Messung der inflammatorischen Aktivität von Metallionen und Metall-Abriebpartikeln von Endoprothesen im Vergleich zu Ultra-High-Molecular-Weight Polyethylenen (UHMWPE) am Tiermodell

Objective/Aim/Hypothesis: Aseptic prosthetic loosening is a major problem of total hip arthroplasty (THA). In addition to the considerable suffering of the affected patient, it usually leads to a complex prosthetic replacement requiring long-term rehabilitation with considerable costs involved. An inflammatory reaction within the periprosthetic tissue due to wear particles is considered a main contributing factor of aseptic loosening of the prosthesis. While the mechanisms are understood incompletely, it is known that wear particles of different materials are able to trigger different inflammatory reactions. Particularly, wear debris of metal-on-metal bearings have caused heavy tissue reactions and periprosthetic pseudotumorous. The aim of the present study was the in vivo investigation of the inflammatory activity of metallic degradation products. The focus was to elucidate the reaction of cobalt and chromium ions, as well as of CoCr29Mo6 metal wear particles and of ultra-high-molecular-weight polyethylene (UHMWPE) compared to the reaction to a control group (PBS). Design/Approach/Methods: Data from the present study were collected using an established murine in vivo inflammatory. The Balb/c mice were randomized in four treatment groups of 10 animals each. 50µl of CoCr29Mo6 metal particles [0,1 Vol.-% - 8,3 mg/ml], metal ions [200 µg / l], UHMWPE particles [0,1 Vol.-%] suspension or physiological PBS solution [0,1 Vol.-%] for the control group were injected into the knee joints of the animals on day 1. After one week of incubation, the patellar tendon was partially resected to visualize the synovial tissue. To assess the synovial microcirculation, the fluorescent markers FITC-dextran and rhodamine 6G were injected intravenously and the in vivo imaging via fluorescence microscopy was performed. A histological examination after hematoxylin-eosin using an established inflammatory score and measuring the thickness of the synovial membrane followed this procedure. Results: There was a significant enhanced leukocyte-endothelial cell interaction as reaction to metal (p<0.001) and polyethylene particles (p<0.001) in comparison to the control group, but no significant difference between PBS and the metal ion group (p=0.190). The functional capillary density was significantly increased after exposure to polyethylene particles (p=0.003) and tendentially increased after the incubation with metal particles (p=0.023) compared to the control group. There was no difference detectable between the control and the metal ion group (p=0.247). After the exposition to metal ions (p<0.001), and polyethylene particles (p<0.001), a significant, but moderately thickening of the synovial membrane occurred. Within the metal particle group, a massive proliferated synovial membrane was found (p<0.001). The inflammatory score increased over all groups in comparison to PBS. For the metal ion (p=0.003) and polyethylene groups (p=0.002) to the same extent, but to a much higher extent for the metal particle group (p<0.001). Conclusions: The results of this experimental study suggest, that metal particles are strong inducers of an inflammatory reaction and able to cause pseudotumor-like tissue formations. It can be also concluded, that metal ions by themselves are capable to evoke an inflammatory reaction, independent of metal particles. Suggesting that metal ions play an important role in the periprosthetic reaction to metallic wear. (UHMW-) polyethylene particles trigger an inflammatory reaction, too and we could detect histologically osseous changes

Messung der inflammatorischen Aktivität von Metallionen und Metall-Abriebpartikeln von Endoprothesen im Vergleich zu Ultra-High-Molecular-Weight Polyethylenen (UHMWPE) am Tiermodell

Objective/Aim/Hypothesis: Aseptic prosthetic loosening is a major problem of total hip arthroplasty (THA). In addition to the considerable suffering of the affected patient, it usually leads to a complex prosthetic replacement requiring long-term rehabilitation with considerable costs involved. An inflammatory reaction within the periprosthetic tissue due to wear particles is considered a main contributing factor of aseptic loosening of the prosthesis. While the mechanisms are understood incompletely, it is known that wear particles of different materials are able to trigger different inflammatory reactions. Particularly, wear debris of metal-on-metal bearings have caused heavy tissue reactions and periprosthetic pseudotumorous. The aim of the present study was the in vivo investigation of the inflammatory activity of metallic degradation products. The focus was to elucidate the reaction of cobalt and chromium ions, as well as of CoCr29Mo6 metal wear particles and of ultra-high-molecular-weight polyethylene (UHMWPE) compared to the reaction to a control group (PBS). Design/Approach/Methods: Data from the present study were collected using an established murine in vivo inflammatory. The Balb/c mice were randomized in four treatment groups of 10 animals each. 50µl of CoCr29Mo6 metal particles [0,1 Vol.-% - 8,3 mg/ml], metal ions [200 µg / l], UHMWPE particles [0,1 Vol.-%] suspension or physiological PBS solution [0,1 Vol.-%] for the control group were injected into the knee joints of the animals on day 1. After one week of incubation, the patellar tendon was partially resected to visualize the synovial tissue. To assess the synovial microcirculation, the fluorescent markers FITC-dextran and rhodamine 6G were injected intravenously and the in vivo imaging via fluorescence microscopy was performed. A histological examination after hematoxylin-eosin using an established inflammatory score and measuring the thickness of the synovial membrane followed this procedure. Results: There was a significant enhanced leukocyte-endothelial cell interaction as reaction to metal (p<0.001) and polyethylene particles (p<0.001) in comparison to the control group, but no significant difference between PBS and the metal ion group (p=0.190). The functional capillary density was significantly increased after exposure to polyethylene particles (p=0.003) and tendentially increased after the incubation with metal particles (p=0.023) compared to the control group. There was no difference detectable between the control and the metal ion group (p=0.247). After the exposition to metal ions (p<0.001), and polyethylene particles (p<0.001), a significant, but moderately thickening of the synovial membrane occurred. Within the metal particle group, a massive proliferated synovial membrane was found (p<0.001). The inflammatory score increased over all groups in comparison to PBS. For the metal ion (p=0.003) and polyethylene groups (p=0.002) to the same extent, but to a much higher extent for the metal particle group (p<0.001). Conclusions: The results of this experimental study suggest, that metal particles are strong inducers of an inflammatory reaction and able to cause pseudotumor-like tissue formations. It can be also concluded, that metal ions by themselves are capable to evoke an inflammatory reaction, independent of metal particles. Suggesting that metal ions play an important role in the periprosthetic reaction to metallic wear. (UHMW-) polyethylene particles trigger an inflammatory reaction, too and we could detect histologically osseous changes

