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1.
Bone Marrow Transplant ; 45(6): 979-84, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20190836

RESUMEN

We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.


Asunto(s)
Infecciones del Sistema Nervioso Central/inducido químicamente , Infecciones por Citomegalovirus/inducido químicamente , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones del Sistema Nervioso Central/etiología , Infecciones por Citomegalovirus/etiología , Resistencia a Medicamentos , Humanos , Huésped Inmunocomprometido , Infecciones Oportunistas
2.
Leukemia ; 17(11): 2183-8, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12931210

RESUMEN

In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.


Asunto(s)
Supervivencia sin Enfermedad , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Análisis de Varianza , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Inducción de Remisión , Análisis de Supervivencia , Sobrevivientes , Factores de Tiempo , Resultado del Tratamiento
3.
Bone Marrow Transplant ; 28(2): 187-96, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11509937

RESUMEN

Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.


Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones/epidemiología , Leucemia/terapia , Linfoma/terapia , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Niño , Preescolar , Ciclosporina/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Prueba de Histocompatibilidad , Humanos , Inmunoglobulinas Intravenosas/efectos adversos , Terapia de Inmunosupresión/métodos , Depleción Linfocítica , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Análisis de Supervivencia , Factores de Tiempo , Donantes de Tejidos/estadística & datos numéricos , Trasplante Homólogo
4.
Clin Infect Dis ; 32(3): 381-90, 2001 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-11170945

RESUMEN

In a double-blind, multicenter trial, 541 febrile granulocytopenic patients were randomized to receive either intravenous (iv) clinafloxacin (200 mg every 12 h) or i.v. imipenem (500 mg every 6 h) as empirical monotherapy. More baseline pathogens were susceptible to clinafloxacin (259 [99%] of 262 organisms) than to imipenem (253 [95%] of 265; P=.03). Initial favorable clinical response rates for clinafloxacin (88 [32%] of 272 patients) and imipenem (89 [33%] of 269) were similar. After addition of other antimicrobial agents, overall response rates were 259 (95%) of 272 for clinafloxacin and 251 (93%) of 269 for imipenem. During the study, only 13 clinafloxacin (5%) and 18 imipenem (7%) recipients died. Both drugs were generally well tolerated. Drug-related skin rash occurred more often with clinafloxacin (11% vs. 6%; P=.07), whereas nausea (2% vs. 5%; P=.16), Clostridium-difficile-associated diarrhea (3% vs. 8%; P=.02), and seizures (0% vs. 2%; P=.06) occurred more often with imipenem. These results suggest that clinafloxacin and imipenem have similar efficacy as empirical monotherapy in febrile granulocytopenic patients.


Asunto(s)
Agranulocitosis/tratamiento farmacológico , Antiinfecciosos/uso terapéutico , Fluoroquinolonas , Imipenem/uso terapéutico , Tienamicinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Agranulocitosis/microbiología , Antiinfecciosos/efectos adversos , Recuento de Células Sanguíneas , Canadá , Método Doble Ciego , Femenino , Humanos , Imipenem/efectos adversos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tienamicinas/efectos adversos , Resultado del Tratamiento , Estados Unidos
5.
Am J Med ; 108(4): 282-9, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11014720

RESUMEN

PURPOSE: To compare the efficacy and safety of fluconazole and amphotericin B as empiric antifungal therapy of febrile neutropenic patients with cancer. PATIENTS AND METHODS: A total of 317 neutropenic patients (<500 cells/mm3) with persistent or recrudescent fever despite 4 or more days of antibacterial therapy were randomly assigned to receive either fluconazole (400 mg intravenously once daily) or amphotericin B (0.5 mg/kg once daily). Patients were evaluated for the efficacy and safety of each drug by clinical criteria, frequent cultures and radiological procedures, and laboratory values. A response was classified as satisfactory at the end of therapy if the patient was afebrile, had no clinical or microbiological evidence of fungal infection, and did not require study termination due to lack of efficacy, drug toxicity, or death. RESULTS: A satisfactory response occurred in 68% of the patients treated with fluconazole (107 of 158 patients) and in 67% of patients treated with amphotericin B (106 of 159 patients). Progressive or new fungal infections during therapy occurred in 13 (8%) patients treated with fluconazole (8 with Candida, 5 with Aspergillus) and in 10 (6%) patients treated with amphotericin B (5 with Candida, 3 with Aspergillus, 2 with other fungi). Adverse events related to study drug (especially fever, chills, renal insufficiency, electrolyte disturbances, and respiratory distress) occurred more often in patients treated with amphotericin B (128 [81%] of 159 patients) than patients treated with fluconazole (20 [13%] of 158 patients, P = 0.001). Eleven (7%) patients treated with amphotericin B but only 1 (1%) patient treated with fluconazole were terminated from the study owing to an adverse event (P = 0.005). Overall mortality (27 [17%] patients treated with fluconazole versus 34 [21%] patients treated with amphotericin B) and mortality from fungal infection (7 [4%] patients treated with fluconazole versus 5 [3%] patients treated with amphotericin B) were similar in each study group. CONCLUSIONS: Intravenous fluconazole can be an effective and safe alternative to amphotericin B for empiric antifungal therapy in many febrile neutropenic patients. However, because fluconazole may be ineffective in the treatment of Aspergillus, patients at risk for that infection should be evaluated by chest radiograph, computed tomographic scanning, and cultures before the use of empiric fluconazole therapy.


Asunto(s)
Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Fiebre/tratamiento farmacológico , Fluconazol/uso terapéutico , Micosis/tratamiento farmacológico , Neoplasias/complicaciones , Neutropenia/complicaciones , Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Causas de Muerte , Femenino , Fiebre/etiología , Fluconazol/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Micosis/etiología , Micosis/mortalidad , Micosis/prevención & control , Resultado del Tratamiento
6.
Clin Infect Dis ; 30(5): 790-7, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10817685

RESUMEN

The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.


Asunto(s)
Quimioterapia Combinada/uso terapéutico , Enterococcus faecium/efectos de los fármacos , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Resistencia a la Vancomicina , Virginiamicina/uso terapéutico , Adolescente , Adulto , Anciano , Antibacterianos/farmacología , Niño , Preescolar , Quimioterapia Combinada/farmacología , Femenino , Infecciones por Bacterias Grampositivas/mortalidad , Hospitalización , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Resultado del Tratamiento , Virginiamicina/farmacología
7.
Clin Infect Dis ; 30(1): 195-7, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10619754

RESUMEN

From March 1997 through November 1997, 8 allogenic bone marrow transplant (BMT) patients developed Stenotrophomonas maltophilia bacteremia on the hematology service at UCLA Medical Center (Los Angeles). Five of these patients had undergone transplantation during the same hospitalization that S. maltophilia bacteremia was detected (case patients). Compared with 7 concurrently hospitalized allogenic BMT patients (control patients), the 5 case patients were more likely to have been hospitalized in room A (P=.045), to have severe neutropenia on the culture date (P=.028), to have a longer duration of severe neutropenia (P=.05), to have severe mucositis (P=. 028), and to have received total parenteral nutrition (P=.028). Pulsed-field gel electrophoresis revealed that 2 of 3 isolates from case patients hospitalized in room A were identical. In allogenic BMT patients, severe neutropenia and severe mucositis may promote infection with S. maltophilia by impairing host defenses.


Asunto(s)
Bacteriemia/epidemiología , Trasplante de Médula Ósea/efectos adversos , Brotes de Enfermedades , Infecciones por Bacterias Gramnegativas/epidemiología , Stenotrophomonas/clasificación , Stenotrophomonas/aislamiento & purificación , Bacteriemia/etiología , Bacteriemia/microbiología , Estudios de Casos y Controles , Electroforesis en Gel de Campo Pulsado , Infecciones por Bacterias Gramnegativas/etiología , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Mucosa Bucal , Neutropenia/complicaciones , Nutrición Parenteral Total , Factores de Riesgo , Stenotrophomonas/genética , Estomatitis/complicaciones , Trasplante Homólogo/efectos adversos
9.
Proc Natl Acad Sci U S A ; 96(21): 12010-5, 1999 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-10518567

RESUMEN

We previously have demonstrated that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified low density lipoprotein (MM-LDL), activates endothelial cells to bind monocytes. 1-Palmitoyl-2- (5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC) and 1- palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine (PGPC), which are present in OxPAPC, MM-LDL, and atherosclerotic lesions, were shown to have a major role in the activation of endothelial cells. We now demonstrate that these two highly similar molecules have dramatically different effects on leukocyte endothelial interactions. POVPC is a potent regulator of monocyte-specific endothelial interactions. Treatment of endothelial cells with POVPC increased monocyte binding by inducing the surface expression of the connecting segment 1 domain of fibronectin; no increase in neutrophil binding was observed. In addition, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. This inhibition was mediated by a protein kinase A-dependent pathway, resulting in down-regulation of NF-kappaB-dependent transcription. In contrast, PGPC induced both monocyte and neutrophil binding and expression of E-selectin and vascular cell adhesion molecule 1. We present evidence to suggest that the two phospholipids act by different novel receptors present in Xenopus laevis oocytes and that POVPC, but not PGPC, stimulates a cAMP-mediated pathway. At concentrations equal to that present in MM-LDL, the effect of POVPC dominates and inhibits PGPC-induced neutrophil binding and E-selectin expression in endothelial cells. In summary, our data provide evidence that both POVPC and PGPC are important regulators of leukocyte-endothelial interactions and that POVPC may play a dominant role in a number of chronic inflammatory processes where oxidized phospholipids are known to be present.


