RESUMEN
Pulmonary thromboembolism associated with pancreatic endocrine neoplasia is extremely uncommon in man and animals. Post-mortem examination of an adult owl monkey (Aotus nancymae) revealed extensive pulmonary arterial thromboembolism and a well-demarcated mass attached to the pancreas. Microscopically, the mass consisted of areas of interstitial fibrosis with loss of acini and islets and replacement by nests and sheets of polygonal cells with amphophilic cytoplasm, an eccentric round nucleus with stippled chromatin and, in some cells, with a single prominent eccentric nucleolus. Clusters of these cells were noted within vessels and adjacent lymph nodes. The cells did not express S100 or insulin, but were labelled strongly with SP-1/chromogranin. Rare individual cells expressed glucagon and somatostatin. A few cells in pulmonary thrombi/emboli and the adjacent lymph node also expressed SP-1/chromogranin. Based on cell morphology, location and immunohistochemistry the tumour was classified as pancreatic endocrine (islet cell) carcinoma with metastasis to regional lymph nodes and lung.
Asunto(s)
Adenoma de Células de los Islotes Pancreáticos/veterinaria , Enfermedades de los Monos/patología , Neoplasias Pancreáticas/veterinaria , Embolia Pulmonar/veterinaria , Adenoma de Células de los Islotes Pancreáticos/complicaciones , Adenoma de Células de los Islotes Pancreáticos/patología , Animales , Aotidae , Masculino , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Embolia Pulmonar/etiología , Embolia Pulmonar/patologíaRESUMEN
Ureteral fibroepithelial polyps are benign mesodermal tumors in humans that occur predominantly in the proximal ureter. During a routine necropsy of a wild-caught, research naïve, adult, male, Aotus nancymae, the left ureter just distal to the renal pelvis contained a pedunculated, lobulated neoplasm with a narrow stalk at the base projecting into the lumen. The left renal pelvis was found to be mildly dilated. The histologic characteristics of the ureteral mass were consistent with a fibroepithelial polyp. To our knowledge, this is the first report describing a ureteral fibroepithelial polyp in a nonhuman primate.
Asunto(s)
Aotidae , Enfermedades de las Aves/patología , Neoplasias Fibroepiteliales/veterinaria , Pólipos/veterinaria , Neoplasias Ureterales/veterinaria , Animales , Resultado Fatal , Histocitoquímica/veterinaria , Masculino , Neoplasias Fibroepiteliales/patología , Pólipos/patología , Neoplasias Ureterales/patologíaRESUMEN
A model of allergic pulmonary inflammation is described in which the intraperitoneal injection of antigen (Ag)-pulsed cells resulted in T cell priming. Mice received two injections of 10(6) elicited peritoneal macrophages, which had been incubated with Ag for 48 hr, on Days 0 and 6, followed by an aerosol Ag challenge on Day 19. Bronchoalveolar lavage fluid harvested on Day 21 contained increased eosinophil numbers and resembled the cell influx observed following immunization with Ag in alum. Incubation of Ag-presenting cells with interferon-gamma resulted in increased expression of the costimulator molecule B7-2 and of MHC Ags, but did not enhance priming capacity. Using this system, antibodies to CD4 and CD8 were tested for their ability to block sensitization by Ag-pulsed cells. Both anti-CD4 and anti-CD8 antibodies completely blocked the airway eosinophil response following aerosol Ag challenge. This model will be very useful for characterization of the interactions between Ag-presenting cells and T cells which ultimately result in the induction of pulmonary eosinophilia.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Asma/inmunología , Eosinofilia Pulmonar/etiología , Eosinofilia Pulmonar/inmunología , Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/inmunologíaRESUMEN