Local Biological Reactions and Pseudotumor-Like Tissue Formation in relation to Metal Wear in a Murine In Vivo Model

Metal wear debris and released ions (CoCrMo), which are widely generated in metal-on-metal bearings of hip implants, are also found in patients with metal-on-polyethylene bearings due to the mechanically assisted crevice corrosion of modular taper junctions, including head-neck and neck-stem taper interfaces. The resulting adverse reactions to metal debris and metal ions frequently lead to early arthroplasty revision surgery. National guidelines have since been published where the blood metal ion concentration of patients must consistently be monitored after joint replacement to prevent serious complications from developing after surgery. However, to date, the effect of metal particles and metal ions on local biological reactions is complex and still not understood in detail;the present study sought to elucidate the complex mechanism of metal wear-associated inflammation reactions. The knee joints in 4 groups each consisting of 10 female BALB/c mice received injections with cobalt chrome ions, cobalt chrome particles, and ultra-high-molecular-weight polyethylene (UHMWPE) particles or PBS (control). Seven days after injection, the synovial microcirculation and knee joint diameter were assessed via intravital fluorescence microscopy followed by histological evaluation of the synovial layer. Enlarged knee diameter, enhanced leukocyte to endothelial cell interactions, and an increase in functional capillary density within cobalt chrome particle-treated animals were significantly greater than those in the other treatment groups. Subsequently, pseudotumor-like tissue formations were observed only in the synovial tissue layer of the cobalt chrome particle-treated animals. Therefore, these findings strongly suggest that the cobalt chrome particles and not metal ions are the cause for in vivo postsurgery implantation inflammation

Do Children With Functional Abdominal Pain Benefit More From a Pain-Specific Cognitive-Behavioral Intervention Than From an Unspecific Attention Control Intervention? Results of a Randomized Controlled Trial

Introduction: We aimed to compare the efficacy of cognitive-behavioral therapy (CBT) among children with functional abdominal pain with an attention control (AC), hypothesizing the superiority of CBT group intervention regarding pain intensity (primary outcome), pain duration and frequency (further primary outcomes), functional disability, and quality of life and coping strategies (key secondary outcomes). Methods: We conducted a prospective, multicenter, randomized controlled efficacy trial (RCT) with 4 time points (before intervention, after intervention, 3-month follow-up, and 12-month follow-up). One hundred twenty-seven children aged 7-12 years were randomized to either the CBT (n = 63; 55.6% girls) or the AC (n = 64; 57.8% girls). Results: Primary endpoint analysis of the logarithmized area under the pain intensity curve showed no significant difference between groups (mean reduction = 49.04%, 95% confidence interval [CI] -19.98%-78.36%). Treatment success rates were comparable (adjusted odds ratio = 0.53, 95% CI 0.21-1.34, number needed to treat = 16). However, time trend analyses over the course of 1 year revealed a significantly greater reduction in pain intensity (40.9%, 95% CI 2.7%-64.1%) and pain duration (43.6%, 95% CI 6.2%-66.1%) in the CBT compared with the AC, but not in pain frequency per day (1.2, 95% CI -2.7 to 5.2). In the long term, children in the CBT benefitted slightly more than those in the AC with respect to functional disability, quality of life, and coping strategies. Discussion: Both interventions were effective, which underlines the role of time and attention for treatment efficacy. However, in the longer term, CBT yielded more favorable results. Trial registration: ClinicalTrials.gov NCT02030392

Genotyping circulating tumor DNA of pediatric Hodgkin lymphoma

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response

Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis

Background and Objectives To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. Methods We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. Results We identified 2 independent risk loci harboring genome-wide significant variants (p = 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes. Discussion This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism