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OBJECTIVE: Rising anti-double-stranded (ds) DNA titers have been shown by some, but not all, studies to be predictive of disease flares in systemic lupus erythematosus (SLE). We hypothesized that a rapid and substantial rise in anti-dsDNA titer (anti-dsDNA surge) would be a good predictor of a clinically important SLE flare. METHODS: A matched case-control study was conducted in an academic rheumatology practice setting. Our primary endpoint was the occurrence of a severe SELENA-SLEDAI (SS) flare within six months of an anti-dsDNA surge, and secondary endpoints were mild/moderate SS flares, as well as BILAG A and B renal flares. Cases were identified as those patients whose disease course included a surge of anti-dsDNA, defined as an increase of anti-dsDNA titer by the Crithidia luciliae immunofluorescence (CLIF) assay from 0 to 3+/4+, or from 1+ to 4+, within a period of less than 12 months. The date of the anti-dsDNA surge was defined as Day 0. Two control SLE patients were identified for each case and were matched for age, sex, race, and visit date closest to case Day 0, but without an anti-dsDNA surge. Logistic regression models were used to detect associations between anti-dsDNA surges and severe SS flares. RESULT: A higher proportion of cases, compared to controls, experienced a severe SS flare within six months of Day 0 (OR 6.3 (95% confidence intervals 2.0-19.9), p = 0.02). Associations with all flares and hospitalizations for flares were also observed. However, an anti-dsDNA surge was not predictive of a renal flare. CONCLUSION: An anti-dsDNA surge predicts the subsequent development of a severe SS flare within six months. Physicians should closely monitor such patients and treat promptly at the first sign of clinical activity.
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Anticuerpos Antinucleares/sangre , ADN/inmunología , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Centros Médicos Académicos , Adulto , Biomarcadores/sangre , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/diagnóstico , Nefritis Lúpica/sangre , Nefritis Lúpica/diagnóstico , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Valor Predictivo de las Pruebas , Sistema de Registros , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Regulación hacia Arriba , Adulto JovenRESUMEN
OBJECTIVES: We aimed to assess the long-term safety and tolerability of imatinib in diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this open-label, single-arm, extension-phase clinical trial, patients continued imatinib for 24 months following 12 months of initial treatment. RESULTS: Seventeen patients were enrolled. Forty of 92 adverse events (AE) and 0/6 serious (S) AEs were possibly related to medication. The MRSS decreased from a median of 21 to 16, (p=0.002). CONCLUSIONS: This study demonstrates long-term safety and tolerability of imatinib in a substantial proportion of patients with dcSSc. This is important in evaluating the relevance of this therapy in a chronic disease such as SSc.
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Benzamidas/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Esclerodermia Difusa/tratamiento farmacológico , Adulto , Antirreumáticos/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Quimioterapia Combinada , Femenino , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Mesilato de Imatinib , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Pruebas de Función Respiratoria , Esclerodermia Difusa/complicaciones , Resultado del TratamientoRESUMEN
The Reno Atmospheric Mercury Intercomparison Experiment (RAMIX) was in Reno, NV from August 22, 2011 to September 16, 2011. The goals of the experiment were to compare existing and new methods for measurements of ambient elemental and oxidized Hg, and to test these with quantitative spikes of Hg(0), HgBr2, O3 and water vapor. In this paper we describe the design, testing, and deployment of a high flow manifold system designed to deliver ambient air and spiked compounds to multiple instruments simultaneously. The manifold was constructed of 1" OD PFA tubing and heated to 115 °C for the entire active zone. Manifold flow was controlled at â¼200 LPM using a blower and a velocity sensor in a feedback control system. Permeation tubes in controlled ovens were used to deliver Hg(0) and HgBr2. Ozone was generated from a small UV lamp in a flow of high purity O2. Water vapor was generated by pumping a flow of purified N2 through heated, high purity water. The spiking delivery for Hg(0), HgBr2, O3, and water vapor after dilution in the manifold ranged up to 20 ng m(-3), 0.64 ng m(-3), 100 ppbv, and 20 g kg(-1), respectively. During laboratory tests the average transmission efficiencies for Hg(0), HgBr2, and O3 were found to be 92%, 76%, and 93%, respectively.
