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A series of chemically-modified oligonucleotides for targeting the DNA repair nuclease SNM1A have been designed and synthesised. Each oligonucleotide contains a modified internucleotide linkage designed to both mimic the native phosphodiester backbone and chelate to the catalytic zinc ion(s) in the SNM1A active site. Dinucleoside phosphoramidites containing urea, squaramide, sulfanylacetamide, and sulfinylacetamide linkages were prepared and employed successfully in solid-phase oligonucleotide synthesis. All the modified oligonucleotides were found to interact with SNM1A in a gel electrophoresis-based assay, demonstrating the first examples of inhibition of DNA damage repair enzymes for many of these groups in oligonucleotides. One strand containing a sulfinylacetamide-linkage was found to have the strongest interaction with SNM1A and was further tested in a real-time fluorescence assay. This allowed an IC50 value of 231 nM to be determined, significantly lower than previously reported substrate-mimics targeting this enzyme. It is expected that these modified oligonucleotides will serve as a scaffold for the future development of fluorescent or biotin-labelled probes for the in vivo study of DNA repair processes.
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PURPOSE: Intertrochanteric hip fractures are significant and costly injuries and there remains controversy within the orthopaedic literature over the best method of fixation. The Irish Hip Fracture Database (IHFD) was established in 2012 to drive improvements in clinical outcomes and the quality of hip fracture care. This paper will review the outcomes of dynamic hip screw (DHS) versus intra-medullary nailing (IMN) in the treatment of intertrochanteric hip fractures in Ireland. METHODS: Eligible cases for this study include patients >60 years of age with trochanteric hip fractures treated by DHS or IMN between January 2016 and December 2020. Outcomes recorded and compared include length of stay, inpatient mortality, mobilisation on post-operative day 1 (POD 1), and discharge destination. RESULTS: 5668 hip fractures treated with DHS or IMN were identified. There was no significant difference between inpatient mortality, re-operation rate or length of stay between the two groups. Females and patients with a high ASA grade (IV and V) were more likely to receive IMN. Patients receiving DHS were more likely to be mobilised day 1 post-operatively and be discharged directly home. It was noted that the use of IMN increased from 42% of cases in 2016 to 70% in 2020. CONCLUSION: IMN use for intertrochanteric fractures continues to increase. However, patients treated with DHS were more likely to mobilise early post-operatively and to go directly home. Notwithstanding the limitations of national registry data research, the dramatic rise in the use of IMN for these fractures appears unsupported by the evidence.
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Fixação Intramedular de Fraturas , Fraturas do Quadril , Feminino , Humanos , Resultado do Tratamento , Parafusos Ósseos , Fraturas do Quadril/cirurgia , Fixação Interna de Fraturas/métodos , Pinos OrtopédicosRESUMO
BACKGROUND: The aim of this study was to analyse the association between use of cement for stem fixation in hip hemiarthroplasty and the outcomes of mobility, mortality, and discharge destination. METHODS: The Irish Hip Fracture Database was examined from 2016 to 2020 to assess for any difference in post op mobility, 7-day, 14-day and inpatient mortality, and discharge destination. RESULTS: A total of 7109 hemi-arthroplasties were identified from 2016 to 2020. 71.6 % were cemented (n = 5,172), with 28.4 % uncemented (1,937). There was no difference in day 1 post op mobilisation (79.7 % vs 80.9 %) or cumulative ambulatory score on discharge (2.5 vs 2.4). The mortality rate was equivocal at all time points between the cemented and uncemented groups (7 day (.9 % vs 1.2 %), 14 day (1.9 % vs 2.3 %), inpatient (4 % vs 5.1 %)). There was no difference in length of stay (11 vs 12 days) or discharge to home directly (21 % vs 27 %). CONCLUSION: The use of cement did not have any significant difference on post op mortality, mobility or discharge destination.
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We present the first case report of prosthetic joint infection (PJI) caused by Kocuria rhizophila. Our patient is a 74-year-old male who underwent primary total hip replacement for right hip pain. His recovery was uneventful until 6 weeks postoperatively when he presented to his routine outpatient appointment with significant erythema, swelling, and tenderness over his right hip wound. Based on the acuity of his symptoms and the radiological findings, it was determined that the patient should undergo debridement, antibiotics, and implant retention (DAIR procedure). A consensus decision was also made at our PJI multidisciplinary meeting to treat him with 12 weeks of IV antibiotics. After completing this 12 weeks course of IV Vancomycin, his inflammatory markers returned to normal limits. At 6 months follow-up, our patient was mobilizing independently without any signs of infection recurrence. His radiographs showed the implant was in a satisfactory position with no evidence of loosening. This case adds to an emerging body of literature describing invasive infections associated with Kocuria species. We have demonstrated the effectiveness of managing this condition with debridement, implant retention, and IV Vancomycin therapy for 12 weeks.
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We report a two-step validation approach to evaluate the suitability of metal-binding groups for targeting DNA damage-repair metalloenzymes using model enzyme SNM1A. A fragment-based screening approach was first used to identify metal-binding fragments suitable for targeting the enzyme. Effective fragments were then incorporated into oligonucleotides using the copper-catalysed azide-alkyne cycloaddition reaction. These modified oligonucleotides were recognised by SNM1A at >1000-fold lower concentrations than their fragment counterparts. The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage. However, SNM1A and other enzymes of this class are poorly understood, as there is a lack of tools available to facilitate their study. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generating modified oligonucleotide structures with high affinity for DNA damage-repair enzymes.
