Impact of IL12B Gene rs 3212227 Polymorphism on Fibrosis,Liver Inflammation,and Response to Treatment in Genotype 4 Egyptian Hepatitis C Patients

Introduction. Hepatitis C virus (HCV) infection affects almost 3% of the world''s population with the highest prevalence in Egypt (15%). The standard therapy; pegylated interferon (PEG-IFN) and ribavirin, is effective in only 60% of Egyptian patients; moreover it is costly, prolonged, and has severe side effects, so prediction of response is essential to reduce burden of unfavorable treatment. Several viral and host factors have been proved to affect response to the treatment PEG-IFN and ribavirin; the strongest of them is polymorphisms near IL28B; nonetheless, nonresponse in patients with favorable IL28B is still unexplained, which implies the importance of studying other immunological factors that may correlate with response. Interleukin 12 (IL-12) is one of the most important proinflammatory cytokine presented with the initiation of immune response, determining Th1 and Th2 differentiation. A functional single nucleotide polymorphism (A/C) at the 3′ untranslated region (3′UTR) at position 1188 (NCBI SNP database no 3212227) was reported to be associated with responding more efficiently to antiviral combination therapy in HCV genotype 1 infected patients. The present study aims to evaluate association between this polymorphism with fibrosis stages, necroinflammation activity, response to the combined therapy, and gender in Egyptian HCV genotype 4. Material and Methods. A total of 133 Egyptian chronic HCV (CHCV) patients were treated with IFN/RBV and were followed up. IL12B 1188 A/C genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PRC-RFLP) analysis. Results. A nonsignificant trend for higher sustained virological response (SVR) was observed in patients homozygote for IL12B 1188 A/C SNP CC genotype (69% SVR versus 30.8% NR) only but not in AC and AA genotypes. No association was detected between IL12B 1188 A/C polymorphism and less severe fibrosis or less liver activity. By stratification of response according to gender genotype, a significant difference in response between males and females was seen among AA genotype carriers only due to high number of non responder females. Conclusion. IL12B CC genotype appears to have some influence on SVR achievement but not on severe fibrosis and severe necroinflamation activity. Females carrying A/A genotype of IL12B 1188 A/C SNP achieve less SVR than those carrying AC and CC genotypes.     

Anti-Cyclic Citrullinated Peptide Antibodies in Patients with Juvenile Idiopathic Arthritis

The objectives were to determine the prevalence and clinical significance of anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with juvenile idiopathic arthritis (JIA). Anti-CCP antibodies were checked by ELISA in 68 children with JIA, 38 males and 30 females with mean age of 10.6 (±4.02) years and disease duration of 3.7 (±1.8) years. Thirty-eight (56%) patients had polyarticular disease, 20 (29%) patients had oligoarticular disease and 10 (15%) patients had systemic onset disease. All patients had their antinuclear antibodies (ANA), rheumatoid factor (RF) and ESR checked and x-rays performed to look for erosions. Results were compared to those of 20 healthy children, 14 children with juvenile systemic lupus erythematosus (JSLE) and 30 adults with rheumatoid arthritis (RA). Anti-CCP antibodies were positive in 14/68 (20.6%) patients with JIA, all had polyarticular-onset disease. All patients with positive anti-CCP antibodies had RF-positive polyarthritis. Anti-CCP antibodies were negative in all patients with oligoarticular-onset and systemic-onset disease including 2 patients with extended oligoarthritis. Anti-CCP antibodies were negative in healthy and JSLE controls but were positive in 20/30 (66.5%) adults with RA. Anti-CCP antibodies correlated significantly with joint erosions in patients with JIA (p?=?0.004) but no significant relation was found between anti-CCP antibodies and ANA positivity or raised ESR. These data confirm that anti-CCP antibodies are less prevalent in JIA than adult RA but are detectable in a significant proportion of RF-positive patients with polyarticular-onset JIA. The current study showed significant relation between anti-CCP positivity and erosive joint disease in JIA.     

Efficacy and Safety of Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation Undergoing Elective Surgical Procedures: A Meta-analysis

Objective: The study objective was to determine if peri-operative bridging anticoagulation in patients with atrial fibrillation is beneficial or harmful.Design: Systematic review and meta-analysis.Setting: Inpatient or in-hospital setting.Participants: Adults with atrial fibrillation having a CHADS2 score >1 undergoing elective surgical procedure on anticoagulation.Methods: A systemic search of multiple databases (Cochrane, Medline, PubMed) was performed regarding studies conducted on efficacy and safety of perioperative bridging anticoagulation in patients with atrial fibrillation. Studies identified were reviewed by two authors individually before inclusion. The results were then pooled using Review Manager to determine the combined effect. Stroke/systemic embolism was considered as the primary efficacy outcome. Major bleeding was the primary safety outcome.Results: The systematic search revealed 108 potential articles. The full texts of 28 articles were retrieved for assessment of eligibility. After full text review, 25 articles were excluded. Three articles met inclusion criteria. No significant difference in stroke/systemic embolism with bridging anticoagulation was noted (risk ratio, 1.25-95% confidence interval [CI], 0.55–2.85). Bridging was associated with significantly higher risk of major bleeding (risk ratio, 3.29-95% CI, 2.25–4.81).Conclusion: An individualized approach is required when initiating peri-operative bridging anticoagulation. There is certainly a higher risk of bleeding with bridging anticoagulation and no difference in stroke/systemic embolism. However, the results cannot be extrapolated to patients who have valvular atrial fibrillation or CHADS2 score of 5 or greater.     

