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Site: About Arthritis
Methotrexate Plus Enbrel Induces Remission, Slows Rheumatoid Arthritis Progression
Methotrexate in combination with Enbrel (etanercept) induces remission and prevents progression of rheumatoid arthritis in patients with early, moderate to severe disease within one year compared to taking methotrexate alone....
Falls Increase in Elderly Arthritis Patients With Use of Certain Prescription Drugs
Falls are considered the leading cause of fatal and non-fatal injuries in people over 65 years old. Certain prescription drugs, including some used to manage arthritis, increase the risk of...
Rheumatoid Arthritis Patients Live With Significant Emotional and Physical Limitations
For people living with rheumatoid arthritis, there are obvious physical limitations, but there are emotional limitations that are less obvious. Two surveys, known as the GeneRAtions surveys, attempt to paint...
Osteoporosis Drugs Linked to Unusual Fractures
An unusual fracture pattern has been seen in some people who have used bisphosphonates (bone-building drugs) for five years or more. A study published in the May/June issue of The...
Gastrointestinal Bleeding - Arthritis Patients, Don't Ignore Your Symptoms!
Arthritis patients take several medications that increase the risk of gastrointestinal bleeding. If you have taken one of these medications for a long time, you may be lulled into a...
Pomegranate May Reduce Inflammation Related to Arthritis
Eating pomegranate extract can reduce inflammation associated with several diseases, including arthritis. According to researchers from Case Western Reserve University in Cleveland, Ohio, blood tests done on rabbits that were...
Vitamin D Supplementation May Offer Arthritis Pain Relief
Vitamin D deficiency has been linked to chronic pain conditions, including various types of:
bone / joint pain
muscle pain
rheumatic diseases
osteoarthritis
fibromyalgia
After researchers reviewed 22 clinical studies involving patients with chronic pain and...
Juvenile Arthritis Switched On by Master Gene
Researchers from The Children's Hospital of Philadelphia have found a specific gene region that is present in some types of adult rheumatoid arthritis and all types of juvenile arthritis. The...
Non-metal Ankle Replacement Designed
Patients with severe ankle arthritis have been faced with just two surgical options -- a total ankle replacement or an ankle fusion. Now, there's a third option and researchers believe...
Heavy Birthweight Increases Risk of Rheumatoid Arthritis
People with a birthweight of 10 pounds or more are twice as likely to develop rheumatoid arthritis when they are adults compared to people who were of average birthweight....
Site: Arthritis Research & Therapy - Latest articles
High avidity autoreactive T cells with a low signalling capacity through the T-cell receptor: central to rheumatoid arthritis pathogenesis?
Self-reactive T cells with a low signalling capacity through the T cell receptor (TCR) have recently been observed in the SKG mouse model of rheumatoid arthritis (RA) and have been linked to a spontaneous mutation in the ZAP-70 signal transduction molecule. Here we hypothesize that similar mechanisms also drive RA, associated with an abnormal innate and adaptive immune response driven by NF-kappaB activation and TNF secretion. Similar to the essential part played by pathogens in SKG mice, we propose that HLA-associated immunity to chronic viral infection is a key factor in the immune dysregulation and joint inflammation that characterize RA.
Brain-derived neurotrophic factor and its receptor in the human and sand rat intervertebral disc
IntroductionBrain-derived neurotrophic factor (BDNF) was first identified in the intervertebral disc (IVD) when its molecular upregulation was observed in sections of nucleus pulposus cultured under conditions of increased osmolarity. BDNF is now known to be involved in a number of biologic functions, including regulation of differentiation/survival of sensory neurons, regulation of nociceptive function and central pain modulation, and modulation of inflammatory pain hypersensitivity. In addition, more recent investigations now show that BDNF can induce the recruitment of endothelial cells and formation of vascular structures. The objectives of the present study were to 1) Use immunocytochemistry to determine the distribution of BDNF and its receptor (BDNF-tropomyosine receptor kinase B) in the human IVD, and 2) Test for gene expression of BDNF and its receptor in cultured human annulus fibrosus cells.
Methods:
We studied immunohistochemical localization of BDNF and its receptor in the human annulus, quantified the percentage of outer and inner annulus cells and nucleus cells positive for BDNF immunolocalization, and studied gene expression of BDNF and its receptor using microarray analysis.