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Contaminantes Atmosféricos/análisis , Bromuros/análisis , Monitoreo del Ambiente/instrumentación , Compuestos de Mercurio/análisis , Mercurio/análisis , Monitoreo del Ambiente/métodos , Diseño de Equipo , Nevada , Oxidación-Reducción , Ozono/análisis , Agua/análisisRESUMEN
PURPOSE: Lower extremity alignment is an important consideration prior to cartilage surgery and/or osteotomy about the knee. This is measured on full length standing hip to ankle radiographs, which has traditionally been done using hard copy radiographs. However, the advent of PACS (Picture Archiving and Communication Systems) has allowed these measurements to be done on computer based digital radiographs. The objectives of this study were to evaluate the intra- and inter-observer reliability of lower limb alignment measures manually obtained from hard copy radiographs versus using the Philips Easy Vision system, and to assess the subjective ease of use for the two methods. METHODS: Forty-two patients who underwent surgery and who had a standing hip to ankle radiograph on file were identified. Four raters, including two radiologists and two orthopaedic surgeons, measured each hard copy radiograph and computer image on two separate occasions. Three measurements were recorded for each hard copy radiograph and computer image-width of tibial plateau, the distance from the medial aspect of the tibial plateau to the weight-bearing line, and the mechanical axis. RESULTS: All correlations for this study were high. For tibial plateau data, the hard copy radiographs compared to PACS demonstrated intra-class correlation coefficients (ICC) ranging from 0.93 to 0.99 for inter-rater reliability for the four raters. The ICC for intra-rater reliability for hard copies ranged from 0.90 to 0.99 and for PACS from 0.94 to 0.99. The inter-rater data comparing raters ranged from 0.87 to 0.98 for hard copy radiographs and from 0.98 to 0.99 for PACS. For mechanical axis data, the ICC for hard copy radiograph compared to PACS ranged from 0.93 to 0.97 for the intra-rater reliability for the four raters. The intra-rater reliability for mechanical axis data on hard copy radiograph ranged from an ICC of 0.86 to 0.96, and for PACS the ICC ranged from 0.93 to 0.99. The inter-observer data for hard copy radiographs using the mechanical axis ranged from 0.88 to 0.94 and for PACS ranged from 0.93 to 0.97. The physicians rated PACS as statistically significantly easier to use when compared to hard copy (P = 0.03). CONCLUSION: Evaluation of lower extremity alignment using two techniques prior to knee surgery was found to have higher inter- and intra-observer reliability using PACS software. PACS is now used prior to cartilage surgery and/or osteotomy to measure both alignment and the location of the weight bearing line on the tibial plateau both before and after surgery. LEVEL OF EVIDENCE: Diagnostic study, Level I.
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Articulación del Tobillo/diagnóstico por imagen , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Rodilla/diagnóstico por imagen , Sistemas de Información Radiológica , Tibia/diagnóstico por imagen , Articulación del Tobillo/anatomía & histología , Femenino , Articulación de la Cadera/anatomía & histología , Humanos , Articulación de la Rodilla/anatomía & histología , Variaciones Dependientes del Observador , Radiografía , Reproducibilidad de los Resultados , Tibia/anatomía & histologíaRESUMEN
The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin-Sca-1+) and more committed (Lin-Sca-1-) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin-Sca-1+, but not Lin-Sca-1- or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G-CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.
