Metal-on-metal hip arthroplasty : local tissue reactions and clinical outcome

Hip replacements using a metal-on-metal (MoM) bearing surface were reintroduced with the promise of low wear rates and easy revision in case of the resurfacing design. Although initially mid-term results were promising, local adverse soft tissure reactions to metal debris were detected around the year 2008. We studied the prevalence of these adverse reactions, known as pseudotumors, and analysed how well these could be identified with Metal Artefact Reducing Sequence Magnetic Resonance Imaging (MARS-MRI). We also studied the natural development of these pseudotumors and evaluated if measuring pseudotumor size in a clinical setting waa accurate. Based on metal ion analysis, symptoms and MARS-MRI scanning of a large cohort of MoM hip resurfacing patients, we proposed a treatment flow chart for these patients.Anna Fonds|NOREF Arthrex BV Bayer HealthCare Janssen-Cilag B.V. Maatschap Orthopedie St. Anna ziekenhuis Nederlandse Orthopaedische Vereniging St. Anna Ziekenhuis Geldrop T. Theeuwes OrthopedieUBL - phd migration 201

Transcription-coupled nucleotide excision repair is coordinated by ubiquitin and SUMO in response to ultraviolet irradiation

Cockayne Syndrome (CS) is a severe neurodegenerative and premature aging autosomal-recessive disease, caused by inherited defects in the CSA and CSB genes, leading to defects in transcription-coupled nucleotide excision repair (TC-NER) and consequently hypersensitivity to ultraviolet (UV) irradiation. TC-NER is initiated by lesion-stalled RNA polymerase II, which stabilizes the interaction with the SNF2/SWI2 ATPase CSB to facilitate recruitment of the CSA E3 Cullin ubiquitin ligase complex. However, the precise biochemical connections between CSA and CSB are unknown. The small ubiquitin-like modifier SUMO is important in the DNA damage response. We found that CSB, among an extensive set of other target proteins, is the most dynamically SUMOylated substrate in response to UV irradiation. Inhibiting SUMOylation reduced the accumulation of CSB at local sites of UV irradiation and reduced recovery of RNA synthesis. Interestingly, CSA is required for the efficient clearance of SUMOylated CSB. However, subsequent proteomic analysis of CSA-dependent ubiquitinated substrates revealed that CSA does not ubiquitinate CSB in a UV-dependent manner. Surprisingly, we found that CSA is required for the ubiquitination of the largest subunit of RNA polymerase II, RPB1. Combined, our results indicate that the CSA, CSB, RNA polymerase II triad is coordinated by ubiquitin and SUMO in response to UV irradiation. Furthermore, our work provides a resource of SUMO targets regulated in response to UV or ionizing radiation

TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A

Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA-DDB1-CUL4A-RBX1 cullin-RING ubiquitin ligase complex (CRLCSA). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin. TRiC's binding to CSA ensures its stability and DDB1-dependent assembly into the CRLCSA complex. Consequently, loss of TRiC leads to mislocalization and depletion of CSA, as well as impaired transcription recovery following UV damage, suggesting defects in TC-NER. Furthermore, Cockayne syndrome (CS)-causing mutations in CSA lead to increased TRiC binding and a failure to compose the CRLCSA complex. Thus, we uncover CSA as a TRiC substrate and reveal that TRiC regulates CSA-dependent TC-NER and the development of CS

LEAK study:design of a nationwide randomised controlled trial to find the best way to treat wound leakage after primary hip and knee arthroplasty

