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Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of â³0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10-8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells.
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DNA Mitocondrial , Mosaicismo , Mutação , Humanos , DNA Mitocondrial/genética , Heteroplasmia/genética , Taxa de Mutação , Mitocôndrias/genética , Genoma Mitocondrial , Replicação do DNA/genética , Feminino , MasculinoRESUMO
This study aimed to identify the effectiveness and potential complications on the harvest site and knee of bone marrow aspirate concentrate (BMAC) treatment of patients with Kellgren-Lawrence (K-L) grades II-III knee osteoarthritis (OA) over a minimum follow-up period of 6 months. This study retrospectively evaluated data from 231 patients (285 knees) with knee OA treated with BMAC articular injection at a single center from August 2023 to October 2023. The inclusion criteria were a longstanding knee pain unresponsive to conservative treatments for at least 6 weeks with K-L grades II-III OA. The exclusion criteria were age of <40 years or >80 years, previous knee surgery, rheumatological or other systemic disease, malignancy, uncontrolled diabetes mellitus, or infections. Bone marrow was aspirated from the anterior iliac crest and concentrated by the single-spin centrifugation technique. The visual analog scale (VAS) pain score and Knee Society Score were used to evaluate the clinical outcomes and complications associated with harvest and injection sites were evaluated. The mean follow-up period was 7.2 months (range: 6-8 months). The pretreatment VAS pain score decreased from 4.3 to 0.4 points at the final follow-up (p < 0.05). Pretreatment Knee Society knee and function scores were improved from 86.9 to 98.1 (p < 0.05) and from 68.4 to 83.3 points (p < 0.05), respectively. A total of 15 complications (5.3%, 15/285) were observed, including 3 hematomas, 2 numbness, 2 contact dermatitis, and 1 superficial infection in the harvest site and 4 mild and moderate swelling and 3 severe swelling and pain in the injection site. BMAC is a reliable and effective treatment for patients with K-L grades II-III knee OA, but the orthopedic surgeon should consider that bleeding tendency by heparin causes severe joint swelling and pain after intra-articular knee injection.
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Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Resultado do Tratamento , Adulto , Medição da Dor , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/efeitos adversos , Injeções Intra-Articulares , Idoso de 80 Anos ou maisRESUMO
While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin family to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine.
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Gêmeos Dizigóticos , Sequenciamento Completo do Genoma , Zigoto , Humanos , Feminino , Gêmeos Dizigóticos/genética , Zigoto/metabolismo , Gravidez , Quimerismo , Placenta/metabolismo , Masculino , Quimera/genética , Gêmeos Monozigóticos/genéticaRESUMO
BACKGROUND: Supplementation with leucine-enriched essential amino acids (LEAAs) has shown efficacy in the recovery of muscle injury and activation of muscle synthesis. Muscle function in knee osteoarthritis is a crucial factor for managing pain and preserving ambulatory function. However, the efficacy and safety of LEAAs supplementation in patients with knee osteoarthritis have not been evaluated. METHODS: In this prospective analysis, we evaluated the efficacy and safety of supplementation with 12 g of LEAAs daily for 8 weeks in knee-symptomatic osteoarthritis patients. For assessing the efficacy, clinical pain, calf circumference, and disability were assessed using questionnaires (visual analog scale, Knee Society Score, and 36-item short form survey [SF-36]), laboratory analyses (total protein and albumin), and radiologic study (dual-energy X-ray absorptiometry [DEXA]) for muscle and bone density. To evaluate safety, generalized or localized protein allergic reactions, complete blood count, liver and kidney function, and serum glucose were measured. RESULTS: Sixty-five participants, categorized into the experimental (nâ =â 32) and control (nâ =â 33) groups, were included in this 8-week trial from March 2022 to July 2022. A significantly higher efficacy was observed in the experimental group than in the control group, as indicated by muscle density in the DEXA scan (Pâ =â .001) and SF-36 (Pâ <â .001). The safety evaluation revealed no related generalized or local protein allergy. Hematological findings, serum glucose, and kidney and liver toxicity were not significantly different between the groups. CONCLUSION: Supplementation with leucine-enriched proteins is safe and efficacious in the improvement of muscle density and quality of life.