T cells play a critical role in the development of collagen-induced arthritis (CIA). Immunization with heterologous (chick) type II collagen (cII) results in chronic inflammation with progressive damage to the joints. The expression of specific MHC Class II alpha beta dimers, including IAq, is critical to induction of disease. The alpha chains of IAq and IAp are identical in sequence. The IAq and IAp beta chains differ by only four amino acid residues: 85, 86, 88, and 89. However, mice of the H-2p haplotype are not susceptible to CIA. To examine the impact of these structural differences in IA molecules on T cell Ag recognition, we studied presentation of cII peptides and denatured cII by APCs obtained from H-2q and H-2p mice. We also assessed presentation of ovalbumin, myelin basic protein (MBP), and MBP peptides by these APC populations. H-2q APCs presented both peptides and proteins to our T cell hybrids. In contrast, APCs obtained from H-2p mice presented peptides, but were defective in the processing and/or presentation of protein Ags. We then altered pairs of the residues in IAq to those found in IAp using site-directed mutagenesis and transfected these constructs into M 12.C3 B cells. All transfectants were able to present peptides, but those expressing IAp were unable to present protein Ags. The use of transfectants expressing hybrid molecules (residues 85 and 86 from IAp, 88 and 89 from IAq, or vice versa) allowed us to localize the region responsible for this defect to residues 85 and 86 of the beta chain. The presence of IAp residues (glu and thr versus gly and val in IAq) at these sites severely compromised the capacity for protein presentation. Resistance to CIA in H-2p haplotype mice may be a reflection of the limited repertoire of epitopes to which these mice can respond relative to susceptible H-2q mice.
Asunto(s)
Presentación de Antígeno , Antígenos de Histocompatibilidad Clase II/genética , Polimorfismo Genético , Secuencia de Aminoácidos , Animales , Células Presentadoras de Antígenos/fisiología , Antígenos H-2/genética , Haplotipos , Hibridomas/inmunología , Ratones , Datos de Secuencia Molecular , Proteína Básica de Mielina/metabolismo , Ovalbúmina/metabolismoRESUMEN
The expression of specific alleles of the human HLA-DR locus is associated with increased risk for the development of rheumatoid arthritis. Examination of the amino acid sequence of the DR beta chain has revealed that risk for RA correlates with a cluster of polymorphic residues located between positions 67 and 86, and in particular with the identity of residues 70, 71, and 86. To examine the contributions of these HLA-DR polymorphic residues to antigen-specific T cell responses, the DRB1*0401 gene was subjected to site-directed mutagenesis and forms possessing alanine in place of the naturally occurring amino acid at positions 70, 71, 86, and 70/71 were generated. The mutated genes were coexpressed with the DRA gene in Chinese hamster ovary cells and the transfectants were tested as stimulator cells for a panel of three human influenza virus hemagglutinin-specific T cell clones. Additionally, soluble forms of the mutant DR molecules were examined for their ability to bind peptide. All of the mutants had a modest loss of affinity for the peptide relative to the wild type, but there were no significant differences in peptide binding ability among the substituted molecules. In contrast to the relatively uniform influence on peptide binding, the impact of these mutations on T cell stimulation was heterogeneous. Specifically, these studies indicate that residue 71 plays a critical role in T cell stimulation either through direct contact with the T cell receptor or by changing the orientation or conformation of the peptide-MHC complex. Replacement of residue 71 with alanine abrogated stimulation of all of the T cell clones. Two of three clones were affected by changes at residue 70 while none lost recognition when amino acid 86 was converted from Val to Ala. These data emphasize that subtle alterations in structure can have a profound impact on T cell recognition.