Results:
The percentage of cells positive for BDNF localization was significantly greater in the outer annulus (32.3% + 2.7 (22) (mean + s.e.m. (n)) compared to either the inner annulus (8.1% + 1.5 (6)) or the nucleus (10.4% + 2.8 (3) (p < 0.0001). BDNF-receptor immunolocalization showed a pattern similar to that of BDNF, but was not quantitatively assessed. BDNF gene expression levels from cultured annulus cells showed a significant positive correlation with increasing levels of IVD degeneration (p = 0.011).
Conclusions:
These findings provide data on the presence of BDNF and its receptor in the human IVD at the translational level, and the expression of BDNF and its receptor by cultured human annulus cells. Our findings point to the need for further studies to define the role of BDNF in the human IVD and to investigate regulatory events within the disc that control the expression of BDNF and its receptor.
Efficacy of fibromyalgia treatment according to level of care: a meta-analysis
IntroductionThe aim of this paper is to compare the efficacy of the treatments for fibromyalgia available in both primary care and specialized settings.
Methods:
Published reports of randomized controlled trials researching pharmacological and non-pharmacological treatments in patients with fibromyalgia were found in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and PsychInfo. The most recent electronic search was undertaken in June 2006.
Results:
We identified a total of 594 articles. Based on titles and abstracts, 102 full articles were retrieved, 33 of which met the inclusion criteria. These randomized controlled trials (RCTs) assessed 120 treatment interventions on 7789 patients diagnosed with primary fibromyalgia. Of these, 4505 (57.8%) were included in the primary care group and 3284 (42.2%) in the specialized intervention group. The sample was mostly made up of middle-aged women, who had been suffering from this disorder for a mean period of 6-10 years. Mean effect size of efficacy for the 120 treatment interventions on patients with fibromyalgia compared with controls was 0.49 (95% CI= 0.39-0.58; p<0.001). Mean effect size of treatment efficacy in primary care was 0.46 (95% CI= 0.33-0.58) while in specialized care it was 0.53 (95% CI=0.38-0.69); the differences were not significant. We analysed efficacy of treatments by comparing primary and specialized care in the different fibromyalgia dominions and found that there were no significant differences. The variables related to improvement in the efficacy of fibromyalgia treatment are a) low quality of the studies and b) shorter length of treatment. However, they are both biased by the heterogeneity of the studies. Other variables that also improve outcome, and which are not biased by the heterogeneity of the studies, are younger age of the patients and shorter duration of the disorder. On the contrary, gender and kind of treatment (pharmacological vs. psychological) do not affect outcome.
Conclusions:
Based on this meta-analysis, and despite the heterogeneity of specialized care studies and of the other limitations described in this article, treating fibromyalgia in specialized care offers no clear advantages.
No evidence of association or interactions between the IL-4, IL-4R alpha and IL-13 genes and rheumatoid arthritis
IntroductionA feature of rheumatoid arthritis (RA) is an imbalance between pro and anti-inflammatory cytokines. Several recent studies have implicated polymorphism in the interleukin (IL)-4 signalling pathway with the development of erosive RA.
The aim of this study was to investigate the role of polymorphism in the IL-4, IL-4Ralpha and IL-13 genes in RA including an examination of epistasis.
Methods:
A total of 965 Caucasians with RA and 988 healthy controls were genotyped for 5 variants in the IL-4/IL-13 gene cluster (5q31.1) and two functional variants IL-4Ralpha (16p12.1). Individual genotype and haplotype frequencies were compared between cases and controls. The odd ratios (OR) were calculated with asymptotic 95% confidence intervals (CI) and p-values less than 0.05 were considered significant. The potential association with radiological joint damage was also examined. Potential gene interactions were assessed using both stratified analysis and the linkage disequilibrium (LD)-based statistic.
Results:
Genotype, allele and haplotype frequencies were equally distributed between RA cases and controls. Similarly no association was detected between these variants and modified Larsen scores. Furthermore no evidence of epistasis was detected between IL-4 or IL-13 genotypes and IL-4Ralpha.
Conclusions:
These results indicate that common variants of the IL-4/IL-13 pathway do not significantly contribute to RA susceptibility and radiological severity.
Fragmentation of decorin, biglycan, lumican and keratocan is elevated in degenerate human meniscus, knee and hip articular cartilages compared to age-matched macroscopically normal and control tissues
IntroductionThe small leucine repeat proteoglycans (SLRPs) modulate tissue organisation, cellular proliferation, matrix adhesion, growth factor and cytokine responses and sterically protect the surface of collagen type I and II fibrils from proteolysis. Catabolism of SLRPs has important consequences for the integrity of articular cartilage and meniscus by interfering with their tissue homeostatic functions.
