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BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.
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Neoplasias de los Conductos Biliares , Neoplasias Colorrectales , Neoplasias Hepáticas , Dispositivos de Acceso Vascular , Humanos , Neoplasias Colorrectales/patología , Arteria Hepática/patología , Estudios de Factibilidad , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/secundario , Infusiones Intraarteriales , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/etiologíaRESUMEN
BACKGROUND: Guidelines now recommend universal germline genetic testing (GGT) for all pancreatic ductal adenocarcinoma (PDAC) patients. Testing provides information on actionable pathogenic variants and guides management of patients and family. Since traditional genetic counseling (GC) models are time-intensive and GC resources are sparse, new approaches are needed to comply with guidelines without overwhelming available resources. METHODS: A novel protocol was developed for physician-led GGT. Completed test kits were delivered to the GC team, who maintained a prospective database and mailed all orders. If results revealed pathogenic variants for PDAC, patients were offered comprehensive GC, whereas negative and variant of uncertain significance (VUS) test results were reported to patients via brief calls. RESULTS: During protocol implementation between January 2020 and December 2022, 310 (81.5%) patients underwent GGT, with a physician compliance rate of 82.6% and patient compliance rate of 98.7%. Of 310 patients tested, 44 (14.2%) patients had detection of pathogenic variants, while 83 (26.8%) patients had VUS. Pathogenic variants included BRCA1/BRCA2/PALB2 (n = 18, 5.8%), ATM (n = 9, 2.9%), CFTR (n = 4, 1.3%), EPCAM/MLH1/MSH2/MSH6/PMS2 (n = 3, 1.0%), and CDKN2A (n = 2, 0.7%). The GC team successfully contacted all patients with pathogenic variants to discuss results and offer comprehensive GC. CONCLUSION: Our novel protocol facilitated GGT with excellent compliance despite limited GC resources. This framework for GGT allocates GC resources to those patients who would benefit most from GC. As we continue to expand the program, we seek to implement methods to ensure compliance with cascade testing of high-risk family members.
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BACKGROUND: Dietary restraint has been linked to deficits in the ability to recall detailed memories of personally experienced events (referred to as autobiographical memory specificity). As priming with healthy foods increases the salience of restraint it would be expected to lead to greater deficits in memory specificity. OBJECTIVE: To determine if priming word cues with images of healthy or unhealthy foods would influence the specificity of memory retrieval, and if deficits in memory specificity would be more evident in those reporting higher levels of dietary restraint, or currently dieting. METHODS: Sixty female undergraduates self-reported if they were currently dieting and completed measures of mood, restraint, and disinhibition, and a modified version of the autobiographical memory task. Participants were presented with positive and negative words (unrelated to eating concerns) and asked to retrieve a specific memory in response to each cue. A food image was shown prior to each word cue; half of the participants were primed with images of healthy foods and half with images of unhealthy foods. RESULTS: As expected, participants primed with healthy foods retrieved fewer specific memories than did those primed with unhealthy foods. However, neither restraint nor current dieting behaviour was associated with memory specificity. CONCLUSIONS: Differences in memory specificity between the priming conditions cannot be explained in terms of increased salience of restraint. However, it is plausible that unhealthy images led to an increase in positive affect, which in turn improved memory specificity. LEVEL OF EVIDENCE: Level I: Evidence obtained from: at least one properly designed experimental study.
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Memoria Episódica , Humanos , Femenino , Recuerdo Mental/fisiología , Señales (Psicología) , Dieta , AfectoRESUMEN
I add support to Phillips et al.'s thesis that representations of knowledge are more basic than representations of belief through a historical account of the development of philosophical theories of knowledge and belief. On the basis of Aristotle's criticisms of his Presocratic predecessors, I argue that Western philosophy developed theories of knowledge long before it developed theories of belief.