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Aminoácidos Essenciais , Suplementos Nutricionais , Leucina , Osteoartrite do Joelho , Humanos , Feminino , Osteoartrite do Joelho/tratamento farmacológico , Leucina/uso terapêutico , Leucina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Aminoácidos Essenciais/uso terapêutico , Aminoácidos Essenciais/administração & dosagem , Estudos Prospectivos , Idoso , Resultado do Tratamento , Medição da DorRESUMO
The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.
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Rearranjo Gênico , Translocação Genética , Humanos , Animais , Camundongos , Mutação , Genômica , Inversão Cromossômica , MamíferosRESUMO
Throughout an individual's lifetime, genomic alterations accumulate in somatic cells1-11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12-14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.
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Colo , Elementos de DNA Transponíveis , Mucosa Intestinal , Retroelementos , Humanos , Carcinogênese/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Elementos de DNA Transponíveis/genética , Genômica , Elementos Nucleotídeos Longos e Dispersos/genética , Retroelementos/genética , Envelhecimento/genética , Frequência do Gene , Mosaicismo , Epigenômica , Genoma Humano/genética , Colo/metabolismo , Mucosa Intestinal/metabolismo , Desenvolvimento Embrionário/genéticaRESUMO
PURPOSE: The purpose of this study was to assess tibial post fracture between highly cross-linked polyethylene (HXPE) and conventional polyethylene inserts in consecutive posterior-stabilized (PS) total knee arthroplasty (TKA) over a minimum 10-years follow-up period. METHODS: Between July 2008 and December 2011, a consecutive series of 3264 primary TKAs was performed in 2098 patients using a PS total knee prosthesis at a single institution. The final cohort was classified into the HXPE group (792 cases) and the conventional group (2113 cases) according to insert material used during the procedure. RESULTS: The mean follow-up period was 11.4 years in the HXPE group and 11.8 years in the conventional group. Both cases of tibial post fracture occurred in the HXPE group, a complication rate of 0.25%. These two cases required replacement with a thicker tibial insert with retention of the femoral and tibial components. There were no cases of tibial post fracture in the conventional group. CONCLUSION: There was no difference in tibial post fracture rate between the HXPE group and the conventional group in PS TKA on long-term follow-up. LEVEL OF EVIDENCE: IV.
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Artroplastia do Joelho , Prótese do Joelho , Fraturas da Tíbia , Humanos , Polietileno , Articulação do Joelho/cirurgia , Seguimentos , Desenho de Prótese , Prótese do Joelho/efeitos adversos , Fraturas da Tíbia/cirurgia , Falha de PróteseRESUMO
Background: We report 4 cases with a tibial post refracture following isolated tibial insert exchange in posterior-stabilized total knee arthroplasty at a single center. Methods: In our institution, 27 cases (26 patients) underwent reoperation due to tibial post fracture in posterior-stabilized total knee arthroplasty between July 2008 and November 2020. Of these 27 cases, 4 (4 patients) tibial post refractures occurred at a mean follow-up period of 9.1 years. Results: All 4 cases of tibial post refracture occurred in a group of 21 cases with isolated tibial insert exchange. There was no tibial post refracture in patients with a tibial revision surgery. The incidence of this complication following isolated tibial insert exchange was 19.0%. The mean elapsed time from tibial insert exchange to the diagnosis of a post refracture was 2.5 years (range: 1.1-6.6 years). Conclusions: Isolated exchange of a tibial insert with excessive thickness as a treatment for tibial post fracture is associated with a high probability of tibial post refracture. The treatment method should be selected after a thorough analysis according to the cause of fracture. Level of evidence: IV.
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The purpose of this study was to determine the outcomes of the placement of a pin tracker in the distal femur in robotic-assisted total knee arthroplasty (TKA) over a minimum follow-up period of 1 year. A consecutive series of 81 TKAs were performed in 59 patients using a robotic-assisted system (Mako) at our hospital. The mean follow-up period was 1.1 years (range, 1-1.2 years). No periprosthetic fracture at a pin tracker site was reported at a minimum of 1 year of follow-up. No patients reported minor or major complications associated with the distal femoral pins. In addition, unicortical pin-site drilling marks in all patients disappeared on one-postoperative-year follow-up radiographs. Our technique, which used unicortical pin placement in the distal femur in robotic-assisted TKA, demonstrated that it was a safe and reliable method at a minimum follow-up period of 1 year. The level of evidence is IV.