Asunto(s)
Antígeno HLA-DR4/química , Linfocitos T/inmunología , Secuencia de Aminoácidos , Hemaglutininas Virales/inmunología , Humanos , Ligandos , Activación de Linfocitos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Orthomyxoviridae/inmunología , Péptidos/química , Péptidos/metabolismo , Polimorfismo Genético , Receptores de Antígenos de Linfocitos T/metabolismo , Relación Estructura-ActividadRESUMEN
The S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor MDL 28,842 has been demonstrated to be a potent inhibitor of T-cell activation, both in vitro and in vivo. Although the inhibition of T cells in vitro was independent of macrophages, the direct effect of MDL 28,842 on macrophages is unknown. In this report the effects of MDL 28,842 on macrophage cytokine production, cell-surface antigen expression, and antigen processing and presentation were examined. Lipopolysaccharide (LPS) stimulation of IL-1 synthesis by peritoneal macrophages was not effected by MDL 28,842 using cells obtained from B10.A and B10.B mice and weakly inhibited using cells from BALB/C mice (IC50 > 10 microM). In contrast, TNF-alpha synthesis by BALB/C macrophages was inhibited by MDL 28,842 with an IC50 < 0.1 microM. B10.A and B10.B macrophages did not produce detectable TNF-alpha in response to LPS in this system. Treatment with 1-10 microM MDL 28,842 resulted in a modest decrease in major histocompatibility complex class II (MHC-II) determinant expression by Interferon-gamma-activated macrophages. The expression of other cell-surface markers was not altered in the presence of MDL 28,842. The processing of antigen and its presentation by MHC class-II-positive macrophages to a T-cell hybridoma was also not affected by incubation with MDL 28,842.)
Asunto(s)
Adenosina/análogos & derivados , Hidrolasas/antagonistas & inhibidores , Activación de Macrófagos/efectos de los fármacos , Adenosina/farmacología , Adenosilhomocisteinasa , Animales , Presentación de Antígeno/efectos de los fármacos , Antígenos de Superficie/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Técnicas In Vitro , Interleucina-1/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/inmunología , Ratones , Ratones Endogámicos BALB C , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
T lymphocytes play a critical role in the development of murine collagen-induced arthritis (CIA), a syndrome which shares many features with rheumatoid arthritis. In susceptible mouse strains, immunization with type II collagen (cII) results in chronic inflammation with progressive joint destruction. To examine T cell recognition of cII we have isolated T cell hybridomas specific for a cII peptide fragment, cII260-270 (IAGFKGEQGPK). We assessed the importance of particular amino acid residues to formation of the MHC Class II-peptide complex and interaction of this complex with TCRs. Our results indicate that critical residues are concentrated in the N-terminal half of the peptide, with Lys264 and Glu266 having the greatest influence. Replacement of these residues with alanine resulted in loss of detectable activity. Three other residues, Ile260, Gly262, and Phe263, are also important to T cell stimulation because alanine substitution substantially decreased peptide activity. Truncation analyses supported the conclusion drawn from Ala substitutions that C-terminal residues were dispensable. Other alterations in peptide structure resulted in dramatic increases in stimulatory capacity. For example, replacement of either Gly265 or Gly268 with alanine resulted in a 10-fold increase in potency. The addition of 2-5 residues to the N-terminus of the peptide decreased the dose required for maximal T cell stimulation by > 100-fold. The T cell hybridomas exhibited remarkable similarity in their peptide recognition profiles although they express different TCR V beta elements.
Asunto(s)
Colágeno/inmunología , Linfocitos T/inmunología , Secuencia de Aminoácidos , Animales , Antígenos/química , Antígenos/inmunología , Relación Dosis-Respuesta Inmunológica , Epítopos , Hibridomas , Complejo Mayor de Histocompatibilidad , Masculino , Ratones , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Péptidos/química , Péptidos/inmunología , Relación Estructura-ActividadRESUMEN
Low density lipoproteins (LDL) oxidatively modified by macrophages have been shown to be atherogenic in ex vivo studies. We studied the potential role of nitric oxide (NO), a free radical produced by macrophages, in LDL modification. Human LDL (1 mg/ml) were incubated with mouse peritoneal macrophages in Ham's F-10 medium. The cells were then stimulated by interferon-gamma and tumor necrosis factor-alpha to increase their production of NO from 1.3 to 12.2 microM in 24 h, as measured by nitrite. Lipid peroxidation of LDL, as measured by thiobarbituric acid-reactive materials (TBARS), was reduced in stimulated cells in a time-dependent manner. At 24 h, the decrease was about 27%. In the presence of an NO synthase inhibitor (NG-aminophomoarginine), the generation of NO was diminished and the protection against LDL lipid peroxidation was reversed. The extent of LDL protein modification was also assessed by examining its electrophoretic mobility. It was found that macrophage NO reduced the change in LDL electromobility. These data indicate that the production of NO may inhibit the oxidative modification of LDL with cytokine-stimulated macrophages. We suggest that NO plays a protective role in limiting macrophage-induced LDL modification.