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Conocimiento , Filosofía , HumanosRESUMEN
BACKGROUND: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. MATERIALS & METHODS: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. RESULTS: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. CONCLUSION: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Adulto , Anciano , Biomarcadores de Tumor/sangre , Neoplasias Óseas/metabolismo , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Niacinamida/uso terapéutico , Proyectos Piloto , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Estrógenos/metabolismo , Sorafenib , Tamoxifeno/uso terapéutico , Resultado del TratamientoRESUMEN
Abemaciclib was originally FDA approved for patients with ER-positive/HER2-negative breast cancer with Ki-67 expression ≥20%. However, there were no guidelines provided on which specimen to test or which scoring method to use. We performed a comprehensive study evaluating the variation in Ki-67 expression in breast specimens from 50 consecutive patients who could have been eligible for abemaciclib therapy. Three pathologists with breast expertise each performed a blinded review with 3 different manual scoring methods [estimated (EST), unweighted (UNW), and weighted (WT) (WT recommended by the International Ki-67 in Breast Cancer Working Group)]. Quantitative image analysis (QIA) using the HALO platform was also performed. Three different specimen types [core needle biopsy (CNB) (n=63), resection (RES) (n=52), and axillary lymph node metastasis (ALN) (n=50)] were evaluated for each patient. The average Ki-67 for all specimens was 14.68% for EST, 14.46% for UNW, 14.15% for WT, and 11.15% for QIA. For the manual methods, the range between the lowest and highest Ki-67 for each specimen between the 3 pathologists was 8.44 for EST, 5.94 for WT, and 5.93 for UNW. The WT method limited interobserver variability with ICC1=0.959 (EST ICC1=0.922 and UNW=0.949). Using the aforementioned cutoff of Ki-67 ≥20% versus <20% to determine treatment eligibility, the averaged EST method yields 20 of 50 patients (40%) who would have been treatment-eligible, versus 15 (30%) for the UNW, 17 (34%) for the WT, and 12 (24%) for the QIA. There was no statistically significant difference in Ki-67 among the 3 specimen types. The average Ki-67 difference was 4.36 for CNB vs RES, 6.95 for CNB versus ALN, and RES versus ALN (P=0.93, 0.99, and 0.94, respectively). Our study concludes that further refinement in Ki-67 scoring is advisable to reduce clinically significant variation.
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Bencimidazoles , Neoplasias de la Mama , Proyectos de Investigación , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Antígeno Ki-67 , AminopiridinasRESUMEN
The pathogenic virus Panulirus argus virus 1 (PaV1) was first discovered in Caribbean spiny lobsters Panulirus argus from the Florida Keys (USA) in 1999 and has since been reported in Belize, Mexico, and Cuba; its distribution in the wider Caribbean is unknown. We collected tissue samples from adult spiny lobsters from 30 locations in 14 countries bordering the Caribbean Sea and used molecular diagnostics to assay for the presence of PaV1. PaV1 occurred primarily in the northern areas of the Caribbean, where its prevalence was highest. The virus was not found in lobsters from the southeastern Caribbean, and its prevalence was lowest in the southwestern Caribbean. DNA sequence analysis was performed on a fragment of the viral DNA to examine the genetic diversity of PaV1 on a Caribbean-wide scale. Sequence variation in the viral DNA fragment was high, with 61 unique alleles identified from 9 areas. The sharing of viral alleles in lobsters from distant locations supports the hypothesis of a strong genetic connectivity among lobsters within the Caribbean, and further supports the hypothesis that postlarvae infected with PaV1 may serve to disperse the virus over long distances.
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Virus ADN/genética , Virus ADN/aislamiento & purificación , Palinuridae/virología , Animales , Región del Caribe , Interacciones Huésped-PatógenoRESUMEN
