RESUMEN
BACKGROUND: Synovial fluid biomarkers have demonstrated diagnostic accuracy surpassing the currently used diagnostic tests for periprosthetic joint infection (PJI). QUESTIONS/PURPOSES: The purpose of this study is to directly compare the sensitivity and specificity of the synovial fluid α-defensin immunoassay to the leukocyte esterase (LE) colorimetric test strip. METHODS: Synovial fluid was collected from 46 patients meeting the inclusion criteria of this prospective diagnostic study. Synovial fluid samples were tested with both a novel synovial-fluid-optimized immunoassay for α-defensin and the LE colorimetric test strip. The Musculoskeletal Infection Society (MSIS) definition was used to classify 23 periprosthetic infections and 23 aseptic failures; this classification was used as the standard against which the two diagnostic tests were compared. RESULTS: The synovial fluid α-defensin immunoassay correctly predicted the MSIS classification of all patients in the study, demonstrating a sensitivity and specificity of 100% for the diagnosis of PJI. The α-defensin assay could be read for all samples, including those with blood in the synovial fluid. The leukocyte esterase test strip could not be interpreted in eight of 46 samples (17%) as a result of blood interference. Analysis of the LE strips that could be interpreted yielded a sensitivity of 69% and a specificity of 100%. CONCLUSIONS: The synovial fluid α-defensin immunoassay outperformed the LE colorimetric test strip in this study and provided reliable results even when the LE test strip failed as a result of blood interference. The simple analytic results provided by the α-defensin immunoassay, compared with the more complex and interpretive nature of both the MSIS criteria and LE colorimetric test strip, make it a highly attractive diagnostic tool. LEVEL OF EVIDENCE: Level II, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
Asunto(s)
Artroplastia de Reemplazo/efectos adversos , Artroplastia de Reemplazo/instrumentación , Hidrolasas de Éster Carboxílico/análisis , Colorimetría , Inmunoensayo , Prótesis Articulares/efectos adversos , Leucocitos/enzimología , Infecciones Relacionadas con Prótesis/diagnóstico , Tiras Reactivas , Líquido Sinovial/enzimología , alfa-Defensinas/análisis , Biomarcadores/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Infecciones Relacionadas con Prótesis/enzimología , Infecciones Relacionadas con Prótesis/microbiología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The diagnosis of periprosthetic joint infection (PJI) remains a serious clinical challenge. There is a pressing need for improved diagnostic testing methods; biomarkers offer one potentially promising approach. QUESTIONS/PURPOSES: We evaluated the diagnostic characteristics of 16 promising synovial fluid biomarkers for the diagnosis of PJI. METHODS: Synovial fluid was collected from 95 patients meeting the inclusion criteria of this prospective diagnostic study. All patients were being evaluated for a revision hip or knee arthroplasty, including patients with systemic inflammatory disease and those already receiving antibiotic treatment. The Musculoskeletal Infection Society (MSIS) definition was used to classify 29 PJIs and 66 aseptic joints. Synovial fluid samples were tested by immunoassay for 16 biomarkers optimized for use in synovial fluid. Sensitivity, specificity, and receiver operating characteristic curve analysis were performed to assess for diagnostic performance. RESULTS: Five biomarkers, including human α-defensin 1-3, neutrophil elastase 2, bactericidal/permeability-increasing protein, neutrophil gelatinase-associated lipocalin, and lactoferrin, correctly predicted the MSIS classification of all patients in this study, with 100% sensitivity and specificity for the diagnosis of PJI. An additional eight biomarkers demonstrated excellent diagnostic strength, with an area under the curve of greater than 0.9. CONCLUSIONS: Synovial fluid biomarkers exhibit a high accuracy in diagnosing PJI, even when including patients with systemic inflammatory disease and those receiving antibiotic treatment. Considering that these biomarkers match the results of the more complex MSIS definition of PJI, we believe that synovial fluid biomarkers can be a valuable addition to the methods utilized for the diagnosis of infection. LEVEL OF EVIDENCE: Level II, diagnostic study. See Instructions for Authors for a complete description of levels of evidence.