Asunto(s)
Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Animales , Células Cultivadas , Interferón gamma/farmacología , Peroxidación de Lípido , Macrófagos/efectos de los fármacos , Ratones , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
We have assessed the capacity of two novel inhibitors to block cytokine-induced nitric oxide (NO) synthesis by macrophages and vascular smooth muscle cells, as well as NO production by the constitutive enzyme in central nervous system tissue. NG-Cyclopropyl-L-arginine selectively inhibited Ca2+/calmodulin-dependent NO synthesis, with an IC50 of 0.55 microM in brain versus 184 and 258 microM in macrophages and vascular smooth muscle cells, respectively. In contrast, NG-amino-L-homoarginine blocked NO production by all of the cell types examined, with IC50 values ranging from 6.6 to 26 microM. Both inhibitors were active in an in vivo model of endotoxic shock.
Asunto(s)
Arginina/análogos & derivados , Cerebelo/efectos de los fármacos , Homoarginina/análogos & derivados , Macrófagos/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/metabolismo , Animales , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Cerebelo/metabolismo , Homoarginina/farmacología , Macrófagos/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Ratas , Ratas Endogámicas , Choque Séptico/fisiopatologíaRESUMEN
Interleukin-1 beta (IL-1) reduces vascular smooth muscle contractility. The purpose of the present study was to investigate the role of nitric oxide synthesis in mediating this effect of IL-1. We studied the influence of inhibitors of nitric oxide synthesis on the depression of norepinephrine-induced contractions of rat aortic rings by IL-1. Also, we examined the ability of IL-1 to increase the production of nitric oxide by rat aortic smooth muscle cells in culture as determined indirectly by measuring nitrite concentrations. NG-amino-L-arginine blocked the effect of IL-1 on norepinephrine-induced contractions of rat aortic rings whereas NG-monomethyl-L-arginine and NG-nitro-L-arginine were considerably less effective. In addition, this effect of IL-1 was prevented by coincubation of the rings with cycloheximide. IL-1 greatly elevated nitrite production by rat aortic smooth muscle cells, and this effect could also be blocked completely by the arginine analogs. NG-amino-L-arginine was the most potent inhibitor of nitrite synthesis (IC50 = 1.7 microM) whereas NG-monomethyl-L-arginine and NG-nitro-L-arginine were about 10-fold less potent (IC50 = 16 and 22 microM, respectively). These results suggest that IL-1-induced depression of norepinephrine-induced vascular contraction is mediated by the increased synthesis of nitric oxide synthase by vascular smooth muscle cells. The relative potency of the arginine analogs for the inhibition of nitrite synthesis suggests that the synthase in vascular smooth muscle is similar to the synthase in macrophages.
Asunto(s)
Aminoácido Oxidorreductasas/antagonistas & inhibidores , Arginina/análogos & derivados , Interleucina-1/antagonistas & inhibidores , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/farmacología , Norepinefrina/farmacología , Vasoconstricción/efectos de los fármacos , 1-Metil-3-Isobutilxantina/farmacología , Animales , Arginina/farmacología , Células Cultivadas , Interleucina-1/farmacología , Masculino , Óxido Nítrico Sintasa , Nitroarginina , Norepinefrina/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
Inhibition of nitric oxide production by arginine analogues was examined in three cell systems; macrophages, CNS tissue and endothelial cells. Nitric oxide production was assessed indirectly using in vitro assays measuring nitrite production (macrophages), cGMP elevation (CNS) and acetylcholine-induced relaxation of aortic ring segments (endothelium). NG-monomethyl-L-arginine and NG-amino-L-arginine possessed similar inhibitory activity in all three assays, while NG-nitro-L-arginine displayed a striking selectivity for inhibition of brain and endothelial cell nitric oxide synthesis, with IC50 values of 0.05 microM in the CNS versus 200 microM in macrophages. These results suggest that distinct enzymes are responsible for nitric oxide synthesis in different cell types, and indicate that it may be possible to selectively modulate nitric oxide production in vivo.