INTRODUCTION: CA19-9 elevation has been reported to predict recurrence after resection of pancreatic ductal adenocarcinoma (PDAC), although only two-thirds of patients are expressers. Preoperatively, cancer-related symptoms predict outcome; however, it is unknown whether symptoms predict recurrence during surveillance, particularly for CA19-9 non-expressers. METHODS: Patients undergoing resection of PDAC at our institution from 2012 to 21 (n = 165) were retrospectively reviewed for CA19-9 and symptoms, which were correlated with recurrence-free survival (RFS). Multivariate analysis was performed using Cox regression. RESULTS: During postoperative surveillance, CA19-9 elevation and development of symptoms (abdominal pain, weight loss, or jaundice) were associated with worse RFS (P < .05). Multivariate analysis showed that both symptoms and CA19-9 were independently predictive of RFS (HR 1.8 [1.1-2.9; P = .025] and 2.5 [1.0-6.0; P = .048]). Among CA19-9 non-expressers (n = 51), development of symptoms was associated with detection of recurrence (P = .012). CONCLUSIONS: Among CA19-9 non-expressers, development of symptoms predicted recurrence, providing a useful tool for recurrence detection in these patients.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Antígeno CA-19-9 , Estudios Retrospectivos , Pronóstico , Adenocarcinoma/cirugía , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/patología , Neoplasias PancreáticasRESUMEN
In 2000, a pathogenic virus was discovered in juvenile Caribbean spiny lobsters Panulirus argus from the Florida Keys, U.S.A. Panulirus argus virus 1 (PaV1) is the first naturally occurring pathogenic virus reported from lobsters, and it profoundly affects their ecology and physiology. PaV1 is widespread in the Caribbean with infections reported in Florida (U.S.A.), St. Croix, St. Kitts, Yucatan (Mexico), Belize, and Cuba. It is most prevalent and nearly always lethal in the smallest juvenile lobsters, but this declines with increasing lobster size; adults harbor the virus, but do not present the characteristic signs of the disease. No other PaV1 hosts are known. The prevalence of PaV1 in juvenile lobsters from the Florida Keys has been stable since 1999, but has risen to nearly 11% in the eastern Yucatan since 2001. Heavily infected lobsters become sedentary, cease feeding, and die of metabolic exhaustion. Experimental routes of viral transmission include ingestion, contact, and for newly settled juveniles, free virus particles in seawater. Prior to infectiousness, healthy lobsters tend to avoid diseased lobsters and so infected juvenile lobsters mostly dwell alone, which appears to reduce disease transmission. However, avoidance of diseased individuals may result in increased shelter competition between healthy and diseased lobsters, and greater predation on infected lobsters. Little is known about PaV1 outside of Mexico and the USA, but it poses a potential threat to P. argus fisheries throughout the Caribbean.
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Virus ADN/clasificación , Virus ADN/aislamiento & purificación , Palinuridae/virología , Animales , Hibridación Fluorescente in SituRESUMEN
Sociality has evolved in a wide range of animal taxa but infectious diseases spread rapidly in populations of aggregated individuals, potentially negating the advantages of their social interactions. To disengage from the coevolutionary struggle with pathogens, some hosts have evolved various forms of "behavioral immunity"; yet, the effectiveness of such behaviors in controlling epizootics in the wild is untested. Here we show how one form of behavioral immunity (i.e., the aversion of diseased conspecifics) practiced by Caribbean spiny lobsters (Panulirus argus) when subject to the socially transmitted PaV1 virus, appears to have prevented an epizootic over a large seascape. We capitalized on a "natural experiment" in which a die-off of sponges in the Florida Keys (USA) resulted in a loss of shelters for juvenile lobsters over a ~2500km2 region. Lobsters were thus concentrated in the few remaining shelters, presumably increasing their exposure to the contagious virus. Despite this spatial reorganization of the population, viral prevalence in lobsters remained unchanged after the sponge die-off and for years thereafter. A field experiment in which we introduced either a healthy or PaV1-infected lobster into lobster aggregations in natural dens confirmed that spiny lobsters practice behavioral immunity. Healthy lobsters vacated dens occupied by PaV1-infected lobsters despite the scarcity of alternative shelters and the higher risk of predation they faced when searching for a new den. Simulations from a spatially-explicit, individual-based model confirmed our empirical results, demonstrating the efficacy of behavioral immunity in preventing epizootics in this system.
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Palinuridae/inmunología , Animales , Conducta Animal , Palinuridae/fisiología , Indias OccidentalesRESUMEN
Angiosarcomas are exceedingly rare tumors that are often difficult to diagnose. Exceptionally unusual is the presentation of these tumors with Kasabach-Merritt Syndrome, a curious form of intratumoral coagulation that can be impossible to distinguish from intravascular coagulation, which is more common. Instant recognition of this clinical association can help making a prompt diagnosis and timely initiation of therapy.