Methods:
SLRPs were dissociatively extracted from (i) articular cartilage (AC) from total knee and (ii) hip replacements, (iii) menisci from total knee replacements, (iv) macroscopically normal and (v) fibrillated knee AC from mature age-matched donors, and (vi) normal young AC. The tissue extracts were digested with chondroitinase ABC and keratanase-I prior to identification of SLRP core protein species by Western blotting using antibodies to the C-termini of the SLRPs.
Results:
Multiple core-protein species were detected for all of the SLRPs (except fibromodulin) in the degenerate osteoarthritic (OA) AC and menisci. Fibromodulin had markedly less fragments detected with the C-terminal antibody compared with other SLRPs. There were fewer SLRP catabolites in OA hip compared to knee AC. Fragmentation of all SLRPs in normal age-matched, non-fibrillated knee AC was less than in fibrillated AC from the same knee joint or total knee replacement AC specimens of similar age. There was little fragmentation of SLRPs in normal control knee AC. Only decorin demonstrated a consistent increase in fragmentation in menisci in association with OA. There were no fragments of decorin, biglycan, lumican or keratocan that were unique to any tissue. A single fibromodulin fragment was detected in OA articular cartilage but not meniscus. All SLRPs showed a modest age-related increase in fragmentation in knee articular and meniscal cartilage but not other tissues.
Conclusions:
Enhanced fragmentation of SLRPs is evident in degenerate articular cartilage and meniscus. Specific decorin and fibromodulin core protein fragments in degenerate meniscus and/or human articular cartilage may be of value as biomarkers of disease and once the enzymes responsible for their generation have been identified, further research may identify them as therapeutic targets.
Ultrasound properties of articular cartilage in the tibio-femoral joint in knee osteoarthritis: relation to clinical assessment (ICRS grade)
IntroductionThere is a lack of data relating macroscopic appearance of cartilage to its ultrasound properties. The purpose of the present study was to evaluate degenerated and healthy-looking cartilage using an ultrasound system.
Methods:
Ultrasound properties of signal intensity (a measure of superficial cartilage integrity), echo duration (a parameter related to the surface irregularity) and interval between signals (i.e. time-of-flight, which is related to thickness and ultrasound speed of cartilage) of 20 knees were measured at seven sites of lateral femoral condyle (site A; anterior, site B; posterior), medial condyle (site C), lateral tibial plateau (site D; center, site E; under the meniscus) and medial tibial plateau (site F; anterior, site G; posterior). The sites were evaluated macroscopically and classed using the International Cartilage Repair Society (ICRS) grading system.
Results:
Signal intensity of grade 0 cartilage was significantly greater than those of grade 1, grade 2 or grade 3 cartilage. Signal intensity decreased with increasing ICRS grades. Signal intensity was greater at site B than at site C, site D, site F and site G. Signal intensity of grade 0 was greater at site B than at site E. Echo duration did not differ between the grades and between the sites. Interval between signals of grade 3 was less than those of grade 0, grade 1 or grade 2. Interval between signals at site C was less than those at site A, site B, site D, and site E.
Conclusions:
Site-specific differences in signal intensity suggest that superficial collagen network may maintain in cartilage of lateral condyle but deteriorate in cartilage of medial condyle and medial tibial plateau in varus knee osteoarthritis. Signal intensity may be helpful to differentiate ICRS grades, especially grade 0 from grade 1 cartilage.
Low-intensity pulsed ultrasound activates the phosphatidylinositol 3 kinase/Akt pathway and stimulates the growth of chondrocytes in three-dimensional cultures: a basic science study
IntroductionThe effect of low-intensity pulsed ultrasound (LIPUS) on the cell growth in three dimensional (3D)-cultured chondrocytes with a collagen sponge was examined. To elucidate the mechanisms underlying the mechanical activation of chondrocytes, intracellular signaling pathways through Ras/MAPK and Integrin/PI3K/Akt pathways as well as proteins involved in proliferation of chondrocytes were examined in LIPUS-treated chondrocytes.
Methods:
Articular cartilage tissue was obtained from the metatarso-phalangeal joints of freshly sacrificed pigs. Isolated chondrocytes mixed with collagen gel and culture medium composites were added to type-I collagen honeycomb sponges. Experimental cells were cultured with daily 20-minute exposures to LIPUS. The chondrocytes proliferated and a collagenous matrix was formed on the surface of the sponge. Cell counting, histological examinations, immunohistochemical analyses and Western Blotting Analysis were performed.