Asunto(s)
Arginina/farmacología , Sistema Nervioso Central/metabolismo , Endotelio/metabolismo , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Animales , Arginina/análogos & derivados , Sistema Nervioso Central/efectos de los fármacos , GMP Cíclico/metabolismo , Endotelio/efectos de los fármacos , Técnicas In Vitro , Macrófagos/efectos de los fármacos , Ratones , N-Metilaspartato/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Nitroarginina , Ratas , omega-N-MetilargininaRESUMEN
Macrophage activation for tumor cell killing is a multistep pathway in which responsive macrophages interact sequentially with priming and triggering stimuli in the acquisition of full tumoricidal activity. A number of mediators have been identified which have activating capability, including in particular IFN-gamma and bacterial LPS. Although the synergistic functional response of normal macrophages to sequential incubation with these activation signals has been well-established, characterization of the intermediate stages in the activation pathway has been difficult. We have developed a model system for examination of various aspects of macrophage activation, through the use of the murine macrophage tumor cell line, RAW 264.7. These cells, like normal macrophages, exhibit a strict requirement for interaction with both IFN-gamma and LPS in the development of tumor cytolytic activity. In addition, these cells can be stably primed by the administration of gamma-radiation. In the studies reported here, we have used RAW 264.7 cells treated with IFN-gamma alone or with IFN-gamma plus LPS to stimulate the production of rat mAb probes recognizing cell surface changes occurring during the activation process. In this way we have identified three Ag associated with intermediate stages of the activation process. One Ag, TM-1, is expressed on RAW 264.7 cells primed by IFN-gamma or gamma-radiation. This surface Ag thus identifies cells at the primed cell intermediate stage of the tumoricidal activation pathway regardless of the mechanism of activation. A second Ag, TM-2, is expressed on IFN-treated RAW 264.7 cells but not on RAW 264.7 cells primed with gamma-radiation alone. Expression of this Ag can be induced by treatment of irradiated cells with IFN-gamma, but is not induced by IFN-gamma treatment of a noncytolytic cell line, WEHI-3. This Ag thus appears to be an IFN-inducible cell surface protein associated specifically with macrophage activation for tumoricidal activity. Finally, Ag TM-3 is detectable on RAW 264.7 cells primed by either IFN-gamma or gamma-radiation, after subsequent triggering of the primed cells with LPS. The addition of the mAb recognizing this antigen to the function assay of tumor cell killing can inhibit they lytic activity of both triggered cells. Thus, this Ag may play a role in the antitumor effector functions of activated macrophages. Overall, the results suggest that these mAb can serve as useful tools for identification of molecules associated with the process of macrophage activation for tumor cell killing.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Citotoxicidad Inmunológica , Activación de Macrófagos , Macrófagos/inmunología , Animales , Antígenos de Diferenciación Mielomonocítica/inmunología , Células Cultivadas , Rayos gamma , Inmunidad Celular , Técnicas In Vitro , Interferón gamma/farmacología , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de la radiación , Ratones , Neoplasias Experimentales/inmunología , Cavidad Peritoneal/citologíaRESUMEN
We examined the structural characteristics of a peptide Ag that determine its ability to interact with class II-MHC molecules and TCR. The studies reported here focused on recognition of the hen egg white lysozyme (HEL) tryptic fragment HEL(34-45) by two I-Ak-restricted T cell hybridomas. HEL(34-45) bound to I-Ak created more than one antigenic specificity. Experiments with truncated peptides and alanine-substituted peptides indicated that two T cell hybrids either recognized distinct regions of the HEL(34-45) peptide, or different determinants generated by interaction of the peptide with I-Ak. Although we identified residues of HEL(34-45) that were critical to T cell recognition, no positions in the peptide were identified as I-Ak contact sites using single alanine substitutions. This suggests that more than one site or region of the peptide contributes to the binding to I-Ak. Finally, the murine lysozyme equivalent of 34-45 did not bind to I-Ak. Substitution of the corresponding murine lysozyme (self) residue at position 41 of HEL(34-45) abrogated I-Ak binding of the peptide.