Parathyroid hormone 1–34 enhances extracellular matrix deposition and organization during flexor tendon repair

Parathyroid hormone (PTH) 1–34 is known to enhance fracture healing. Tendon repair is analogous to bone healing in its dependence on the proliferation and differentiation of mesenchymal stem cells, matrix formation, and tissue remodeling.^1,2,3 We hypothesized that PTH 1–34 enhances tendon healing in a flexor digitorum longus (FDL) tendon repair model. C57Bl/6J mice were treated with either intraperitoneal PTH 1–34 or vehicle‐control (PBS). Tendons were harvested at 3–28 days for histology, gene expression, and biomechanical testing. The metatarsophalangeal joint range of motion was reduced 1.5–2‐fold in PTH 1–34 mice compared to control mice. The gliding coefficient, a measure of adhesion formation, was 2–3.5‐fold higher in PTH 1–34 mice. At 14 days post‐repair, the tensile strength was twofold higher in PTH 1–34 specimens, but at 28 days there were no differences. PTH 1–34 mice had increased fibrous tissue deposition that correlated with elevated expression of collagens and fibronectin as seen on quantitative PCR. PTH 1–34 accelerated the deposition of reparative tissue but increased adhesion formation. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:17–24, 2015.     

Expression of chemokines and matrix metalloproteinases in early rheumatoid arthritis

OBJECTIVE: To compare macrophage infiltration and expression of chemokines and matrix metalloproteinases (MMPs) in synovial tissue between patients with early and long-standing rheumatoid arthritis (RA). METHODS: Knee synovial biopsies were taken from 22 patients with early (<1 yr) and 22 patients with long-standing (>5 yr) RA and immunostained with antibodies specific for CD68; macrophage inflammatory protein (MIP)-1alpha and monocyte chemoattractant protein (MCP)-1; MMP-1 and -3 and the tissue inhibitors of metalloproteinases (TIMP)-l and -2. Immunostaining was quantified using a colour video image analysis system. RESULTS: CD68+ macrophage infiltration and the expression of MIP-1alpha, MCP-1, MMP-1, MMP-3, TIMP-1, and TIMP-2 were observed in synovial tissue of patients with early RA. In long-standing RA, there was a further increase in CD68+ macrophage infiltration and MIP-1alpha expression in the synovial lining layer. CD68 expression correlated with MIP-1alpha (R=0.39, P=0.01), but not with MCP-1 expression. CONCLUSION: Macrophage accumulation, and the expression of chemokines and MMPs in synovial tissue occur in early RA. Targeting chemokines which play a role in the migration of macrophages into the joints may be of therapeutic benefit in RA patients.     

Optimizing therapy in inflammatory arthritis: prediction of relapse after tapering or stopping treatment for rheumatoid arthritis patients achieving clinical and radiological remission

This study aims to assess clinical, lab/immunological or imaging (joint ultrasonography) markers able to predict disease relapse in RA patients in sustained remission when tapering or stopping their treatment. One hundred fifty-seven RA patients in clinical remission (DAS-28 <2.6 for >6 months), receiving treatment with sDMARDs and bDMARD therapy, were randomly allocated into any of five groups: Group 1: continue full dose DMARDs and taper biologic therapy by 50 % (31 patients); Group 2: taper both DMARDs and biologic therapy dose by 50 % (32 patients); Group 3: taper DMARDs by 50 % and stop biologic therapy (31 patients); Group 4: stop both DMARDs and biologic therapy (31 patients); Group 5: continue medications without change (31 patients). Forty joints were assessed ultrasonographically (DAS-28 joints + ankles + metatarsophalangeal joints) and prospectively monitored for 12 months. The primary endpoint was sustained remission for 12 months. Patients were considered as having a relapse when the DAS-28 score was >3.2 and anti-rheumatic treatment was escalated. The frequency of relapse was 41.9 % in Group 1, 59.3 % in Group 2, 67.7 % in Group 3, 77.4 % in Group 4 and 6.5 % in Group 5. Relapse rates were significantly higher in patients whose ultrasound scores raised within 3 months of stopping their medications (P < 0.001 for both GS and PD scores). Cox regression identified ACPA positivity (at baseline) and progression of functional disability (at 2 months) as predictors for relapse. Tapering therapy is feasible in RA patients. Tailored dynamic approach is advised. Joint ultrasonographic assessment, ACPA positivity and worsening functional disability predicted relapse within a short term after discontinuation of the treatment. RA patients whose DAS-28 score was <2 were more likely to remain in remission.