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Artroplastia do Joelho , Fraturas do Fêmur , Procedimentos Cirúrgicos Robóticos , Humanos , Artroplastia do Joelho/efeitos adversos , Artroplastia do Joelho/métodos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Seguimentos , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/cirurgia , Fêmur/cirurgia , Articulação do Joelho/cirurgiaRESUMO
BACKGROUND: This study compared the functional outcomes, implant survival rates, and complications of total knee arthroplasty (TKA) performed in patients with windswept deformity (WSD) and non-WSD patients over at least 10 years of follow-up. METHODS: From January 2008 to December 2010, 40 TKAs were performed in 20 patients with WSD (WSD group). Additionally, 60 propensity score-matched patients without WSD who had undergone primary bilateral TKA were chosen for the control group in a three-to-one ratio. Then, the functional outcomes, implant survival rates, and complications of TKA in the two groups were compared. The mean follow-up periods were 10.8 years in the WSD group and 11.5 years in the control group. RESULTS: The mean Knee Society knee scores in the WSD and control groups improved from 37.7 to 38.1 points preoperatively to 79.5 and 79.2 points at final follow-up (p = 0.974), while the mean function scores in the WSD and control groups improved from 36.5 to 37.2 points preoperatively to 77.8 and 77.4 points at final follow-up (p = 0.863). Two knees in the WSD group required revision surgery, including one due to septic loosening and one due to aseptic loosening. Five knees in the control group required revision surgery, including three due to septic loosening and two due to aseptic loosening. Kaplan-Meier survivorship analysis with the revision of either component as an endpoint in the WSD and control groups estimated 95.0% and 95.8% chances of survival for 10 years, respectively (p = 0.824). CONCLUSIONS: TKA performed in patients with WSD yielded good clinical outcomes and survivorship at least 10 years later. LEVEL OF EVIDENCE: IV.
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Artroplastia do Joelho , Prótese do Joelho , Humanos , Artroplastia do Joelho/efeitos adversos , Prótese do Joelho/efeitos adversos , Resultado do Tratamento , Falha de Prótese , Articulação do Joelho/cirurgia , Reoperação , Seguimentos , Estudos RetrospectivosRESUMO
The purpose of this study was to determine the effectiveness of the placement of pin trackers in the medial sagittal plane of the distal femur in robotic-assisted total knee arthroplasty (TKA) over a minimum follow-up period of 3 months. From August 2020 to October 2020, a consecutive series of 81 TKAs were performed in 59 patients using the Triathlon posterior-stabilized total knee prosthesis with a robotic-assisted system (Mako) at our hospital. Patient charts were reviewed for complications associated with the pin sites, including fracture, infection, thigh pain, and the need for reoperation. No patients had any minor or major complications associated with distal femoral pins. This technique, which used pin trackers in the medial sagittal plane of the distal femur, could be a useful option for surgeons performing robotic-assisted TKA. This is a Level IV study.
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Artroplastia do Joelho , Fraturas do Fêmur , Prótese do Joelho , Osteoartrite do Joelho , Procedimentos Cirúrgicos Robóticos , Cirurgia Assistida por Computador , Humanos , Artroplastia do Joelho/efeitos adversos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Cirurgia Assistida por Computador/métodos , Fêmur/cirurgia , Prótese do Joelho/efeitos adversos , Fraturas do Fêmur/cirurgia , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgiaRESUMO
The cause of early aseptic loosening in total knee arthroplasty (TKA) is uncertain, although several possibilities could be offered. We report that osteonecrosis of the knee should be considered as a possible cause or contributing etiologic factor for early aseptic loosening following primary TKA.