Asunto(s)
Antígenos de Histocompatibilidad Clase II/inmunología , Muramidasa/inmunología , Ovalbúmina/inmunología , Fragmentos de Péptidos/inmunología , Linfocitos T/inmunología , Alanina , Secuencia de Aminoácidos , Animales , Sitios de Unión , Unión Competitiva , Pollos , Ratones , Datos de Secuencia Molecular , Muramidasa/metabolismo , Ovalbúmina/metabolismo , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/metabolismo , Linfocitos T/metabolismoRESUMEN
Macrophage cell lines were used in these studies as a model system to dissect the biochemical and functional mosaic of the macrophage activation process. In particular, the requirements for the induction of tumoricidal and bactericidal activity in the RAW 264.7 and WEHI-3 cell lines by interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS) were determined. Changes in expression of a series of macrophage markers traditionally associated with macrophage activation were monitored during stimulation of the cells in order to determine whether a detectable pattern of activation-associated changes is associated with the development of a particular functional activity. These markers included changes in the cell surface expression of major histocompatibility complex-encoded Class I and Class II antigens and antigens in the Mac-1/LFA-1 family, alterations in the levels of membrane enzymes (5' nucleotidase and alkaline phosphodiesterase), and production of secretory products including hydrogen peroxide and the monokines interleukin-1, interferons-alpha/beta, and tumor necrosis factor-alpha. Our results demonstrate that a given homogeneous macrophage population expresses a distinct subset of functional activities in response to single, defined activating signals such as IFN-gamma and LPS. The display of a variety of macrophage surface antigens, enzymes, and secreted products is activated simultaneously by such treatment; however, the particular pattern of such activation-associated markers cannot reproducibly be used to predict the ability of an activated cell to perform a particular function. The results also suggest that macrophage cell lines expressing differential response patterns following IFN-gamma stimulation provide a valuable system for dissection of the molecular and cell biology of macrophage activation.
Asunto(s)
Interferón gamma/farmacología , Activación de Macrófagos/efectos de los fármacos , 5'-Nucleotidasa , Animales , Antígenos de Superficie/análisis , Factores Biológicos/biosíntesis , Línea Celular , Citocinas , Citotoxicidad Inmunológica , Peróxido de Hidrógeno/metabolismo , Lipopolisacáridos/farmacología , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Nucleotidasas/análisis , Fosfodiesterasa I , Hidrolasas Diéster Fosfóricas/análisisRESUMEN
Macrophage activation for tumor cell killing is a multistep pathway in which responsive macrophages interact sequentially with priming and triggering stimuli in the acquisition of full tumoricidal activity. Although this synergistic response of normal macrophages to sequential incubation with activation signals has been well established, characterization of the intermediate stages in this pathway has been difficult, due in large measure to the instability of the intermediate cell phenotypes. We have developed a model system for examination of macrophage-mediated tumor cell lysis, with the use of the murine macrophage tumor cell line RAW 264.7. These cells, like normal macrophages, exhibit a strict requirement for interaction with both interferon-gamma (IFN-gamma, the priming signal) and bacterial lipopolysaccharide (LPS, the triggering signal) in the development of tumor cytolytic activity. In this system, the priming effects of IFN-gamma decay rapidly after withdrawal of this mediator and the cells become unresponsive to LPS triggering. We have recently observed that gamma-irradiation of the RAW 264.7 cells also results in development of a primed activation state for tumor cell killing. The effects of gamma-radiation on the RAW 264.7 cell line are strikingly similar to those resulting from incubation with IFN-gamma, with the exception that the irradiation-induced primed cell intermediate is stable and responsive to LPS triggering for at least 24 hr. Treatment with gamma-radiation also results in increased cell surface expression of major histocompatibility complex-encoded class I antigens; however, class II antigen expression is not induced. Irradiation-induced development of the primed phenotype is not solely the result of cytostatic effects as treatment of the cells with a radiomimetic drug, mitomycin C, results in decreases in [3H]thymidine incorporation that are similar to those observed after irradiation, without concomitant development of cytolytic potential. In addition, priming by gamma-radiation does not appear to be mediated by the release of soluble autoregulatory factors. This alternate pathway for induction of the primed macrophage activation state should serve as a useful tool for identification of molecules important to the functional potential of primed cells, and for elucidation of the biochemical mechanisms of the priming event in tumoricidal activation.
