Treatment of osteochondral lesions of the talus: a systematic review

The aim of this study was to summarize all eligible studies to compare the effectiveness of treatment strategies for osteochondral defects (OCD) of the talus. Electronic databases from January 1966 to December 2006 were systematically screened. The proportion of the patient population treated successfully was noted, and percentages were calculated. For each treatment strategy, study size weighted success rates were calculated. Fifty-two studies described the results of 65 treatment groups of treatment strategies for OCD of the talus. One randomized clinical trial was identified. Seven studies described the results of non-operative treatment, 4 of excision, 13 of excision and curettage, 18 of excision, curettage and bone marrow stimulation (BMS), 4 of an autogenous bone graft, 2 of transmalleolar drilling (TMD), 9 of osteochondral transplantation (OATS), 4 of autologous chondrocyte implantation (ACI), 3 of retrograde drilling and 1 of fixation. OATS, BMS and ACI scored success rates of 87, 85 and 76%, respectively. Retrograde drilling and fixation scored 88 and 89%, respectively. Together with the newer techniques OATS and ACI, BMS was identified as an effective treatment strategy for OCD of the talus. Because of the relatively high cost of ACI and the knee morbidity seen in OATS, we conclude that BMS is the treatment of choice for primary osteochondral talar lesions. However, due to great diversity in the articles and variability in treatment results, no definitive conclusions can be drawn. Further sufficiently powered, randomized clinical trials with uniform methodology and validated outcome measures should be initiated to compare the outcome of surgical strategies for OCD of the talus

Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab

Objective. For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination. Methods. Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4-8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6-10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity. Results. Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX-treated group and in healthy controls, but for no strains in the rituximab-treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab-treated group than in the MTX-treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab-treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab-treated group, previously vaccinated patients in the rituximab-treated group had higher pre- and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination. Conclusion. Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6-10 months after rituximab administration. Previous influenza vaccination in rituximab-treated patients increases pre- and postvaccination titers. RA activity was not influenced

Homocysteine-Induced Apoptosis in Endothelial Cells Coincides With Nuclear NOX2 and Peri-nuclear NOX4 Activity

Apoptosis of endothelial cells related to homocysteine (Hcy) has been reported in several studies. In this study, we evaluated whether reactive oxygen species (ROS)-producing signaling pathways contribute to Hcy-induced apoptosis induction, with specific emphasis on NADPH oxidases. Human umbilical vein endothelial cells were incubated with 0.01-2.5 mM Hcy. We determined the effect of Hcy on caspase-3 activity, annexin V positivity, intracellular NOX1, NOX2, NOX4, and p47(phox) expression and localization, nuclear nitrotyrosine accumulation, and mitochondrial membrane potential (ΔΨ m). Hcy induced caspase-3 activity and apoptosis; this effect was concentration dependent and maximal after 6-h exposure to 2.5 mM Hcy. It was accompanied by a significant increase in ΔΨ m. Cysteine was inactive on these parameters excluding a reactive thiol group effect. Hcy induced an increase in cellular NOX2, p47(phox), and NOX4, but not that of NOX1. 3D digital imaging microscopy followed by image deconvolution analysis showed nuclear accumulation of NOX2 and p47(phox) in endothelial cells exposed to Hcy, but not in control cells, which coincided with accumulation of nuclear nitrotyrosine residues. Furthermore, Hcy enhanced peri-nuclear localization of NOX4 coinciding with accumulation of peri-nuclear nitrotyrosine residues, a reflection of local ROS production. p47(phox) was also increased in the peri-nuclear region. The Hcy-induced increase in caspase-3 activity was prevented by DPI and apocynin, suggesting involvement of NOX activity. The data presented in this article reveal accumulation of nuclear NOX2 and peri-nuclear NOX4 accumulation as potential source of ROS production in Hcy-induced apoptosis in endothelial cell

Intracellular S-adenosylhomocysteine increased levels are associated with DNA hypomethylation in HUVEC.

Contains fulltext : 48583.pdf (publisher's version ) (Closed access)Hyperhomocysteinemia is a risk factor for atherosclerosis and vascular disease; however, the mechanism underlying this association remains poorly understood. Increased levels of intracellular S-adenosylhomocysteine (AdoHcy), secondary to homocysteine-mediated reversal of the AdoHcy hydrolase reaction, have been associated with reduced DNA methylation patterns and pointed as responsible for the hyperhomocysteinemia-related endothelial dysfunction. Methylation is an epigenetic feature of genomic DNA, which leads to alterations in gene expression. So far, the effect of intracellular AdoHcy accumulation on DNA methylation patterns has not yet been fully substantiated by experimental evidence. The present study was designed to evaluate, in cultured endothelial cells, the effect of AdoHcy accumulation on genomic global DNA methylation status. Experimental intracellular accumulation of AdoHcy was induced by adenosine-2,3-dialdehyde (ADA), an inhibitor of AdoHcy hydrolase. Increased concentrations of inhibitor were tested, and unsupplemented medium incubations were used as controls. Cytosolic and nuclear fractions were obtained from trypsinized cells after 72 h of incubation. Total homocysteine concentration was quantified (culture medium and cytosolic fractions) by high-performance liquid chromatography (HPLC). S-Adenosylmethionine and AdoHcy concentrations were measured (cytosolic fractions) by stable-isotope dilution LC-tandem mass spectrometry method. Genomic DNA was obtained from the nuclear fraction, and global DNA methylation status was evaluated by the cytosine extension assay. The results showed that supplementation of the culture medium with ADA had no cytotoxic effect and increased the intracellular AdoHcy concentration in a dose-dependent manner. A significant negative correlation was observed between intracellular AdoHcy and genomic DNA methylation status. These findings strongly point to the importance of AdoHcy as a pivotal biomarker of genomic DNA methylation status