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Background: Achieving proper axis alignment can be difficult in the presence of posttraumatic extra-articular deformities in either the femur or the tibia. We present radiological outcomes following robot-assisted total knee arthroplasty (TKA) in patients with osteoarthritis of the knee accompanied by posttraumatic extra-articular deformities. Methods: We analyzed the outcomes of five knees in five patients with (1) Kellgren-Lawrence (K-L) Grade III-IV osteoarthritic knees, (2) the presence of posttraumatic extra-articular deformities either in the femur or the tibia, and (3) who underwent robot-assisted TKA. Their radiological findings were evaluated. Results: All five knees with initial deformity (mean 14.8°, range 12.7-18.5°) were corrected to neutral alignment (mean 0.7°, range -1.1-2.7°). There was no postoperative outlier of hip-knee-ankle (HKA) angle. Conclusion: Our results indicate that robot-assisted TKA can be used to achieve proper limb alignment in patients with posttraumatic extra-articular deformities.
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PURPOSE: The purpose of this study was to compare the mechanical axis, accuracy of component positioning, and polyethylene liner thickness between robot-assisted total knee arthroplasty (TKA) and conventional TKA. METHODS: From July 2020 to December 2020, 154 TKAs were performed in 110 patients with Kellgren-Lawrence grade IV varus knees using a robot-assisted system (MAKO group). Additionally, 110 propensity score-matched patients who had undergone primary conventional TKA were chosen in a one-to-one ratio for the conventional group. Post-operative radiographs were used to evaluate mechanical axis and component coronal and sagittal positioning. The polyethylene liner thickness was investigated. The respective mean error values and outliers were obtained for the two study groups and were compared to determine the mechanical axis and the accuracy of the postoperative component positioning. RESULTS: Patients in the MAKO group achieved better accuracy than those in the conventional group in terms of postoperative mean mechanical axis (1.9Ë vs. 2.8Ë, p < 0.05), femur coronal inclination (91.2Ë vs. 91.8Ë, p < 0.05), tibia coronal inclination (90.8Ë vs. 91.1Ë, p < 0.05), and tibia sagittal inclination (90.7Ë vs. 91.7Ë, p < 0.05). However, there was no difference between the two groups in polyethylene liner thickness. CONCLUSIONS: Robot-assisted TKA showed improved mechanical axis and higher accuracy of component positioning compared to the conventional TKA technique, with no significant difference in polyethylene liner thickness between the two groups. Long-term follow-up studies are needed to compare the clinical outcomes of robot-assisted TKA. LEVEL OF EVIDENCE: IV.
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Purpose: The purpose of this study was to assess the medium-term results of trabecular metal cones for the reconstruction of large bone defects in revision TKA. Methods: Thirteen patients who had undergone revision TKA using trabecular metal cones for femoral and/or tibial large bone defects were identified. We included patients who had a minimum of three years follow-up in the study. We evaluated their functional outcomes, implant survivorship, radiological findings, and complications. Results: At a mean follow-up of 6.9 years (range of 3.5-9.4 years), all trabecular metal cones and implants were well fixed and did not exhibit any radiographic evidence of migration or loosening. At the final follow-up, the mean Knee Society knee scores had improved from 37.2 to 78.1 (p < 0.05), and function scores had improved from 35.5 to 77.5 points (p < 0.05). One intraoperative fracture in the distal femur occurred in an 85-year-old woman during impaction of a single trabecular metal cone. The fracture was successfully affixed to the femoral cone and bone three months postoperatively. Conclusion: The present study of trabecular metal cones demonstrates excellent clinical outcomes and survivorship in revision TKA during medium-term follow-up periods. However, longer-term follow-up studies are needed to further investigate these implants in revision TKA. Additionally, the necessity of metal cones in revision procedures should be carefully considered depending on patient needs and economic capabilities.
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Arthroscopic saucerization of the lateral discoid meniscus is considered due to an increase in the load of the lateral compartment after high tibial osteotomy (HTO). We report a case of lateral discoid meniscus regeneration after arthroscopic saucerization in a middle-aged female patient who underwent HTO.
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Total knee arthroplasty (TKA) is technically demanding in patients with pre-existing hardware around the knee. We report two cases of knee osteoarthritis in patients with retained hardware who would have difficulty undergoing conventional TKA. Robot-assisted TKA can be a useful treatment for knee osteoarthritis in patients with retained hardware.