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Factores de Crecimiento de Célula Hematopoyética/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Interleucina-11/farmacología , Interleucina-12/farmacología , Proteínas Proto-Oncogénicas/farmacología , Proteínas Tirosina Quinasas Receptoras/farmacología , Animales , Sinergismo Farmacológico , Interleucina-6/farmacología , Ratones , Ratones Endogámicos C57BL , Quimera por Radiación , Ratas , Proteínas Recombinantes de Fusión/farmacología , Factor de Células Madre , Tirosina Quinasa 3 Similar a fmsRESUMEN
Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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Antígenos CD , Células Dendríticas/efectos de los fármacos , Lectinas Tipo C , Proteínas de la Membrana/farmacología , Animales , Presentación de Antígeno , Antígenos CD8/análisis , Femenino , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Antígenos de Histocompatibilidad Clase II , Integrina alfaXbeta2/análisis , Interleucina-4/farmacología , Activación de Linfocitos , Complejo Mayor de Histocompatibilidad , Glicoproteínas de Membrana/análisis , Ratones , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor , Receptores de Superficie Celular/análisis , Bazo/citología , Bazo/inmunología , Factor de Células Madre/farmacología , Linfocitos T/inmunología , Distribución TisularRESUMEN
IL-4, a pleiotropic cytokine produced by T lymphocytes, plays an important role in immune responsiveness by regulating proliferation and differentiation of a variety of lymphoid and myeloid cells via binding to high affinity receptors. In this report we describe the isolation and functional expression of a human IL-4-R cDNA. When transfected into COS-7 cells, the cDNA encodes a 140-kD cell-surface protein. After transfection into a murine T cell line, the cDNA encodes a protein that binds human IL-4 with high affinity and can confer responsiveness to human IL-4. The predicted extracellular domain of the IL-4-R exhibits significant amino acid sequence homology with the beta subunit of the IL-2-R (p75), and the receptors for IL-6, erythropoietin, and prolactin. These receptors comprise a novel superfamily with extracellular domains characterized by four conserved cysteine residues and a double tryptophan-serine (WSXWS) motif located proximal to the transmembrane region.
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Interleucina-4/metabolismo , Receptores Mitogénicos/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN/análisis , Humanos , Interleucina-4/farmacología , Ratones , Datos de Secuencia Molecular , ARN Mensajero/análisis , Receptores de Interleucina-4 , Receptores Mitogénicos/análisis , Transducción de SeñalRESUMEN
SUMMARY: Recent evidence has linked long-term bisphosphonate use with insufficiency fractures of the femur in postmenopausal women. In this case-control study, we have identified a significant association between a unique fracture of the femoral shaft, a transverse fracture in an area of thickened cortices, and long-term bisphosphonate use. Further studies are warranted. INTRODUCTION: Although clinical trials confirm the anti-fracture efficacy of bisphosphonates over 3-5 years, the long-term effects of bisphosphonate use on bone metabolism are unknown. Femoral insufficiency fractures in patients on prolonged treatment have been reported. METHODS: We performed a retrospective case-control study of postmenopausal women who presented with low-energy femoral fractures from 2000 to 2007. Forty-one subtrochanteric and femoral shaft fracture cases were identified and matched by age, race, and body mass index to one intertrochanteric and femoral neck fracture each. RESULTS: Bisphosphonate use was observed in 15 of the 41 subtrochanteric/shaft cases, compared to nine of the 82 intertrochanteric/femoral neck controls (Mantel-Haenszel odds ratio (OR), 4.44 [95% confidence interval (CI) 1.77-11.35]; P = 0.002). A common X-ray pattern was identified in ten of the 15 subtrochanteric/shaft cases on a bisphosphonate. This X-ray pattern was highly associated with bisphosphonate use (OR, 15.33 [95% CI 3.06-76.90]; P < 0.001). Duration of bisphosphonate use was longer in subtrochanteric/shaft cases compared to both hip fracture controls groups (P = 0.001). CONCLUSIONS: We found a significantly greater proportion of patients with subtrochanteric/shaft fractures to be on long-term bisphosphonates than intertrochanteric/femoral neck fractures. Bisphosphonate use was highly associated with a unique X-ray pattern. Further studies are warranted.
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Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Fracturas del Fémur/inducido químicamente , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Conservadores de la Densidad Ósea/administración & dosificación , Estudios de Casos y Controles , Difosfonatos/administración & dosificación , Esquema de Medicación , Femenino , Fracturas del Fémur/diagnóstico por imagen , Fracturas del Fémur/etiología , Fracturas del Cuello Femoral/inducido químicamente , Fracturas del Cuello Femoral/etiología , Humanos , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/tratamiento farmacológico , RadiografíaRESUMEN
In vivo studies on the dynamics of the nuclear pore complex (NPC) in yeast suggested that NPCs are highly mobile in the nuclear envelope. However, new evidence indicates that in mammalian cells NPCs are stably attached to a flexible lamina framework, but a peripheral component can exchange rapidly with an intranuclear pool.
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Núcleo Celular/metabolismo , Membrana Nuclear/metabolismo , Proteínas de Complejo Poro Nuclear , Poro Nuclear/metabolismo , Transporte Activo de Núcleo Celular , Animales , Membrana Basal/química , Modelos Biológicos , Proteínas Nucleares/químicaRESUMEN
To clarify the roles of Kar2p (BiP) and Sec63p in translocation across the ER membrane in Saccharomyces cerevisiae, we have utilized mutant alleles of the essential genes that encode these proteins: kar2-203 and sec63-1. Sanders et al. (Sanders, S. L., K. M. Whitfield, J. P. Vogel, M. D. Rose, and R. W. Schekman. 1992. Cell. 69:353-365) showed that the translocation defect of the kar2-203 mutant lies in the inability of the precursor protein to complete its transit across the membrane, suggesting that the lumenal hsp70 homologue Kar2p (BiP) binds the transiting polypeptide in order to facilitate its passage through the pore. We now show that mutation of a conserved residue (A181-->T) (Nelson, M. K., T. Kurihara, and P. Silver. 1993. Genetics. 134:159-173) in the lumenal DnaJ box of Sec63p (sec63-1) results in an in vitro phenotype that mimics the precursor stalling defect of kar2-203. We demonstrate by several criteria that this phenotype results specifically from a defect in the lumenal interaction between Sec63p and BiP: Neither a sec62-1 mutant nor a mutation in the cytosolically exposed domain of Sec63p causes precursor stalling, and interaction of the sec63-1 mutant with the membranebound components of the translocation apparatus is unimpaired. Additionally, dominant KAR2 suppressors of sec63-1 partially relieve the stalling defect. Thus, proper interaction between BiP and Sec63p is necessary to allow the precursor polypeptide to complete its transit across the membrane.
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Retículo Endoplásmico/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas de Choque Térmico , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Sitios de Unión , Mutación , Precursores de Proteínas/metabolismo , Señales de Clasificación de Proteína/metabolismo , Saccharomyces cerevisiae/genéticaRESUMEN
An antibody to a platelet integral membrane glycoprotein was found to cross-react with the previously identified CD31 myelomonocytic differentiation antigen and with hec7, an endothelial cell protein that is enriched at intercellular junctions. This antibody identified a complementary DNA clone from an endothelial cell library. The 130-kilodalton translated sequence contained six extracellular immunoglobulin (Ig)-like domains and was most similar to the cell adhesion molecule (CAM) subgroup of the Ig superfamily. This is the only known member of the CAM family on platelets. Its cell surface distribution suggests participation in cellular recognition events.
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Antígenos de Diferenciación Mielomonocítica/genética , Moléculas de Adhesión Celular/genética , Clonación Molecular , Genes de Inmunoglobulinas , Secuencia de Aminoácidos , Anticuerpos Monoclonales , ADN/análisis , Endotelio Vascular/análisis , Endotelio Vascular/inmunología , Epítopos/inmunología , Humanos , Immunoblotting , Inmunoglobulinas , Técnicas de Inmunoadsorción , Datos de Secuencia Molecular , Molécula-1 de Adhesión Celular Endotelial de Plaqueta , Glicoproteínas de Membrana Plaquetaria/inmunología , Conformación Proteica , Secuencias Repetitivas de Ácidos Nucleicos , Homología de Secuencia de Ácido Nucleico , Transducción de SeñalRESUMEN
Gender differences in hip and core strength and range of motion may contribute to the gender based variance in injury risk. This study was designed to test the primary hypothesis that hip and core strength, flexibility and lower extremity dynamic alignment differ in male and female soccer athletes. Ninety-eight collegiate soccer players (54 male, 44 female) participated in this study. Athletes were evaluated for hip range of motion, and hip and abdominal strength. Both male and female soccer players demonstrated limited hip rotation, with less hip internal rotation in males (p<0.0001), and poor abdominal core control, although the males are stronger (p=0.02). Overall hip ROM is shifted towards internal rotation in females compared to males. Female soccer players also have a significant side-to-side disparity in hip abductor strength (p<0.0001), not present in males. The shift in hip ROM towards internal rotation combined with the hip abductor imbalance may be associated with a position of ACL risk with internally rotated hips and valgus knees in female soccer players. Limitations in hip and core strength and range of motion may play a role in the disparity between the male and female rate of ACL injury.
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Músculos Abdominales/fisiología , Articulación de la Cadera/fisiología , Rango del Movimiento Articular/fisiología , Fútbol/fisiología , Adolescente , Lesiones del Ligamento Cruzado Anterior , Femenino , Humanos , Articulación de la Rodilla/fisiología , Masculino , Riesgo , Rotación , Factores Sexuales , Adulto JovenRESUMEN
The amino acid sequences of several, recently cloned cytokine receptors show significant homologies, primarily in their extracellular, ligand-binding domains. With one exception, their cognate cytokines mediate biological activities on a variety of hematopoietic cell types; thus we have designated the receptors as the hematopoietic receptor superfamily.
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Factores Biológicos/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/metabolismo , Secuencia de Aminoácidos , Animales , Citocinas , Humanos , Datos de Secuencia Molecular , Conformación Proteica , Receptores de Superficie Celular/clasificación , Receptores Inmunológicos/clasificación , Homología de Secuencia de Ácido NucleicoRESUMEN
AIMS: The outcomes of total knee arthroplasty (TKA) depend on many factors. The impact of implant design on patient-reported outcomes is unknown. Our goal was to evaluate the patient-reported outcomes and satisfaction after primary TKA in patients with osteoarthritis undergoing primary TKA using five different brands of posterior-stabilized implant. PATIENTS AND METHODS: Using our institutional registry, we identified 4135 patients who underwent TKA using one of the five most common brands of implant. These included Biomet Vanguard (Zimmer Biomet, Warsaw, Indiana) in 211 patients, DePuy/Johnson & Johnson Sigma (DePuy Synthes, Raynham, Massachusetts) in 222, Exactech Optetrak Logic (Exactech, Gainesville, Florida) in 1508, Smith & Nephew Genesis II (Smith & Nephew, London, United Kingdom) in 1415, and Zimmer NexGen (Zimmer Biomet) in 779 patients. Patients were evaluated preoperatively using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Lower Extremity Activity Scale (LEAS), and 12-Item Short-Form Health Survey questionnaire (SF-12). Demographics including age, body mass index, Charlson Comorbidity Index, American Society of Anethesiologists status, sex, and smoking status were collected. Postoperatively, two-year KOOS, LEAS, SF-12, and satisfaction scores were compared between groups. RESULTS: Outcomes were available for 4069 patients (98%) at two years postoperatively. In multiple regression analysis, which separately compared each implant group with the aggregate of all others, there were no clinically significant differences in the change of KOOS score from baseline to two-year follow-up between any of the groups. More than 80% of patients in each group were satisfied at this time in all domains. In a multivariate regression model, patients in the NexGen group were the most likely to be satisfied (odds ratio (OR) 1.63; p = 0.006) and Optetrak Logic patients were the least likely to be satisfied (OR 0.60; p < 0.001). CONCLUSION: TKA provides improvement in function and satisfaction regardless of the type of implant. We could not demonstrate superiority of one design above others across these groups of implants, and any price premium for one above the other systems may not be justified. Healthcare administrators may find these similarities in outcomes helpful when negotiating purchasing contracts. Cite this article: Bone Joint J 2019;101-B(7 Supple C):48-54.
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Artroplastia de Reemplazo de Rodilla/métodos , Articulación de la Rodilla/cirugía , Prótesis de la Rodilla , Osteoartritis de la Rodilla/cirugía , Medición de Resultados Informados por el Paciente , Rango del Movimiento Articular/fisiología , Recuperación de la Función/fisiología , Anciano , Femenino , Estudios de Seguimiento , Humanos , Articulación de la Rodilla/fisiopatología , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/fisiopatología , Diseño de Prótesis , Sistema de Registros , Estudios Retrospectivos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: Custom flange acetabular components (CFACs) are a patient-specific option for addressing large acetabular defects at revision total hip arthroplasty (THA), but patient and implant characteristics that affect survivorship remain unknown. This study aimed to identify patient and design factors related to survivorship. PATIENTS AND METHODS: A retrospective review of 91 patients who underwent revision THA using 96 CFACs was undertaken, comparing features between radiologically failed and successful cases. Patient characteristics (demographic, clinical, and radiological) and implant features (design characteristics and intraoperative features) were collected. There were 74 women and 22 men; their mean age was 62 years (31 to 85). The mean follow-up was 24.9 months (sd 27.6; 0 to 116). Two sets of statistical analyses were performed: 1) univariate analyses (Pearson's chi-squared and independent-samples Student's t-tests) for each feature; and 2) bivariable logistic regressions using features identified from a random forest analysis. RESULTS: Radiological failure and revision rates were 23% and 12.5%, respectively. Revisions were undertaken at a mean of 25.1 months (sd 26.4) postoperatively. Patients with radiological failure were younger at the time of the initial procedure, were less likely to have a diagnosis of primary osteoarthritis (OA), were more likely to have had ischial screws in previous surgery, had fewer ischial screw holes in their CFAC design, and had more proximal ischial fixation. Random forest analysis identified the age of the patient and the number of locking and non-locking screws used for inclusion in subsequent bivariable logistic regression, but only age (odds ratio 0.93 per year) was found to be significant. CONCLUSION: We identified both patient and design features predictive of CFAC survivorship. We found a higher rate of failure in younger patients, those whose primary diagnosis was not OA, and those with more proximal ischial fixation or fewer ischial fixation options. Cite this article: Bone Joint J 2019;101-B(6 Supple B):68-76.
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Acetábulo/cirugía , Artroplastia de Reemplazo de Cadera/métodos , Acetábulo/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Cadera/instrumentación , Tornillos Óseos , Femenino , Prótesis de Cadera , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/diagnóstico por imagen , Osteoartritis de la Cadera/cirugía , Diseño de Prótesis , Falla de Prótesis , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
The platelet fibrinogen receptor is composed of a complex of glycoproteins (GP) IIb and IIIa on the surface of platelets. Deficient function of this receptor prevents normal platelet aggregation, resulting in Glanzmann's thrombasthenia (GT). In this paper, we describe a black thrombasthenic patient who is either homozygous or hemizygous for a deletion within the GPIIb gene. Initial Western blot analysis of platelet proteins from this patient did not detect any GPIIb, but did detect small amounts of GPIIIa of normal mobility. Quantitation of vitronectin receptor (VNR) demonstrated that this thrombasthenic patient had approximately 1.5-2 times the number of these receptors per platelet compared with controls, a finding that has previously been noted in other thrombasthenic patients with defects in GPIIb. Genomic Southern blot studies demonstrated a deletion in the GPIIb gene of approximately 4.5 kilobasepairs (kb). Analysis of the isolated GPIIb gene demonstrated that the deletion begins between two Alu repeats within intron 1 and ends in intron 9. Polymerase chain reaction (PCR) studies using platelet RNA and oligonucleotides directed to both the 5' and 3' ends of the GPIIb cDNA sequence easily detected GPIIb transcript, suggesting that the genomic deletion of exons 2-9 does not significantly decrease the level of the GPIIb mRNA. Sequence analysis of PCR-generated GPIIb cDNA showed that a cryptic AG splice acceptor sequence was being utilized, resulting in a transcript that contained a portion of introns 1 and 9, as well as having a deletion of exons 2-9. Unlike the GPIIb gene, the GPIIIa gene appears to be intact by Southern blot analysis. PCR studies using platelet RNA and oligonucleotides directed to the GPIIIa cDNA sequence demonstrated the presence of GPIIIa mRNA. In summary, the thrombasthenic state in this patient appears to be due to a GPIIb gene deletion resulting in an abnormal transcript and no detectable platelet GPIIb. Platelet GPIIIa levels were secondarily low presumably due to the known instability of GPIIIa in the absence of GPIIb.
