major genes involved in susceptibility for several systemic autoimmune diseases. In particular, results for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) are reviewed here. While most genes are shared between diseases, few seem to be unique reflecting that we still are long before knowing all genes, their interactions with other genes and the environment and their impact on biological functions.