Significance of Elevated Blood Metal Ion Levels in Patients with Metal-on-Metal Prostheses: An Evaluation of Oxidative Stress Markers

It is widely known that cobalt and chromium ions can enhance the production of reactive oxygen species, known to be damaging to cells by disturbing their redox status and then generating oxidative stress. The aim of the present study was to determine if increased metal ion levels induce a state of oxidative stress in patients with metal-on-metal (MM) hip arthroplasty. Results indicated that there was no significant difference in the concentration of oxidative stress markers (total antioxidants, peroxides, and nitrated proteins) in the patients with MM bearings compared to patients without prostheses. The activity antioxidant enzymes was stable (catalase and glutathione peroxidase) or slightly decreased (superoxide dismutase and heme oxygenase-1) over time. This work is the first to determine the biological effects of metal ions released from MM hip implants with regards to mid-term systemic oxidative stress and showed that the increased levels of Co and Cr ions are not associated with significant oxidative stress damage in the plasma of patients with these implants

Ions released from metal-on-metal hip implants: «in vitro» and «in vivo» investigations

Studies have shown that Co and Cr particles and ions can enter the bloodstream and accumulate in tissues and organs of patients after metal-on-metal (MM) total hip arthroplasty (THA). These ions can generate reactive oxygen species (ROS) that can be deleterious for cells. We first assessed the biological effects of Cr(VI), Co(II), and Cr(III) by testing their effect on antioxidant enzymes (SODs, CAT, GPx, HO-1) that represent a primary defense system against ROS. We demonstrated that Cr(VI) induced the protein expression (translation) of antioxidant enzymes, whereas it had no effect on the mRNA expression (transcription). Co(II) induced the expression of both protein and mRNA of HO-1 only. Cr(III) had no effect on the activity of these enzymes. We then suggested that a difference in molecular structure may be at the origin of their differential effects and showed that Cr(III) can form precipitable complexes, whereas Co(II) and Cr(VI) cannot form complexes in the same experimental conditions. These Cr(III) complexes, formed in simulated-physiological fluids, were constituted by an organic phase (amino acids, phosphate) tangled with an inorganic phase (Cr, Ca, Na). Interestingly, these Cr(III) complexes interacted only with albumin in presence of fetal bovine serum, whereas they interacted with 8 different human serum proteins in presence of human serum. The interaction of Cr(III) complexes with serum proteins affect their internalization by macrophages, complexes formed with human serum being more easily internalized than those bound to bovine proteins. Lastly, results suggested that the levels of Co and Cr ions in patients with MM THA are not sufficient to induce significant oxidative stress in the blood of these patients, bringing optimism over concern for the long term biological effects of Co and Cr ions released from metal-metal bearings. In conclusion, this thesis gives very valuable information on the biological effects of Cr and Co ions and gives insight iDe nombreuses études ont montré que les particules et ions métalliques (Cr(III), Co(II) et Cr(VI)) générés par l'usure de prothèses de hanche métalliques (PHM) se retrouvent dans le flux sanguin des patients et s'accumulent également dans leurs tissus et leurs organes. Ces ions peuvent génèrer des radicaux libres qui peuvent à leur tour être nocifs pour la cellule. Nous avons déterminé les effets de ces ions sur les enzymes antioxidantes (SODs, CAT, GPx, HO-1) qui représentent la première ligne de défense cellulaire contre les radicaux libres. Nos travaux ont révélé que le Cr(VI) induit l'expression de ces protéines (traduction) mais non l'expression de leur ARNm (transcription). Le Co(II) induit l'expression de la proteine et de l'ARNm de HO-1 seulement alors que le Cr(III) n'a aucun effet sur l'expression de ces enzymes. Nous avons par la suite suggéré, que la structure moléculaire de ces ions pouvait avoir une influence sur leurs différents effets. Les résultats ont montré que le Cr(III) formait des complexes constitués d'une partie organique (acides aminés et phosphates) et d'une partie inorganique (Cr, calcium et sodium), alors que ni le Co(II), ni le Cr(VI) ne formaient de complexes dans les mêmes conditions expérimentales. En présence de sérum bovin fétal, les complexes de Cr(III) pouvent se lier seulement à l'albumine, alors qu'en présence de sérum humain, ces mêmes complexes intéragissent avec 8 protéines de nature differente. Cette intéraction avec les protéines humaines semble augmenter l'internalisation des complexes par les macrophages. Finalement, les résultats démontrent que la concentration d'ions Co et Cr présents dans le sang de patients portant une PHM est insuffisante pour induire un stress oxydant et apportent un souffle optimiste sur les effets à long terme des ions métalliques chez les patients. Dans son ensemble ce projet apporte de nouveaux éléments de connaissances sur les effets biologi

Adherence and dosing interval of subcutaneous antitumour necrosis factor biologics among patients with inflammatory arthritis: analysis from a Canadian administrative database