Results:
The rate of chondrocyte proliferation was slightly, but significantly higher in the LIPUS group in comparison to the control group during the two-week culture period. A Western blot analysis showed intense staining of type-IX collagen, cyclins B1 and D1, p-FAK, and p-Akt in the LIPUS group in comparison to the control. However, no differences were detected in the MAPK, p-MAPK and type-II collagen levels.
Conclusions:
LIPUS promoted the proliferation of cultured chondrocytes and the production of type-IX collagen in a 3-D culture using a collagen sponge. In addition, the anabolic LIPUS signal transduction to the nucleus via the Integrin/PI3K/Akt pathway rather than the Integrin /MAPK pathway was generally associated with cell proliferation.
The renal metallothionein expression profile is altered in human lupus nephritis
IntroductionMetallothionein (MT) isoforms I + II are polypeptides with potent antioxidative and anti-inflammatory properties. In healthy kidneys, MT-I+II have been described as intracellular proteins of proximal tubular cells. The aim of the present study was to investigate whether the renal MT-I+II expression profile is altered during lupus nephritis.
Methods:
Immunohistochemistry was performed on renal biopsies from 37 patients with lupus nephritis. Four specimens of healthy renal tissue served as controls. Clinicopathological correlation studies and renal survival analyses were performed by means of standard statistical methods.
Results:
Proximal tubules displaying epithelial cell MT-I+II depletion in combination with luminal MT-I+II expression were observed in 31 out of 37 of the lupus nephritis specimens, but not in any of the control sections (P = 0.006). The tubular MT score, defined as the median number of proximal tubules displaying this MT expression pattern per high-power microscope field (40× magnification), was positively correlated to the creatinine clearance in the lupus nephritis cohort (P = 0.01). Furthermore, a tubular MT score below the median value of the cohort emerged as a significant predictor of a poor renal outcome in renal survival analyses. Thus, patients with a tubular MT score < 1.0 had a 6.2-times higher risk of developing end-stage renal disease than patients with a tubular MT score ? 1.0 (P = 0.03).
Conclusion:
Lupus nephritis is associated with significant alterations in renal MT-I+II expression. Our data indicate that important prognostic information can be deduced from the renal MT-I+II expression profile in systemic lupus erythematosus patients with nephritis.
Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project
IntroductionThe present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.
Methods:
Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.
Results:
At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases ? although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.
Conclusion:
Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.
Human infrapatellar fat pad-derived stem cells express the pericyte marker 3G5 and show enhanced chondrogenesis after expansion in fibroblast growth factor-2
IntroductionInfrapatellar fat pad (IPFP) is a possible source of stem cells for the repair of articular cartilage defects. In this study, adherent proliferative cells were isolated from digests of IPFP tissue. The effects of the expansion of these cells in fibroblast growth factor-2 (FGF-2) were tested on their proliferation, characterisation, and chondrogenic potential.
Methods:
IPFP tissue was obtained from six patients undergoing total knee replacement, and sections were stained with 3G5, alpha smooth muscle actin, and von Willebrand factor to identify different cell types in the vasculature. Cells were isolated from IPFP, and both mixed populations and clonal lines derived from them were characterised for cell surface epitopes, including 3G5. Cells were expanded with and without FGF-2 and were tested for chondrogenic differentiation in cell aggregate cultures.
Results:
3G5-positive cells were present in perivascular regions in tissue sections of the IPFP, and proliferative adherent cells isolated from the IPFP were also 3G5-positive. However, 3G5 expression was on only a small proportion of cells in all populations and at all passages, including the clonally expanded cells. The cells showed cell surface epitope expression similar to adult stem cells. They stained strongly for CD13, CD29, CD44, CD90, and CD105 and were negative for CD34 and CD56 but were also negative for LNGFR (low-affinity nerve growth factor receptor) and STRO1. The IPFP-derived cells showed chondrogenic differentiation in cell aggregate cultures, and prior expansion with FGF-2 enhanced chondrogenesis. Expansion in FGF-2 resulted in greater downregulation of many cartilage-associated genes, but on subsequent chondrogenic differentiation, they showed stronger upregulation of these genes and this resulted in greater matrix production per cell.
Conclusion:
These results show that these cells express mesenchymal stem cell markers, but further work is needed to determine the true origin of these cells. These results suggest that the expansion of these cells with FGF-2 has important consequences for facilitating their chondrogenic differentiation.
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