Asunto(s)
Endotelio Vascular/fisiología , Monocitos/fisiología , Neutrófilos/fisiología , Éteres Fosfolípidos/farmacología , Fosfolípidos/química , Aorta/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Adhesión Celular/fisiología , Supervivencia Celular , Células Cultivadas , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Selectina E/metabolismo , Endotelio Vascular/efectos de los fármacos , Fibronectinas/metabolismo , Humanos , Modelos Biológicos , Monocitos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , ARN Mensajero/metabolismo , Transfección , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/metabolismo
10.
J Clin Invest ; 103(5): 613-25, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10074478

RESUMEN

We have shown previously that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) induces monocyte but not neutrophil binding. This monocyte binding was not mediated by endothelial E-selectin, P-selectin, vascular cell adhesion molecule-I, or intercellular adhesion molecule-I, suggesting an alternative monocyte-specific adhesion molecule. We now show that moncytic alpha4beta1 integrins mediate binding to MM-LDL-treated endothelial cells. We present data suggesting that the expression of the connecting segment-1 (CS-1) domain of fibronectin (FN) is induced on the apical surface of HAEC by MM-LDL and is the endothelial alpha4beta1 ligand in MM-LDL-treated cells. Although the levels of CS-1 mRNA and protein were not increased, we show that MM-LDL treatment causes deposition of FN on the apical surface by activation of beta1integrins, particularly those associated with alpha5 integrins. Activation of beta1 by antibody 8A2 also induced CS-1-mediated monocyte binding. Confocal microscopy demonstrated the activated beta1 and CS-1colocalize in concentrated filamentous patches on the apical surface of HAEC. Both anti-CS-1 and an antibody to activated beta1 showed increased staining on the luminal endothelium of human coronary lesions with active monocyte entry. These results suggest the importance of these integrin ligand interactions in human atherosclerosis.


Asunto(s)
Endotelio Vascular/citología , Integrina beta1/metabolismo , Lipoproteínas LDL/farmacología , Monocitos/citología , Péptidos/metabolismo , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Endotelio Vascular/metabolismo , Fibronectinas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular , Lipoproteínas LDL/metabolismo , Microscopía Confocal , Monocitos/metabolismo
11.
Circ Res ; 84(3): 345-51, 1999 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-10024309

RESUMEN

Atherosclerotic lesion development is characterized by the recruitment of leukocytes, principally monocytes, to the vessel wall. Considerable interest has been focused on the adhesion molecule(s) involved in leukocyte/endothelial interactions. The goal of the present study was to determine the role of the very late antigen-4 (VLA-4) integrin/ligand interaction in fatty streak development using murine models. Because alpha4 null mice are not viable, a peptidomimetic was used to block VLA-4-mediated leukocyte binding. The ability of a synthetic peptidomimetic of connecting segment-1 (CS-1 peptide) to block the recruitment of leukocytes and the accumulation of lipid in the aortic sinus of either wild-type mice (strain C57BL/6J) or mice with a low-density lipoprotein null mutation (LDLR-/-) maintained on an atherogenic diet was assessed. The active (Ac) CS-1 peptide or scrambled (Sc) CS-1 peptide was delivered subcutaneously into mice using a mini osmotic pump. Mice were exposed to the peptide for 24 to 36 hours before the onset of the atherogenic diet. In C57BL/6J mice, leukocyte entry into the aortic sinus, as assessed by en face preparations, was inhibited by the active peptide (Ac=28+/-4, Sc=54+/-6 monocytes/valve; P=0.004). Additionally, frozen sections stained with Oil Red O were analyzed to assess lipid accumulation in the aortic sinus. C57BL/6J mice that received the (Ac) compound demonstrated significantly reduced lesion areas as compared with mice that received the (Sc) peptide (Ac=4887+/-4438 microm2, Sc=15 009 +/-5619 microm2; P<0.0001). In a separate study, LDLR-/- mice were implanted with pumps containing either the (Ac) or (Sc) peptide before initiation of the atherogenic diet. Because LDLR-/- mice fed a chow diet displayed small lesions at 14 weeks, the effects of the peptide seen in these animals represented a change in early lipid accumulation rather than initiation. By using whole-mount preparations, the (Ac) but not the (Sc) peptide significantly reduced the area of lipid accumulation in the aortic sinus, resulting in an approximate 66% decrease. Plasma analysis from all studies revealed concentrations of peptide to be present at levels previously determined by in vitro analysis to block adhesion. (Ac) CS-1 peptide, which blocks VLA-4 on the leukocyte surface, is effective in reducing leukocyte recruitment and lipid accumulation in the aortic sinus. The present study provides in vivo evidence that the VLA-4 integrin plays an important role in the initiation of the atherosclerotic lesion and lipid accumulation, and it suggests a potential therapeutic strategy for this disease.