Asunto(s)
Artritis Infecciosa/diagnóstico , Biomarcadores/análisis , Prótesis de Cadera/efectos adversos , Prótesis de la Rodilla/efectos adversos , Infecciones Relacionadas con Prótesis/diagnóstico , Líquido Sinovial/química , Proteínas de Fase Aguda/análisis , Adulto , Anciano , Anciano de 80 o más Años , Péptidos Catiónicos Antimicrobianos/análisis , Artritis Infecciosa/microbiología , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Proteínas Sanguíneas/análisis , Proteína C-Reactiva/análisis , Análisis de Falla de Equipo , Femenino , Factor Estimulante de Colonias de Granulocitos/análisis , Humanos , Interleucina-1alfa/análisis , Inestabilidad de la Articulación/etiología , Lactoferrina/análisis , Elastasa de Leucocito/análisis , Lipocalina 2 , Lipocalinas/análisis , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Infecciones Relacionadas con Prótesis/etiología , Proteínas Proto-Oncogénicas/análisis , Curva ROC , Sensibilidad y Especificidad , Factor A de Crecimiento Endotelial Vascular/análisis , alfa-Defensinas/análisisRESUMEN
Biased G protein-coupled receptor ligands engage subsets of the receptor signals normally stimulated by unbiased agonists. However, it is unclear whether ligand bias can elicit differentiated pharmacology in vivo. Here, we describe the discovery of a potent, selective ß-arrestin biased ligand of the angiotensin II type 1 receptor. TRV120027 (Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH) competitively antagonizes angiotensin II-stimulated G protein signaling, but stimulates ß-arrestin recruitment and activates several kinase pathways, including p42/44 mitogen-activated protein kinase, Src, and endothelial nitric-oxide synthase phosphorylation via ß-arrestin coupling. Consistent with ß-arrestin efficacy, and unlike unbiased antagonists, TRV120027 increased cardiomyocyte contractility in vitro. In rats, TRV120027 reduced mean arterial pressure, as did the unbiased antagonists losartan and telmisartan. However, unlike the unbiased antagonists, which decreased cardiac performance, TRV120027 increased cardiac performance and preserved cardiac stroke volume. These striking differences in vivo between unbiased and ß-arrestin biased ligands validate the use of biased ligands to selectively target specific receptor functions in drug discovery.
Asunto(s)
Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Arrestinas/metabolismo , Presión Sanguínea/efectos de los fármacos , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Receptor de Angiotensina Tipo 1/agonistas , Transducción de Señal/efectos de los fármacos , Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Arrestinas/genética , Unión Competitiva , Línea Celular Tumoral , Interacciones Farmacológicas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasa 1 de Adhesión Focal/metabolismo , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Interferente Pequeño/genética , Ratas , Receptor de Angiotensina Tipo 1/genética , Transducción de Señal/fisiología , Transfección , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología , beta-Arrestinas , Familia-src Quinasas/metabolismoRESUMEN
BACKGROUND: The diagnosis of periprosthetic joint infection remains a challenge. The purpose of this study was to evaluate the combined measurement of the levels of two synovial fluid biomarkers, α-defensin and C-reactive protein (CRP), for the diagnosis of periprosthetic joint infection. METHODS: One hundred and forty-nine synovial fluid aspirates, including 112 from patients with an aseptic diagnosis and thirty-seven from patients with periprosthetic joint infection, met the inclusion criteria for this prospective study. Synovial fluid aspirates were tested for α-defensin and CRP levels with use of enzyme-linked immunosorbent assay (ELISA). The Musculoskeletal Infection Society (MSIS) definition of periprosthetic joint infection was utilized for the classification of cases as aseptic or infected. Comorbidities, such as inflammatory conditions, that could confound a test for periprosthetic joint infection were documented, but the patients with such comorbidities were included in the study. RESULTS: The combination of synovial fluid α-defensin and CRP tests demonstrated a sensitivity of 97% and a specificity of 100% for the diagnosis of periprosthetic joint infection. Synovial fluid α-defensin tests alone demonstrated a sensitivity of 97% and a specificity of 96% for the diagnosis of periprosthetic joint infection. Synovial fluid CRP tests, with a low threshold of 3 mg/L, reversed all-false positive α-defensin results without affecting the sensitivity of the test. The diagnostic characteristics of these assays were achieved in a population of patients demonstrating a 23% rate of systemic inflammatory diseases (in the series as a whole) and a 27% rate of concurrent antibiotic treatment (in the infection group). The synovial fluid levels of α-defensin in the setting of periprosthetic joint infection were unchanged during concurrent antibiotic treatment. CONCLUSIONS: The combined measurement of synovial fluid α-defensin and CRP levels correctly diagnosed 99% of the cases in this study as aseptic or infected. This was achieved despite the inclusion of patients with systemic inflammatory disease and those receiving treatment with antibiotics. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.