ObjectivesSubcutaneous tumour necrosis factor alpha TNFαinhibitors (SC-TNFis) such as golimumab (GLM), adalimumab (ADA), etanercept (ETA) and certolizumab pegol (CZP) have been used for many years for the treatment of inflammatory arthritis. Non-adherence to therapy is an important modifiable factor that may compromise patient outcomes. The aim of this analysis was to compare adherence and dosing interval of SC-TNFis in the treatment of people with inflammatory arthritis.DesignWe used the IMS Brogan database combining both Canadian private and public drug plan databases of Ontario and Quebec. Target drugs included SC-TNFis for inflammatory arthritis. The index period was from 1 January 2010 to 30 June 2012 and patients were followed for 24 months through 30 June 2014. Inclusion criteria were adult patients newly prescribed a SC-TNFis with at least three prescriptions and retained on therapy at 24 months.Dosing regimens as per the product monographs were used to compare actual versus expected drug utilisation. The mean possession ratio was used as a marker for adherence. Patients who scored &gt;80% were considered adherent. The average days between units was estimated by taking the total days on therapy and divided by the number of units the patient received.Results4035 patients were included: 683 (16.9%), 1400 (34.7%), 1765 (43.7%) and 187 (4.6%) were treated with GLM, ADA, ETA and CZP, respectively. The proportion of adherent patients in the GLM cohort (n=595/683, 87%, p&lt;0.0001) was greater compared with ADA (n=1044/1400, 75%), ETA (n=1285/1765, 73%) and CZP-treated patients (132/187, 71%). In addition, the number of patients receiving biological drug at a shorter dosing interval was similar between cohorts, and was 5%, 6%, 12% and 4% in GLM (≤26 days), ADA (≤12 days), ETA (≤6 days) and CZP-treated patients (≤12 days), respectively.ConclusionsIn this real-life administrative database, GLM had better adherence compared with other SC-TNFis.</jats:sec

Delivery Platform for Hydrophobic Drugs: Prodrug Approach Combined with Self-Assembled Multilayers

We report the design of a platform for the delivery of hydrophobic drugs via a macromolecular prodrug approach combined with LbL-assembled polyelectrolyte multilayers. A hyaluronan ester prodrug of the chemotherapeutic drug paclitaxel has been synthesized. Conjugation of the drug to hyaluronan through a labile succinate ester did not inhibit its activity. Using quartz crystal microbalance, atomic force microscopy, and UV spectroscopy, we have shown that the presence of the hydrophobic paclitaxel moieties does not prohibit the layer-by-layer construction of the multilayers. Release of the drug from the paclitaxel-loaded multilayers upon hydrolysis of the ester linkage resulted in a drastic cell death. Application of this delivery platform to substrates such as colloids, biomedical implants, or vascular tissues may lead to new therapeutic strategies

Real-world validation of the minimal disease activity index in psoriatic arthritis: an analysis from a prospective, observational, biological treatment registry

ObjectiveTo describe the minimal disease activity (MDA) rate over time in patients with psoriatic arthritis (PsA) receiving antitumour necrosis factor agents, evaluate prognostic factors of MDA achievement and identify the most common unmet criteria among MDA achievers.DesignBiologic Treatment Registry Across Canada (BioTRAC): ongoing, prospective registry of patients initiating treatment for rheumatoid arthritis, ankylosing spondylitis or PsA with infliximab (IFX), golimumab (GLM) or ustekinumab.Setting46 primary-care Canadian rheumatology practices.Participants223 patients with PsA receiving IFX (enrolled since 2005) and GLM (enrolled since 2010) with available MDA information at baseline, 6 months and/or 12 months.Primary and secondary outcome measuresMDA was defined as ≥5 of the following criteria: 28-item tender joint count (TJC28) ≤1, 28-item swollen joint count (SJC28) ≤1, Psoriasis Area and Severity Index (PASI) ≤1 or body surface area≤3, Pain Visual Analogue Scale (VAS) ≤15 mm, patient’s global assessment (PtGA) (VAS) ≤20 mm, Health Assessment Questionnaire (HAQ) ≤0.5, tender entheseal points ≤1. Independent prognostic factors of MDA achievement were assessed with multivariate logistic regression.ResultsMDA was achieved by 11.7% of patients at baseline, 43.5% at 6 months, 44.8% at 12 months and 48.8% at either 6 or 12 months. Among MDA achievers at 6 months, 75.7% had sustained MDA at 12 months. Lower baseline HAQ (OR=0.210; 95% CI: 0.099 to 0.447) and lower TJC28 (OR=0.880; 95% CI: 0.804 to 0.964), were significant prognostic factors of MDA achievement over 12 months of treatment. The most commonly unmet MDA criteria among MDA achievers was patient reported pain (25%), PtGA (15%) and PASI (12%).ConclusionsAlmost 50% of patients treated with IFX or GLM in routine clinical care achieved MDA within the first year of treatment. Lower baseline HAQ and lower TJC28, were identified as significant prognostic factors of MDA achievement. The most commonly unmet criteria in patients who achieved MDA were pain, PtGA and PASI.Trial registration numberBioTRAC (NCT00741793).</jats:sec

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10(−8)) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41–6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10(–9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR