RESUMEN
A high-throughput fragment-based screen has been employed to discover a series of quinazolinone inositol hexakisphosphate kinase (IP6K) inhibitors. IP6Ks have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, blood coagulation, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to form pyrophosphate 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7). Molecular docking studies and investigation of structure-activity relationships around the quinazolinone core resulted in compounds with submicromolar potency and interesting selectivity for IP6K1 versus the closely related IP6K2 and IP6K3 isoforms.
RESUMEN
Biophysical affinity screening is increasingly being adopted as a high-throughput hit finding technique in drug discovery. Automation is highly beneficial to high-throughput screening (HTS) since a large number of compounds need to be reproducibly tested against a biological target. Herein, we describe how we have automated two biophysical affinity screening methods that rely on a thermal shift in protein melting temperature upon small molecule binding: differential scanning fluorimetry (DSF) and the cellular thermal shift assay (CETSA).
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Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento/métodos , Descubrimiento de Drogas/métodos , Proteínas/metabolismo , Temperatura , Fluorometría/métodosRESUMEN
Challenged by ageing infrastructure and increasingly demanding screening cascades, AstraZeneca High Throughput Screening department has developed advanced automation systems that can support both current needs and future strategies in drug discovery. Through collaboration with HighRes Biosolutions and other third-party vendors, highly versatile automated modular platforms have been designed. Safety features such as collaborative robots allow enhanced system accessibility, and adaptive scheduling software has improved protocol design and system recovery. These innovations have led to significant improvements in system flexibility while maintaining screening productivity.
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Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Automatización/métodos , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Programas InformáticosRESUMEN
The Anti- Wolbachia (A·WOL) consortium at the Liverpool School of Tropical Medicine (LSTM) has partnered with the Global High-Throughput Screening (HTS) Centre at AstraZeneca to create the first anthelmintic HTS for neglected tropical diseases (NTDs). The A·WOL consortium aims to identify novel macrofilaricidal drugs targeting the essential bacterial symbiont ( Wolbachia) of the filarial nematodes causing onchocerciasis and lymphatic filariasis. Working in collaboration, we have validated a robust high-throughput assay capable of identifying compounds that selectively kill Wolbachia over the host insect cell. We describe the development and validation process of this complex, phenotypic high-throughput assay and provide an overview of the primary outputs from screening the AstraZeneca library of 1.3 million compounds.
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Antibacterianos/farmacología , Ensayos Analíticos de Alto Rendimiento , Interacciones Huésped-Patógeno/efectos de los fármacos , Wolbachia/efectos de los fármacos , Antibacterianos/química , Técnicas de Cultivo de Célula/métodos , Descubrimiento de Drogas , Filariasis Linfática/tratamiento farmacológico , Humanos , Citometría de Imagen , Oncocercosis/tratamiento farmacológico , Wolbachia/patogenicidad , Wolbachia/ultraestructuraRESUMEN
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca's 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (AâWOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.
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Descubrimiento de Drogas , Filaricidas/análisis , Ensayos Analíticos de Alto Rendimiento , Aedes , Animales , Línea Celular , WolbachiaRESUMEN
The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.
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Adenosina Trifosfato/metabolismo , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Piridinas/uso terapéutico , Quinina/análogos & derivados , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacología , Éteres/química , Éteres/farmacocinética , Éteres/farmacología , Éteres/uso terapéutico , Humanos , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacología , Quinina/química , Quinina/farmacocinética , Quinina/farmacología , Quinina/uso terapéutico , Tuberculosis/metabolismoRESUMEN
MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently in colorectal cancer, where their function and pathobiological importance have been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant-negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain tumorigenic phenotypes, we reconstituted its signaling axis in colon cancer cells harboring MLK4-inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3, and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor-suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.
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Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Animales , Carcinogénesis , Neoplasias del Colon/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chloride, bromide and iodide are inhibitors of the copper-catalysed azide-alkyne cycloaddition, with iodide exhibiting the most detrimental effects on rates and yields. A study of this inhibition is presented, along with experimental protocols to accommodate the presence of halides in this widely used reaction.
RESUMEN
Knee wear is commonly measured with the most recent radiograph based on the assumption that wear progresses at a constant rate. Changing patient activity or in vivo polyethylene deterioration are examples of factors that could cause wear rates to change over time. Using six or more radiographs on each of 251 knees over a mean 10-year follow-up, we determined the pattern of polyethylene wear. 92% of knees had linear wear with a mean wear rate of 0.09 ± 0.12 mm/yr. Ten knees (4%) had late accelerated wear. Knees with accelerated wear and those with a wear rate of 0.15 mm/yr or greater had lower survivorship rates. We conclude that wear is linear with rare exceptions and that higher wear is correlated with failure.
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Artroplastia de Reemplazo de Rodilla , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/cirugía , Prótesis de la Rodilla , Falla de Prótesis , Radiografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Interpretación Estadística de Datos , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/cirugía , Polietileno , Valor Predictivo de las Pruebas , Prevalencia , Estudios RetrospectivosRESUMEN
Sceloporus bicanthalis is a viviparous lizard that lives at higher elevations in Mexico. Adult male S. bicanthalis were collected (n = 36) from the Nevado de Toluca, Mexico (elevation is 4200 m) during August to December, 2007 and January to July, 2008. Testes were extracted, fixed in Trumps, and dehydrated in a graded series of ethanol. Tissues were embedded, sectioned (2 µm), stained, and examined via a light microscope to determine the spermatogenic developmental strategy of S. bicanthalis. In all months examined, the testes were spermiogenically active; based on this, plus the presence of sperm in the lumina of seminiferous tubules, we inferred that S. bicanthalis had year-round or continuous spermatogenesis, unlike most reptiles that occupy a temperate or montane habitat. It was recently reported that seasonally breeding reptiles had a temporal germ cell development strategy similar to amphibians, where germ cells progress through spermatogenesis as a single population, which leads to a single spermiation event. This was much different than spatial development within the testis of other derived amniotes. We hypothesized that germ cell development was temporal in S. bicanthalis. Therefore, we wanted to determine whether reptiles that practice continuous spermatogenesis have a mammalian-like spatial germ cell development, which is different than the typical temperate reptile exhibiting a temporal development. In the present study, S. bicanthalis had a temporal development strategy, despite its continuous spermatogenic cycle, making them similar to tropical anoles.
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Lagartos/fisiología , Espermatogénesis/fisiología , Espermatozoides/crecimiento & desarrollo , Animales , Clima , Ecosistema , Masculino , Estaciones del AñoRESUMEN
This study shows that honeydew prompts arrestment and reduced activity, but not attraction, by the mite Balaustium sp. nr. putmani. When presented with short-range, two-choice bioassays, mites ceased their characteristic rapid crawling activity when they encountered honeydew-treated surfaces, resulting in them clustering around the honeydew. Approximately 80% of mites were retained by honeydew, with responses being independent of both mite life-history stage and source of honeydew (coccid scale insect or aphid). No obvious crawling movements or redirection of running path were made to the honeydew by the mites, implying the lack of any kind of attractant. Response of mites to single-sugar presentations of the main honeydew components--glucose, sucrose, fructose and trehalose--(0.001-0.1 mmol l(-1)) were inconsistent and failed to reproduce the arrestment/clustering associated with raw honeydew, suggesting that none of these sugars is an active arrestant ingredient. Formation of feeding clusters on honeydew does not contribute to enhancing water conservation by suppressing net transpiration (water loss) rates of individual mites as group size increases, indicating that the clustering is an artifact of arrestment. We hypothesize that release of neryl formate by the mites reduces negative interactions with the local ant species commonly associated with honeydew. We hypothesize that honeydew serves as: (1) a cue that facilitates discovery of scale/aphid prey; (2) a retainer on plants where these prey are present, signaling abundance and quality; and (3) an alternative and supplemental food source like that noted for other plant-inhabiting predatory mites. Neryl formate serves as an alarm pheromone and foul-tasting allomonal defense secretion that prevents predation of mites by ants that co-exist with aphid/scale insects in these honeydew-rich habitats.
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Hormigas/efectos de los fármacos , Hormigas/fisiología , Áfidos/fisiología , Ecosistema , Miel , Ácaros/fisiología , Feromonas/farmacología , Conducta Predatoria/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Animales , Áfidos/efectos de los fármacos , Conducta Apetitiva/efectos de los fármacos , Bioensayo , Femenino , Larva/efectos de los fármacos , Larva/fisiología , Masculino , Ácaros/efectos de los fármacos , Modelos Biológicos , AguaRESUMEN
Cottonmouth (Agkistrodon piscivorus leucostoma) testes were examined histologically to determine the germ cell development strategy employed during spermatogenesis. Testicular tissues from Cottonmouths were collected monthly from swamps around Hammond, Louisiana. Pieces of testis were fixed in Trump's fixative, dehydrated in ethanol, embedded in Spurr's plastic, sectioned with an ultramicrotome, and stained with toluidine blue and basic fuchsin. Spermatogenesis within Cottonmouths occurs in two independent events within a single calendar year. The testes are active during the months of March-June and August-October with spermiation most heavily observed during April-May and October. To our knowledge, this is the first study that describes bimodal spermatogenesis occurring in the same year within the subfamily Crotalinae. During spermatogenesis, no consistent spatial relationships are observed between germ cell generations. Typically, either certain cell types were missing (spermatocytes) or the layering of 3-5 spermatids and/or spermatocytes within the same cross-section of seminiferous tubule prevented consistent spatial stages from occurring. This temporal pattern of sperm development is different from the spatial development found within birds and mammals, being more reminiscent of that seen in amphibians, and has now been documented within every major clade of reptile (Chelonia, Serpentes, Sauria, Crocodylia). This primitive-like sperm development, within a testis structurally similar to mammals and birds, may represent an intermediate testicular model within the basally positioned (phylogenetically) reptiles that may be evolutionarily significant.
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Agkistrodon/anatomía & histología , Agkistrodon/crecimiento & desarrollo , Espermatogénesis/fisiología , Testículo/citología , Envejecimiento , Análisis de Varianza , Animales , Ecosistema , Louisiana , Masculino , Estaciones del Año , Células de Sertoli/citología , Células de Sertoli/fisiología , Espermatozoides/citología , Espermatozoides/fisiología , Testículo/crecimiento & desarrollo , Testículo/fisiología , Testosterona/sangreRESUMEN
UNLABELLED: The valgus, osteoarthritic knee is challenging technically and it is unknown whether and how technical and implant variables influence outcomes. We therefore determined the influence of surgical technique of soft tissue balancing and patient and implant factors from 100 unselected cruciate-retaining TKAs for valgus osteoarthritis in patients younger than 75 years of age. From 1987 to 1990, lateral soft tissue balancing was done with an outside-in progression in which the lateral collateral ligament and popliteus were typically released from the femur. From 1991 to 1994, an inside-out technique was use in which the lateral collateral ligament and/or popliteus were typically preserved. The minimum followup was 0.1 year (mean, 8.2 years; range, 0.1-18.2 years). Fourteen of 16 revisions were for wear and/or instability. Popliteus release, lateral collateral ligament release, or greater polyethylene shelf age increased the risk of revision. At 10 postoperative years, survival (end point, revision) was 89% (100 knees), 94% when the shelf age was less than 1 year (n = 73 knees), 97% when the popliteus or lateral collateral ligament was not released (n = 57 knees), and 100% when both conditions were met (n = 39 knees). Cruciate-retaining implants can be successfully used in knees with any degree of valgus osteoarthritis and survival is improved when the surgeon preserves at least one of the structures providing lateral stability in flexion and uses polyethylene with a short shelf life. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
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Artroplastia de Reemplazo de Rodilla/métodos , Inestabilidad de la Articulación/prevención & control , Osteoartritis de la Rodilla/cirugía , Ligamento Cruzado Posterior/cirugía , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Archived serial radiographs of knee replacements provide indirect evidence of the clinical performance of ultra-high molecular weight polyethylene tibial bearings. Our purpose was to determine the loss of thickness in polyethylene tibial inserts that were of the same design but had been sterilized differently. METHODS: Four hundred and sixteen knees with an Anatomic Modular Knee primary total knee replacement had five to eighteen years of follow-up and a posterior cruciate ligament-retaining polyethylene tibial insert that had been sterilized with either gamma radiation in air (from 1987 to 1993) or gamma radiation in an inert gas (from 1993 to 1995), or by means of a nonirradiation gas-plasma method (from 1995 to 2001). Readings were taken from 1975 weight-bearing anteroposterior radiographs of the knee on which the top surface of the metal tibial tray had nearly projected as a line. In each tibiofemoral compartment, loss of polyethylene thickness was calculated as the standard thickness of the insert minus the measured magnification-corrected thickness. For each sterilization method, thickness loss was plotted versus the corresponding follow-up time, and a mixed linear regression model was used to quantify the change in thickness over time. Multiple linear regression analysis was used to determine whether loss of thickness was associated with implant factors, patient variables, and early postoperative limb alignment. RESULTS: According to the mixed model regression coefficients, loss of medial compartment thickness was greatest for inserts that had been sterilized with gamma radiation in air (0.15 mm/yr), least for those sterilized with gamma radiation in an inert gas (0.02 mm/yr), and of an intermediate magnitude for those sterilized with a nonirradiation method (0.06 mm/year); loss of lateral compartment thickness ranged from 0.03 to 0.06 mm/yr. Notably, no insert irradiated in an inert gas showed a loss of thickness of >1 mm, and no nonirradiated insert showed a loss of >2 mm. Loss of medial compartment thickness in inserts sterilized with radiation in air increased significantly with a greater polyethylene shelf age, lesser patient age, and more varus alignment of the limb in the early postoperative period (p < 0.01). CONCLUSIONS: In this total knee design, tibial polyethylene performance improved markedly after discontinuation of the gamma radiation in air sterilization technique. Future concerns are that bearings sterilized with radiation in an inert gas may oxidize in vivo and develop fatigue wear because of free radicals generated during sterilization with radiation and that nonirradiated bearings may undergo greater losses in thickness from routine burnishing since they lack the cross-linking that accompanies sterilization with radiation.
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Artroplastia de Reemplazo de Rodilla , Materiales Biocompatibles , Prótesis Articulares , Articulación de la Rodilla/diagnóstico por imagen , Polietileno , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/cirugía , Falla de Prótesis , Radiografía , EsterilizaciónRESUMEN
UNLABELLED: Many surgeons have sought to avoid valgus postoperative limb alignment when performing medial unicondylar arthroplasty under concern that such posture accelerates lateral tibiofemoral compartment joint space narrowing. To test whether postoperative limb alignment was associated with lateral compartment narrowing, we measured the lateral compartment joint space width from the most recent single-leg erect anteroposterior radiograph and similarly-obtained early postoperative radiographs of 113 medial unicompartmental arthroplasties (eight designs, 91 patients) that had a minimum of 10 years (range 10-19 years) clinical followup. The mean (+/- standard deviation) narrowing was 0.03 +/- 0.13 mm per year (< 0.10 mm per year, 89 knees) or 7% +/- 30% (< 25%, 90 knees). Narrowing increased with more valgus (less varus) of the early postoperative hip-knee-ankle angle. However, the effect of alignment was small (narrowing increased by 0.01 mm per year per each 1 degree) and it was not linked with an outcome of 25% or greater, 50% or greater, or 75% or greater narrowing. In summary, narrowing increased slightly with more valgus (less varus) early postoperative limb alignment, but limb alignment was a poor predictor of which knees would develop more complete joint space thinning. LEVEL OF EVIDENCE: Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
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Artroplastia de Reemplazo de Rodilla/métodos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/cirugía , Osteoartritis de la Rodilla/cirugía , Complicaciones Posoperatorias/diagnóstico por imagen , Anciano , Artroplastia de Reemplazo de Rodilla/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/epidemiología , Complicaciones Posoperatorias/epidemiología , Postura , Valor Predictivo de las Pruebas , Radiografía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Wear of the polyethylene tibial bearing is a leading cause of failure of knee replacements done prior to the current decade. The objective of this study was to determine how patient-related factors, implant-related factors, and limb or tibial component alignment influenced the amount of thickness loss in polyethylene tibial bearings that were retrieved at the time of revision surgery or after the death of the patient. METHODS: We retrieved polyethylene tibial bearings from eighty-one unicondylar and eighty-nine total knee replacements that had been performed because of osteoarthritis with varus deformity from 1984 to 1998. All of the polyethylene bearings had been sterilized with gamma radiation in air. Polyethylene loss was quantified as the change in the minimum bearing thickness per years in vivo (the mean time in vivo [and standard deviation] was 8 +/- 4 years). Multiple linear regression was used to assess whether polyethylene loss was associated with age, weight, gender, varus angle of the tibial component, postoperative hip-knee-ankle angle, initial thickness of the polyethylene, shelf age of the polyethylene, and either the type of polyethylene (for total knee replacements, which were of one posterior cruciate ligament-retaining design) or the manufacturer (for unicondylar knee replacements), and to determine the magnitude by which polyethylene loss would change if any of the significant risk factors were changed. RESULTS: The mean loss (and standard deviation) of polyethylene thickness in the medial compartment of total knee replacements (0.33 +/- 0.28 mm/yr) and that in medial unicompartmental knee replacements (0.49 +/- 0.40 mm/yr) were significantly (p < 0.05) associated with the same three variables: patient age, postoperative hip-knee-ankle angle, and shelf age of the polyethylene. A total knee bearing with a one-year increase in shelf age, a unicondylar knee bearing with a six-month increase in shelf age, a patient who was ten years younger at the time of operation, or a limb that was aligned in 5 degrees more varus (less valgus) had similar effects on the loss of polyethylene thickness in the medial compartment; the coefficients of the linear regression equations indicated that any one of these changes would increase polyethylene loss by 0.11 to 0.14 mm/yr. CONCLUSIONS: The wear-related loss of thickness in gamma-irradiated-in-air polyethylene bearings from unicondylar and total knee replacements implanted in osteoarthritic knees with varus deformity is influenced mainly by the shelf age of the polyethylene, the age of the patient, and the postoperative angulation of the knee in the coronal plane. CLINICAL RELEVANCE: Although polyethylene bearings have not been sterilized with gamma radiation in air since the end of the last decade, many arthroplasty patients have polyethylene bearings that were sterilized with use of this method. An understanding of the findings of this study may be of value as these patients return for follow-up care. Whether the study findings have relevance to bearings sterilized with other methods is unclear and will remain so for many years. LEVEL OF EVIDENCE: Prognostic Level II.