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Proteínas de Ciclo Celular , Exodesoxirribonucleases , Exodesoxirribonucleases/metabolismo , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Reparo do DNA , Oligonucleotídeos/químicaRESUMO
Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5'-3' exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5'-position, as well as zinc-binding groups at the 3'-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5'-phosphate dramatically increased the potency of the inhibitors.
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Exodesoxirribonucleases , Nucleosídeos , Reparo do DNA , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Exodesoxirribonucleases/química , Exodesoxirribonucleases/metabolismo , Nucleosídeos/farmacologia , Fosfatos , Fosforilação , Zinco/farmacologiaRESUMO
SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3'-position, and a thymidine derivative bearing a 5'-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC50 determination showed that a thymidine derivative bearing a 5'-thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3'-squaric acid. UV-Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications.
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Enzimas Reparadoras do DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quinina/análogos & derivados , Enzimas Reparadoras do DNA/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Quinina/síntese química , Quinina/química , Quinina/farmacologia , Relação Estrutura-AtividadeRESUMO
Osteoarthritis is a significant cause of chronic pain in the elderly population with hip osteoarthritis as one of the main causes of functional disability and joint pain in adults older than 55 years. Recently, platelet rich plasma (PRP) injections have been introduced for treatment of osteoarthritis. The aim of this systematic review is to assess its effectiveness in the management of hip osteoarthritis. We performed a search of the literature for published prospective studies that assessed the effectiveness of PRP injections in the treatment of hip osteoarthritis, with a minimum follow-up of 3 months. Primary outcome measures were WOMAC and VAS scores. Five trials were identified with 185 patients undergoing treatment with ultrasound-guided intra-articular injections of PRP, compared with patients treated with hyaluronic acid alone (n = 148) or hyaluronic acid combined with PRP (n = 31) in one study. PRP was shown to improve patient outcome scores at follow-up at 6 and 12 months; however, there was no significant difference seen between patients treated with PRP or hyaluronic acid alone. Following this systematic review, we cannot currently recommend the use of intra-articular injections of PRP for the treatment of hip OA. Given that intra-articular steroid injections are the only such injection recommended by international guidelines for the treatment of hip OA, further studies comparing PRP to steroid would be of benefit to determine the value of PRP injections in hip OA.
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Osteoartrite do Quadril , Plasma Rico em Plaquetas , Adulto , Idoso , Humanos , Injeções Intra-Articulares , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: The rising incidence of acetabular fractures in the elderly presents an increasing surgical challenge due to patient co-morbidities, complex fracture patterns' and osteoporotic bone. Of interest in this study are those of the quadrilateral plate, which are more common in elderly patients with osteoporosis. Following such injuries, the weight-bearing surface of the femoral head moves medially. Non-operative management of these fractures can lead to the acetabulum articulating on the femoral neck increasing the risk of subsequent femoral neck fracture as a result of the altered biomechanics.Using finite element analysis (FEA) this study seeks to understand the changing biomechanics of the proximal femur in such instances and to determine if there is a threshold of femoral head medialisation that can predict probability of femoral neck fracture. METHODS: A femoral neck FEA model was created from the CT and MRI scans of a healthy hip. Using FEA, the model was used to apply point loading to the femoral head at the anatomical weight bearing area and subsequent lateralization of this point down to the femoral neck-shaft junction. This simulates the changing forces acting on the femur as the head medialises into a fractured acetabulum. RESULTS: As the point of contact moved laterally the stress levels within the proximal femur increased steadily, particularly along the superior neck. Bending moment at the medial neck shaft junction also increased. This increase in stress levels can be seen as a corollary for risk of fracture within the femur. CONCLUSION: With medialisation of the femur into a fractured acetabulum there is a significant change in the stress distribution within the femoral neck. Clinically, this is indicates that patients with such injuries are at an increased risk of femoral neck fractures once they begin to mobilise after the initial injury, a devastating result. This model may be of use to treating surgeons in predicting the risk of femoral neck fracture.
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INTRODUCTION: Farming is a major industry in Ireland, employing 6% of the workforce but accounts for 40% of workplace fatalities (Meredith, 2008).1 The use of machinery and proximity to large livestock poses significant risk for spinal injuries. This study reviews mechanism of injury, injuries sustained, and the treatment undertaken. RESULTS: Of 31 patients, 26 sustained high-energy injuries with machinery and livestock implicated in the majority of accidents. 77% sustained poly-trauma and 52% had permanent neurological injury. CONCLUSIONS: The proximity to heavy machinery and livestock pose significant risk for spinal injuries. This study should encourage increased efforts to improve farm safety.
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PURPOSE: The aim of this study was to compare transfusion requirements in patients before and after the introduction of tranexamic acid as standard in patients undergoing spinal surgery for idiopathic scoliosis in a national orthopaedic hospital. METHODS: A retrospective chart review of 56 idiopathic scoliosis patients who underwent posterior spinal instrumentation and fusion between 2009 and 2013 at our institution. Preoperative, intraoperative, and postoperative data were measured. RESULTS: Patients who received tranexamic acid as standard (n = 31) showed a trend towards a decrease in transfusion requirements compared with those who received no tranexamic acid (n = 25). These patients had a statistically significant decrease in operative time (223 vs 188 min, p = 0.005), and estimated intraoperative blood loss was reduced by nearly 50% in the tranexamic acid group. They also had an associated reduced decrease in haemoglobin between preoperative and postoperative levels (4 vs 5 g/dL, p = 0.01). CONCLUSIONS: Since February 2012, no patient has required intraoperative or postoperative allogeneic blood product transfusion in this hospital. The routine use of antifibrinolytic medications in patients undergoing surgery for adolescent idiopathic scoliosis has effectively eliminated the need for allogeneic blood products.