INTRODUCTION: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are highly successful treatment modalities for advanced osteoarthritis. However, prolonged wound leakage after arthroplasty is linked to prosthetic joint infection (PJI), which is a potentially devastating complication. On the one hand, wound leakage is reported as a risk factor for PJI with a leaking wound acting as a porte d'entrée for micro-organisms. On the other hand, prolonged wound leakage can be a symptom of PJI. Literature addressing prolonged wound leakage is scarce, contradictory and of poor methodological quality. Hence, treatment of prolonged wound leakage varies considerably with both non-surgical and surgical treatment modalities. There is a definite need for evidence concerning the best way to treat prolonged wound leakage after joint arthroplasty. METHODS AND ANALYSIS: A prospective nationwide randomised controlled trial will be conducted in 35 hospitals in the Netherlands. The goal is to include 388 patients with persistent wound leakage 9-10 days after THA or TKA. These patients will be randomly allocated to non-surgical treatment (pressure bandages, (bed) rest and wound care) or surgical treatment (debridement, antibiotics and implant retention (DAIR)). DAIR will also be performed on all non-surgically treated patients with persistent wound leakage at day 16-17 after index surgery, regardless of amount of wound leakage, other clinical parameters or C reactive protein. Clinical data are entered into a web-based database. Patients are asked to fill in questionnaires about disease-specific outcomes, quality of life and cost effectiveness at 3, 6 and 12 months after surgery. Primary outcome is the number of revision surgeries due to infection within a year of arthroplasty. ETHICS AND DISSEMINATION: The Review Board of each participating hospital has approved the local feasibility. The results will be published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NTR5960;Pre-results

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR-Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms

Pulsed Radiofrequency 2 Hz Preserves the Dorsal Root Ganglion Neuron Physiological Ca2+ Influx, Cytosolic ATP Level, Δψm, and pERK Compared to 4 Hz: An Insight on the Safety of Pulsed Radiofrequency in Pain Management

Ristiawan Muji Laksono,1 Taufiq Agus Siswagama,1 Fa’urinda Riam Prabu Nery,1 Walter van der Weegen,2 Willy Halim3 1Department of Anesthesiology and Intensive Therapy, Faculty of Medicine, Brawijaya University, Dr. Saiful Anwar General Hospital, Malang, Indonesia; 2Sports & Orthopedics Research Centre., St. Anna Hospital, Geldrop, the Netherlands; 3Medical Department, Faculty of Medicine, Brawijaya University, Malang, IndonesiaCorrespondence: Ristiawan Muji Laksono, Department of Anesthesiology and Intensive Therapy, Faculty of Medicine, Brawijaya University, Jl. Jaksa Agung Suprapto No. 2, Malang, East Java, Indonesia, Tel +62 812-3377-3593, Email [email protected]: Pulsed radiofrequency (PRF) is beneficial for radicular pain and is commonly administered at pulse frequencies of 2 or 4 Hz. However, its effects on healthy neurons have not yet been widely studied. This study aims to determine the effect of PRF at 2 Hz and 4 Hz on the physiology of healthy dorsal root ganglion (DRG) neurons.Methods: An in vitro experimental study was conducted using DRG neuron cultures divided into three groups. Control cells received no treatment, one cell group received 20 ms 2 Hz PRF for 360 s, and one cell group received a 4 Hz PRF 10 ms pulse for 360 s with similar energy. Ca2+ influx, mitochondrial membrane potential (Δψm), cytosolic Adenosine triphosphate (ATP), and phosphorylated extracellular signal-regulated kinase (pERK) levels were measured. The data were analyzed using the One-Way ANOVA variance with α=5%.Results: DRG neurons exposed to PRF 2 Hz did not experience a significant change in Ca2+ influx, whereas PRF 4 Hz caused a significant decrease in Ca2+ influx compared to the basal level. PRF at 2 Hz did not cause a change in Δψm, whereas PRF at 4 Hz caused a significant decrease in Δψm (p 0.05), indicating that there was no significant neuron activation.Conclusion: Both frequencies did not significantly activate DRG neurons, but with similar energy delivery, PRF 2 Hz preserved the physiological properties of healthy neurons better than PRF 4 Hz did. A 2 Hz PRF is the preferred frequency in clinical applications for neuron-targeted therapy.Keywords: pulsed radiofrequency, neurons, physiology, dorsal root ganglion neuro