Asunto(s)
Inmunidad Celular/efectos de la radiación , Activación de Macrófagos/efectos de la radiación , Macrófagos/efectos de la radiación , Neoplasias Experimentales/inmunología , Animales , División Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Rayos gamma , Antígenos H-2/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Interferón gamma/farmacología , Macrófagos/inmunología , Ratones , Monocinas , Proteínas/fisiología , Factores de TiempoRESUMEN
Coronary bypass surgery was performed on 439 patients between the years 1969 and 1973 (group A) and on 1,760 patients between the years 1974 and 1979 (group B). The operative mortality for group A was 3.9%; for group B, 1.3%; four-year survival for group A patients was 88.9% +/- 1.5% (mean +/- SE); for group B patients, 92.5% +/- 0.9%. The difference between the relative four-year survival rates (based on age- and sex-matched Oregon population) between group B and A was 6.2%; the lower operative mortality would account for only 2.6%. We conclude that the results of coronary bypass surgery have improved because of (1) a lower operative mortality, and (2) other factors that cannot be precisely defined at the present time but probably are the long-term result of better and more complete operative and perioperative techniques.
Asunto(s)
Puente de Arteria Coronaria/mortalidad , Evaluación de Procesos y Resultados en Atención de Salud , Adulto , Anciano , Angina de Pecho/cirugía , Puente de Arteria Coronaria/métodos , Puente de Arteria Coronaria/estadística & datos numéricos , Enfermedad Coronaria/cirugía , Vasos Coronarios/fisiopatología , Femenino , Ventrículos Cardíacos/fisiopatología , Hemodinámica , Hospitales con 300 a 499 Camas , Humanos , Masculino , Persona de Mediana Edad , OregonRESUMEN
Our experience over a 20-year period consists of 2,135 patients with initial caged-ball valve replacement: 52% aortic, 34% mitral, 12% double, and 2% triple-valve replacements, with 59.2, 39.8, 10.3, and 2.7 patient-centuries of follow-up, respectively. Fifteen-year actuarial survival (+/- standard error) was 43 +/- 2% for aortic and 44 +/- 3% for mitral valve replacement, and 27 +/- 5% for double-valve and 23 +/- 7% for triple-valve replacement. Restricting attention to patients operated on since 1973 divides the series almost in half and does not dramatically improve the 5-year actuarial survival (from 66 +/- 2% to 71 +/- 3% and from 70 +/- 2% to 78 +/- 3% for aortic valve replacement and mitral valve replacement, respectively). There was some alteration in the causes of late death: the largest percentage of deaths in both the earlier and current groups, 52%, was cardiac related whereas only 24% and 13%, respectively, were valve related. Over the past two decades operative mortality has declined and, to a lesser extent, late survival after mitral valve replacement has improved. The incidence of embolism has decreased significantly, most notably with the Silastic ball valves. Dramatic improvements in late results will occur primarily by modifying the cardiac-related death rate through earlier operation and improvements in the medical management of postoperative arrhythmias and congestive heart failure.