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Deleción Cromosómica , Glicoproteínas de Membrana Plaquetaria/genética , Trombastenia/genética , Adolescente , Secuencia de Bases , Plaquetas/química , Southern Blotting , Humanos , Immunoblotting , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Receptores Inmunológicos/análisis , Receptores de VitronectinaRESUMEN
The growth of human leukemic cells in culture and in vivo is dependent upon the presence of hematopoietic growth factors. Most populations of human leukemic acute myeloblastic leukemia (AML) cells express c-Kit on their surface and respond to Kit ligand (KL) in culture. To determine if this interaction was of potential significance in vivo we used a mouse model system. 32D cells, a murine IL-3-dependent myeloid cell line, were rendered KL responsive by transfection of the murine c-Kit. After injection of 32D or 32D-Kit cells into syngeneic hosts, animals bearing 32D-Kit cells, but not 32D cells, became moribund and were killed. These animals had circulating leukemic blast cells, infiltration of bone marrow, spleen, brain, liver, lung, and kidney. Cells recovered from some of the animals continued to be dependent upon IL-3 or KL for growth while in other cases the cells were factor independent. This model illustrates that the constitutive expression of c-Kit enhances the leukemic potential of 32D cells. The model will be useful for studying the progression of leukemia in vivo and testing whether interruption of the interaction of Kit and KL can affect the growth of leukemic cells.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia Experimental/genética , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes , Proteínas Tirosina Quinasas Receptoras/genética , Receptores del Factor Estimulante de Colonias/genética , Secuencia de Aminoácidos , Animales , Células de la Médula Ósea , División Celular , Células Cultivadas , Factores de Crecimiento de Célula Hematopoyética/fisiología , Técnicas In Vitro , Leucemia Experimental/patología , Ratones , Ratones Endogámicos C3H , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-kit , ARN Mensajero/genética , Factor de Células Madre , TransfecciónRESUMEN
To gain insight into region of the platelet GPIIb-IIIa complex involved in receptor biogenesis and function, we examined the biochemical properties of a defective GPIIb-IIIa complex from patient suffering from type II Glanzmann thrombasthenia. Flow cytometric as well as immunoblot analysis of patient platelets showed significantly reduced levels of GPIIb and GPIIIa compared with a normal control. Patient platelets, however, retained the ability to retract a fibrin clot. Sequence analysis of PCR-amplified platelet GPIIb mRNA revealed an Arg327-->His amino acid substitution between the second and third calcium-binding domains of the GPIIb heavy chain, a residue that is highly conserved among integrin alpha-subunits. The recombinant His327 form of GPIIb was found to be fully capable of associating with GPIIIa, therefore the role of the calcium-binding domains in intersubunit association was further examined by constructing amino-terminal segments of GPIIb that ended before the first, second, and third calcium-binding domains. All three fragments were found to associate with GPIIIa, demonstrating that the calcium-binding domains of GPIIb are not necessary for initial complex formation. Regions amino-terminal to the calcium-binding domains of GPIIb may play a heretofore unappreciated role in integrin subunit association.
Asunto(s)
Calcio/metabolismo , Fibrinógeno/metabolismo , Mutación , Glicoproteínas de Membrana Plaquetaria/genética , Trombastenia/genética , Adolescente , Secuencia de Aminoácidos , Secuencia de Bases , Plaquetas/fisiología , Femenino , Citometría de Flujo , Humanos , Integrinas/metabolismo , Datos de Secuencia Molecular , Procesamiento Proteico-Postraduccional , Relación Estructura-ActividadRESUMEN
The Susan McDonough strain of feline sarcoma virus contains an oncogene, v-fms, which is capable of transforming fibroblasts in vitro. The mature protein product of the v-fms gene (gp140fms) is found on the surface of transformed cells; this glycoprotein has external, transmembrane, and cytoplasmic domains. To assess the functional role of these domains in transformation, we constructed a series of nine linker insertion mutations throughout the v-fms gene by using a dodecameric BamHI linker. The biological effects of these mutations on the function and intracellular localization of v-fms-encoded proteins were determined by transfecting the mutated DNA into Rat-2 cells. Most of the mutations within the external domain of the v-fms-encoded protein eliminated focus formation on Rat-2 cells; three of these mutations interfered with the glycosylation of the v-fms protein and interfered with formation of the mature gp140fms. One mutation in the external domain led to cell surface expression of v-fms protein even in the absence of complete glycosylational processing. Cell surface expression of mutated v-fms protein is probably necessary, but is not sufficient, for cell transformation since mutant v-fms protein was found on the surface of several nontransformed cell lines. Mutations that were introduced within the external domain had little effect on in vitro kinase activity, whereas mutations within the cytoplasmic domain all had strong inhibitory effects on this activity.
Asunto(s)
Transformación Celular Viral , Proteínas Oncogénicas Virales/genética , Oncogenes , Proteínas Tirosina Quinasas/genética , Retroviridae/genética , Virus del Sarcoma Felino/genética , Compartimento Celular , Técnica del Anticuerpo Fluorescente , Mutación , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.