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Artroplastia de Reemplazo de Rodilla , Prótesis de la Rodilla , Falla de Prótesis , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Falla de Equipo , Rayos gamma , Humanos , Persona de Mediana Edad , Osteoartritis/cirugía , Polietileno , Reoperación , TibiaRESUMEN
The goal of this report is to review reoperations undertaken on the initial 221 unicompartmental arthroplasties performed using a minimally invasive technique. A comparison was then performed between these cases and the previous 514 open medial unicompartmental arthroplasties performed at our institution. In the minimally invasive group, 9 (4.1%) of 221 knees were revised (8 for component loosening, 1 for deep infection). Of 212 unrevised knees, 16 have required a total of 18 nonrevision reoperations. Overall, 25 of 221 knees required at least 1 reoperation (total reoperation rate, 11.3%). Despite an accelerated recovery and decreased hospital stay in our minimally invasive unicompartmental arthroplasties, the rate of revision due to aseptic loosening (3.7% vs 1.0%) and the overall reoperation rate (11.3% vs 8.6%) compare unfavorably with those performed with an open technique.
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Artroplastia de Reemplazo de Rodilla/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Falla de Prótesis , Adulto , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Rodilla/métodos , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Tiempo de Internación , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/estadística & datos numéricos , Radiografía , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The investigators reviewed 245 fixed-bearing unicondylar arthroplasties that one surgeon performed as treatment of medial compartment osteoarthritis between 1988 and 1997 using a variety of cemented metal-backed tibial components and gamma-irradiated-in-air polyethylene bearings. Multivariate statistical analysis was used to evaluate how the event of revision was influenced by 3 patient factors, 3 implant factors, and 7 factors assessed from preoperative and early postoperative radiographs. Five factors were statistically associated with revision: (younger) patient age, (thinner) tibial component initial thickness, (longer) polyethylene shelf age, (lesser) angular reduction of medial tibial plateau varus, and (more varus) postoperative hip-knee-ankle angle. Besides illustrating deleterious consequences of using gamma-irradiated-in-air polyethylene in medial unicompartmental arthroplasty, our results support reducing varus angulation of the medial tibial plateau and knee at surgery.
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Artroplastia de Reemplazo de Rodilla/efectos adversos , Prótesis de la Rodilla/efectos adversos , Osteoartritis/cirugía , Polietileno/efectos adversos , Falla de Prótesis , Factores de Edad , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Rodilla/métodos , Fenómenos Biomecánicos , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Radiografía , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Tibia/anatomía & histología , Tibia/cirugíaRESUMEN
Unicondylar arthroplasty survival rates have varied widely. Implant- and patient-specific factors may be contributory. One surgeon placed 411 medial compartment arthroplasties of 12 designs from 1984 to 1998. In most cases, the fixed bearing tibial component was placed with cement and featured gamma-sterilized-in-air polyethylene and a metal backing. Tibial component initial thickness averaged 8.5 +/- 1.4 mm. Polyethylene shelf age averaged 1.3 +/- 1.2 years. Age and weight at arthroplasty averaged 67 +/- 8 years and 83 +/- 15 kg, respectively. Survival (no revision) at 9 years was 80%. Revision was more common in younger patients, in those with a thinner tibial component or longer polyethylene shelf age, and when some designs were used rather than others; weight and gender were not associated with revision. Nine-year survival improved to 94% when tibial component thickness was > 7 mm and polyethylene shelf age was < 1 year (154 knees). Per our experience, placement of a thin or shelf-aged gamma-irradiated-in-air polyethylene bearing into a young or active subject could explain most failures of unicondylar arthroplasties done in the 1980s and 1990s. Unicondylar patients of that era who were fortunate enough to avoid a thin or aged oxidation-prone polyethylene bearing probably have enjoyed superior outcomes.