Asunto(s)
Válvula Aórtica/cirugía , Prótesis Valvulares Cardíacas/mortalidad , Válvula Mitral/cirugía , Análisis Actuarial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Pronóstico , Análisis de Regresión , Factores de TiempoRESUMEN
The actuarial thromboembolic rates of aortic and mitral silicone ball valves used during the second decade of cardiac valve replacement are significantly lower than the rates for the same prostheses implanted during the first decade, as shown in the following table: (Formula: see text). The embolus-free rates are significantly different (p < 0.01) in both the mitral and aortic series. Five-year embolus-free rates for the composite-strut caged-ball, Björk-Shiley tilting disc, and porcine xenograft valves all fall in the range of from 81% to 92% for the mitral position and from 91% to 97% for the aortic. Thus the standard silicone ball-valve prosthesis, used during the current era, has a thromboembolic risk as low as that reported with other concurrently utilized valve substitutes. This striking reduction in thrombogenicity demonstrates that the time frame of implantation must be considered when evaluating the results of cardiac valve replacement.
Asunto(s)
Válvula Aórtica/cirugía , Bioprótesis/mortalidad , Prótesis Valvulares Cardíacas/mortalidad , Válvula Mitral/cirugía , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Prótesis Valvulares Cardíacas/normas , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Riesgo , Tromboembolia/complicaciones , Factores de TiempoRESUMEN
One hundred four patients survived isolated aortic valve replacement with the model 1200 prosthesis between 1965 and 1968, with a 12-year survival of 64%. Multiple regression survival analysis was employed in an attempt to determine which of 26 preoperative variables affected late survival and to devise a formula to predict survival for a given individual. The most important variables in the regression equation were right atrial mean pressure, etiology, and sex. The effect of the last two were found to vary with time over the 12-year post-operative period. An extension of the standard regression analysis technique was developed to incorporate time-related cofactors into the model. Based on the multiple regression model, 12-year survival was estimated to range from 92% to 14% for the best and worst combinations, respectively, of the three significant variables. The advantages of the regression method are outlined and the findings of other studies with regard to factors affecting survival after aortic valve replacement are summarized and discussed.
Asunto(s)
Válvula Aórtica/cirugía , Prótesis Valvulares Cardíacas/mortalidad , Adulto , Anciano , Femenino , Humanos , Masculino , Matemática , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
The Starr-Edwards Models 6120 mitral and 1200/60 aortic valves are caged-ball prostheses with cloth-covered sewing rings and bare-metal struts. Introduced in 1965, they have been in continuous clinical use longer than any other currently available heart valve prostheses. Late results with this valve are analyzed and compared with recent series employing other current valve prostheses. One hundred thirty-four mitral 6120 prostheses were inserted at the University of Oregon Health Sciences Center from 1965 through 1977, with 118 operative survivors followed for a mean of 5.4 years. Twelve-year survival rate (+/- standard error) was 50 (+/-8) percent. Twelve percent of late deaths were valve related. Eighty-eight (+/-5) percent of valves were still in place at 12 years. The embolic rate was 5.8 (+/-1.0) percent per patient-year for all emboli and 2.2(+/-0.6) percent per patient-year for serious emboli. Two hundred forty-nine operative survivors among 282 patients undergoing aortic valve replacement during the same period of time were followed for a mean of 4.3 years. Twelve-year survival was 61 (+/-6) percent and the removal-free rate was 92(+/-5) percent. Six percent of late deaths were valve related. Embolic rates were 5.0 (+/-.7) percent and 1.8 (+/-.4) percent per patient-year for all emboli and serius emboli, respectively. Structural failure, specifically ball variance, was not encountered with this prosthesis. Ninety percent of 10 year survivors are in N.Y.H.A. Functional Class I or II. There was one anticoagulant-related death in 1,698 patient-years of follow-up. The current non--cloth-covered caged-ball valves provide unquestionable durability and well-documented results into their second decade of use. They provide a base line for comparison with newer prostheses and offer a valid, current choice for both aortic and mitral valve replacement.