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The putatively toxic dinoflagellates Pseudopfiesteria shumwayae (Glasgow et J. M. Burkh.) Litaker, Steid., P. L. Mason, Shields et P. A. Tester and Pfiesteria piscicida Steid. et J. M. Burkh. have been implicated in massive fish kills and of having negative impacts on human health along the mid-Atlantic seaboard of the USA. Considerable debate still remains as to the mechanisms responsible for fish mortality (toxicity vs. micropredation) caused by these dinoflagellates. Genetic differences among these cultures have not been adequately investigated and may account for or correlate with phenotypic variability among strains within each species. Genetic variation among strains of Ps. shumwayae and P. piscicida was examined by PCR-RFLP analysis using cultures obtained from the Provasoli-Guillard National Center for Culture of Marine Phytoplankton (CCMP), as well as those from our own and other colleagues' collection efforts. Examination of restriction digest banding profiles for 22 strains of Ps. shumwayae revealed the presence of 10 polymorphic restriction endonuclease sites within the first and second internal transcribed spacers (ITS1 and ITS2) and the 5.8S gene of the rDNA complex, and the cytochrome oxidase subunit I (COI) gene. Three compound genotypes were represented within the 22 Ps. shumwayae strains. Conversely, PCR-RFLP examination of 14 strains of P. piscicida at the same ITS1, 5.8S, and ITS2 regions revealed only one variable restriction endonuclease site, located in the ITS1 region. In addition, a dinoflagellate culture listed as P. piscicida (CCMP 1928) and analyzed as part of this study was identified as closely related to Luciella masanensis P. L. Mason, H. J. Jeong, Litaker, Reece et Steid.
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Oysters were collected from coastal locations in China from 1999-2006 for parasite analyses by molecular, culture, and histological techniques. Polymerase chain reaction-based assays targeting the internal transcribed spacer (ITS) region of the ribosomal RNA gene complex were performed to detect the presence of Perkinsus species. Sequencing and phylogenetic analysis of amplified Perkinsus sp. DNAs indicated that a novel Perkinsus sp. infects Crassostrea hongkongensis, Crassostrea ariakensis, and other bivalve hosts from Fujian to Guangxi provinces in southern China. Prevalence of this Perkinsus sp. reaches as high as 60% in affected oyster populations. Analyses of nucleotide sequences of the rRNA ITS region and of large subunit rRNA and actin genes, consistently confirmed the genus affiliation of this Perkinsus sp., but distinguished it from currently accepted Perkinsus species. Parasite cell types, such as signet ring trophozoites of 2-8 microm diameter, were observed by histology, and application of both genus Perkinsus and Perkinsus species-specific in situ hybridization probes consistently labelled the same Perkinsus sp. cells in histological sections from infected oyster tissues. Combined phylogenetic and histological results support the identity of a new parasite species, Perkinsus beihaiensis n. sp.
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Ostreidae/parasitología , Parásitos/clasificación , Actinas/genética , Animales , China , ADN Protozoario/química , ADN Protozoario/genética , ADN Ribosómico/química , ADN Ribosómico/genética , ADN Espaciador Ribosómico/química , ADN Espaciador Ribosómico/genética , Histocitoquímica , Hibridación in Situ , Datos de Secuencia Molecular , Parásitos/aislamiento & purificación , Filogenia , Reacción en Cadena de la Polimerasa , Proteínas Protozoarias/genética , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido NucleicoRESUMEN
Continuous in vitro cultures of Perkinsus mediterraneus were established from tissues of infected European flat oysters, Ostrea edulis. The parasite proliferated in protein-free medium and divided by schizogony in vitro. Cell morphology was similar to that observed for P. mediterraneus in tissues of naturally infected O. edulis and for other Perkinsus spp. cultured in vitro. Parasite cells enlarged approximately 8-fold when placed in alternative Ray's fluid thioglycollate medium, and stained black with Lugol's iodine solution, a response characteristic of Perkinsus spp. DNA sequences matched those determined previously for P. mediterraneus, and phylogenetic analyses on three different data sets indicated that this was a Perkinsus species with a close relationship to another recently described species, Perkinsus honshuensis. Parasite viability was high (>90%) in vitro, but the proliferation rate was low, with densities generally increasing 2-to-6-fold between subcultures at 6-wk intervals. Enzyme analysis of cell-free culture supernatants revealed protease-, esterase-, glycosidase-, lipase-, and phosphatase-like activities. Incubation with class-specific protease inhibitors showed that P. mediterraneus produced serine proteases, and eight proteolytic bands with molecular weights ranging from 34 to 79 kDa were detected in the supernatants by gelatin sodium dodecylsulfate-polyacrylamide gel electrophoresis.