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PURPOSE: The purpose of this study was to assess tibial post-fracture between highly cross-linked polyethylene (HXPE) and conventional polyethylene inserts in consecutive posterior-stabilized (PS) total knee arthroplasty (TKA) over a minimum 12-year follow-up period. METHODS: Between January 2007 and June 2008, a consecutive series of 2446 primary TKAs was performed in 1478 patients at a single institution. The final cohort was classified into two groups (1559 in the HXPE group and 887 in the conventional group) based on the insert material used during the procedure. RESULTS: The mean follow-up period was 13.1 years in the HXPE group and 13.4 years in the conventional group. All 16 cases of tibial post-fracture occurred in the HXPE group. This complication rate was 1.03%. The mean elapsed time from primary TKA to the diagnosis of post-fracture was 3.9 years (range 0.5-10.0 years). Ten cases required replacement with a thicker polyethylene insert, and six cases underwent tibial revision surgery. There were no cases of tibial post-fracture in the conventional group. CONCLUSION: Tibial post-fracture is not a rare complication in PS TKA with HXPE. Therefore, the possibility of a tibial post-fracture should be considered if newly developed pain, acute subluxation, effusion, patellar clunking, or instability occurs in patients treated with PS Scorpio knee system TKA using an HXPE insert. LEVEL OF EVIDENCE: IV.
Assuntos
Artroplastia do Joelho , Prótese do Joelho , Fraturas da Tíbia , Humanos , Artroplastia do Joelho/efeitos adversos , Polietileno , Seguimentos , Falha de Prótese , Articulação do Joelho/cirurgia , Reoperação , Fraturas da Tíbia/cirurgiaRESUMO
With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) framework based on Mendel's law of inheritance, to quantify DNA mixture between family members in genome sequencing data of parent-offspring trios. TrioMix can accurately deconvolute any intrafamilial DNA contamination, including parent-offspring, sibling-sibling, parent-parent, and even multiple familial sources. In addition, TrioMix can be applied to detect genomic abnormalities that deviate from Mendelian inheritance patterns, such as uniparental disomy (UPD) and chimerism. A genome-wide depth and variant allele frequency plot generated by TrioMix facilitates tracing the origin of Mendelian inheritance deviations. We showed that TrioMix could accurately deconvolute genomes in both simulated and real data sets.
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Contaminação por DNA , Genoma , Humanos , Mapeamento Cromossômico , Dissomia Uniparental , Bases de Dados GenéticasRESUMO
PURPOSE: The purpose of this study was to compare the functional outcomes, activity levels, mortalities, implant survival rates, and complications of total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA) with those in patients with osteoarthritis (OA) over a minimum 10-year follow-up period. METHODS: Between January 2007 and December 2009, 90 TKAs performed in 57 patients with RA (RA group) were retrospectively reviewed and matched with a control group of 180 TKAs performed in 114 patients with OA. The functional outcomes (Knee Society Score), activity levels (Koval grade), mortalities, implant survival rates, and complications were compared between the two groups with a minimum 10-year follow-up period. The mean follow-up periods were 12.3 years in the RA group and 12.6 years in the OA group. RESULTS: The mean Knee Society knee scores in the RA and OA groups improved from 37.7 ± 5.4 to 38.2 ± 5.3 preoperatively to 72.9 ± 22.8 to 83.1 ± 11.0 points, respectively, at the final follow-up (p < 0.05). At the final follow-up, 38 of 48 (79.2%) in the RA group and 105 of 109 (96.3%) in the OA group (p < 0.05) were outdoor ambulatory patients. The cumulative mortality rates in the RA and OA groups were 15.8% (9/57) and 4.4% (5/114) (p < 0.05) at the final follow-up, respectively. Kaplan-Meier survivorship analysis with revision of either component as an endpoint in the RA and OA groups estimated 94.4% and 98.3% chance of survival for 10 years, respectively. CONCLUSION: TKA in patients with RA had worse functional outcomes and higher mortality over a minimum 10-year follow-up period, compared with TKA in patients with OA. LEVEL OF EVIDENCE: IV.