RESUMEN
BACKGROUND: Echocardiography has been used as a primary means to detect cellular rejection in infant heart transplant recipients. There is, however, limited information correlating echocardiography and biopsy-proven rejection in this age group. METHODS: Between September 1989 and July 1994, 32 consecutive heart transplantations were done in infants younger than 20 months old, who were followed up for 2 to 58 months (mean 28 months) with concurrent endomyocardial biopsy and M-mode echocardiography with digitization. M-mode data from all 16 episodes of rejection (International Society for Heart and Lung Transplantation grade 3A or greater) that occurred in 12 grafts were compared with data from the same grafts with histologic resolution of rejection 2 weeks after treatment and with data from biopsy-proven nonrejecting control grafts matched for sex, time after transplantation, donor weight, and donor age. RESULTS: Left ventricular mass index increased in rejection (86 +/- 9 gm/m2) versus resolution (64 +/- 6 gm/m2) and versus that in nonrejecting control grafts (59 +/- 8 gm/m2). Left ventricular shortening fraction increased in rejection (40% +/- 2%) versus resolution (38% +/- 10%). Septal thickening fraction decreased in rejection (33% +/- 9%) versus nonrejection (68% +/- 16%). These changes became significant only in grafts transplanted more than 1 month before study. Substantial overlap of measurements prevented identification of threshold values. Intraobserver and interobserver variabilities for standard M-mode data were 7% to 8% and 12% to 22%, respectively, whereas those for digitized parameters were markedly elevated at 37% to 71% and 51% to 81%, respectively. CONCLUSIONS: We found (1) left ventricular mass index increases in cellular rejection but may be unreliable less than 1 month after transplantation and (2) significant interobserver and intraobserver variability may limit the applicability of digitized echo parameters to the detection of rejection in infant heart transplant recipients.
Asunto(s)
Ecocardiografía/métodos , Rechazo de Injerto/diagnóstico por imagen , Trasplante de Corazón/diagnóstico por imagen , Miocardio/patología , Enfermedad Aguda , Biopsia , Ecocardiografía/estadística & datos numéricos , Estudios de Seguimiento , Rechazo de Injerto/patología , Trasplante de Corazón/patología , Trasplante de Corazón/estadística & datos numéricos , Humanos , Terapia de Inmunosupresión , Lactante , Variaciones Dependientes del Observador , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
Receptor specificity is an essential mechanism governing the activity of fibroblast growth factors (FGF). To begin to understand the developmental role of FGF-9/glial activating factor, we have cloned and sequenced the murine FGF-9 cDNA and expressed the protein in mammalian cells and in Escherichia coli. We demonstrate that the FGF-9 protein is highly conserved between mouse and human. Receptor specificity was determined by direct binding to soluble and cell surface forms of FGF receptor (FGFR) splice variants and by the mitogenic activity on cells, which express unique FGF receptor splice variants. Our data demonstrate that FGF-9 efficiently activates the "c" splice forms of FGFR2 and FGFR3, receptors expressed in potential target cells for FGF-9. Significantly, FGF-9 also binds to and activates the "b" splice form of FGFR3, thus becoming the first FGF ligand besides FGF-1 to activate this highly specific member of the FGF receptor family.
Asunto(s)
Encéfalo/metabolismo , Factores de Crecimiento de Fibroblastos , Sustancias de Crecimiento/biosíntesis , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , División Celular/efectos de los fármacos , Línea Celular , Clonación Molecular , Secuencia Conservada , Cartilla de ADN , ADN Complementario , Escherichia coli , Factor 9 de Crecimiento de Fibroblastos , Variación Genética , Sustancias de Crecimiento/metabolismo , Sustancias de Crecimiento/farmacología , Humanos , Mamíferos , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Receptores de Factores de Crecimiento de Fibroblastos/biosíntesis , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Homología de Secuencia de Ácido Nucleico , TransfecciónRESUMEN
The Fgf8 gene is expressed in developing limb and craniofacial structures, regions known to be important for growth and patterning of the mouse embryo. Although Fgf8 is alternatively spliced to generate at least 7 secreted isoforms that differ only at their mature amino terminus, the biological significance of these multiple isoforms is not known. In this report, we demonstrate that multiple FGF-8 isoforms are present at sites of Fgf8 expression during mouse development. To address the possibility that the FGF-8 isoforms might interact with different fibroblast growth factor receptors, we prepared recombinant FGF-8 protein isoforms. We examined the ability of these proteins to activate alternatively spliced forms of fibroblast growth factor receptors 1-3, and fibroblast growth factor receptor 4. Recombinant FGF-8b and FGF-8c activate the 'c' splice form of FGFR3, and FGFR4, while FGF-8b also efficiently activates 'c' splice form of FGFR2. No activity could be detected for recombinant or cell expressed FGF-8a. Furthermore, none of the isoforms tested interact efficiently with 'b' splice forms of FGFR1-3, or the 'c' splice form of FGFR1. These results indicate that the FGF-8b and FGF-8c isoforms, produced by ectodermally derived epithelial cells, interact with mesenchymally expressed fibroblast growth factor receptors. FGF-8b and FGF-8c may therefore provide a mitogenic signal to the underlying mesenchyme during limb and craniofacial development.