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Eucariontes/citología , Eucariontes/fisiología , Ostreidae/parasitología , Proteínas Protozoarias/química , Actinas/genética , Animales , Técnicas de Cultivo de Célula , ADN Protozoario/genética , ADN Ribosómico/genética , Electroforesis en Gel de Poliacrilamida , Enzimas/metabolismo , Eucariontes/química , Eucariontes/clasificación , Europa (Continente) , Péptido Hidrolasas/química , Filogenia , Reacción en Cadena de la Polimerasa , Infecciones Protozoarias en Animales/parasitología , Proteínas Protozoarias/metabolismo , ARN Ribosómico/genética , Análisis de Secuencia de ADNRESUMEN
Perkinsus olseni infections are reported at 10%-84% prevalences among Austrovenus stutchburyi clams (cockles) in northern New Zealand coastal waters. However, P. olseni has not yet been propagated in vitro from New Zealand clams. In our sample of A. stutchburyi clams from Mangemangaroa Stream, New Zealand, 24% (8/34) showed low-intensity Perkinsus sp. infections among mantle and gill tissues incubated in alternative Ray's fluid thioglycollate medium (ARFTM), and 5% (4/79) showed Perkinsus sp. lesions by histological analyses. Among clams that were screened using a polymerase chain reaction (PCR) assay, 16% (3/19) were positive for Perkinsus sp. DNA. Alternative Ray's fluid thioglycollate medium-enlarged hypnospores from tissues of five infected clams yielded three in vitro Perkinsus sp. isolate cultures that were cloned before sequencing internal transcribed spacer (ITS) regions of their rRNA gene complex. For one isolate, ATCC PRA-205, large subunit (LSU) rRNA and actin genes were also sequenced. All nucleotide sequences from all isolates consistently identified them as P. olseni, as did their in vitro cell cycles and zoosporulation characteristics. All in vitro isolate cultures and their respective monoclonal derivative strains were cryopreserved and deposited for archiving and distribution by the American Type Culture Collection (http://www.atcc.org).
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Técnicas de Cocultivo , Eucariontes/aislamiento & purificación , Mya/parasitología , Infecciones Protozoarias en Animales/parasitología , Agua de Mar/parasitología , Técnicas de Cultivo de Tejidos , Actinas/genética , Animales , Ciclo Celular , Clonación Molecular , ADN Protozoario/genética , ADN Ribosómico/genética , ADN Espaciador Ribosómico/genética , Eucariontes/clasificación , Eucariontes/citología , Eucariontes/fisiología , Genes Protozoarios , Branquias/parasitología , Nueva Zelanda , Reacción en Cadena de la Polimerasa , Proteínas Protozoarias/genética , Especificidad de la Especie , Esporas ProtozoariasRESUMEN
Fibronectin (FN), a large dimeric glycoprotein, functions primarily as a connecting molecule in the extracellular matrices of tissues by mediating both cell-matrix and matrix-matrix interactions. All members of the FN family are products of a single FN gene; heterogeneity arises from the alternative splicing of at least three regions (IIIB, IIIA, and V) during processing of a common primary transcript. During chick embryonic limb chondrogenesis, FN structure changes from B+A+ in precartilage mesenchyme to B+A- in differentiated cartilage, and exon IIIA has been shown to be necessary for the process of mesenchymal cellular condensation, a requisite event that precedes overt expression of chondrocyte phenotype. This study aims to investigate the mechanistic action of the FN isoforms in mesenchymal chondrogenesis and, in particular, to identify the specific cellular function in mesenchymal condensation mediated by the mesenchymal (B+A+) FN isoform. Full-length cDNAs corresponding to four splice variants (B+A+, B+A-, B-A+, B-A-) of FN were constructed, and expressed the corresponding proteins using a baculovirus expression vector system. Cell adhesion assays with purified proteins showed that, although the relative levels of cell attachment were approximately the same, chick limb-bud mesenchymal cells spread up to 40 % less on mesenchymal (B+A+) FN than on cartilage (B+A-) FN, (B-A+) FN, or plasma (B-A-) FN. Cellular condensation and chondrogenic differentiation were also promoted in high-density micromass cultures of limb mesenchymal cells plated onto B+A+ FN. These observations suggest that the process of mesenchymal condensation is mediated at least in part by the enhanced ability of chondrogenic mesenchymal cells to migrate and aggregate as a consequence of residing in and interacting with mesenchymal FN. Our findings are consistent with and provide a mechanistic basis for previous observations that rounding of limb mesenchymal cells precedes the onset of chondrogenesis.