Asunto(s)
Arteriosclerosis/prevención & control , Integrinas/fisiología , Leucocitos/fisiología , Receptores Mensajeros de Linfocitos/fisiología , Animales , Aorta/metabolismo , Femenino , Fibronectinas/fisiología , Humanos , Integrina alfa4beta1 , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Conejos , Receptores de LDL/genética , Receptores de LDL/fisiología , Molécula 1 de Adhesión Celular Vascular/fisiología
12.
Clin Infect Dis ; 26(3): 576-83, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9524826

RESUMEN

In a prospective, randomized, controlled trial, we compared sulbactam/cefoperazone with imipenem as empirical monotherapy for febrile, granulocytopenic patients; 101 patients received sulbactam/cefoperazone (2 g/4 g every 12 hours) and 102 patients received imipenem (500 mg every 6 hours). Documented infections were present in 40% of patients treated with sulbactam/cefoperazone (40 of 101) and in 39% of patients receiving imipenem (40 of 102). The number of pretherapy gram-positive pathogens (52 isolates) was twice the number of pretherapy gram-negative pathogens (26 isolates). The overall favorable clinical response rates for sulbactam/cefoperazone (91 of 103 patients, or 88%) and imipenem (84 of 104 patients, or 81%) were similar. Both drugs were generally well tolerated. However, diarrhea occurred more often in patients treated with sulbactam/cefoperazone (31 of 101 patients, or 31%, vs. 15 of 102 patients, or 15%; P = .007), while seizures developed only in patients receiving imipenem (0 of 101 patients vs. 3 of 102 patients, or 3%). Superinfections developed in 16% of patients in both study groups but were infrequently caused by beta-lactam-resistant gram-negative bacilli (two cases with sulbactam/cefoperazone therapy and six cases with imipenem). These results support the efficacy and safety of either sulbactam/cefoperazone or imipenem as empirical monotherapy for febrile granulocytopenic patients.


Asunto(s)
Agranulocitosis/tratamiento farmacológico , Cefoperazona/uso terapéutico , Quimioterapia Combinada/uso terapéutico , Imipenem/uso terapéutico , Sulbactam/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Agranulocitosis/microbiología , Cefoperazona/efectos adversos , Femenino , Fiebre/tratamiento farmacológico , Fiebre/microbiología , Humanos , Imipenem/efectos adversos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Prospectivos , Sulbactam/administración & dosificación , Sulbactam/efectos adversos , Sobreinfección
13.
Circ Res ; 80(6): 810-8, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9168783

RESUMEN

Leukocyte binding to the endothelium is one of the earliest events in the occurrence of atherosclerosis. Leukocyte adhesion molecules involved in this process have not been definitely identified. We have found that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) for 24 hours caused a 2- to 3-fold increase of P-selectin protein, with little change in P-selectin surface expression. A 15-minute histamine treatment of cells exposed to MM-LDL caused a 50% to 100% increase in P-selectin surface expression compared with cells not treated with the lipoprotein. This increase resulted in a 2-fold increase in binding of leukocytes to the endothelium. Immunostaining of permeabilized HAECs after MM-LDL treatment also revealed a highly reproducible increase in intracellular P-selectin associated with rod-shaped structures, typical of Weibel-Palade bodies. Oxidized phospholipids were shown to be mainly responsible for the action of MM-LDL. This increased P-selectin expression was associated with MM-LDL-induced cAMP elevation. Like histamine, highly oxidized low-density lipoprotein, especially the oxidized fatty acids, caused immediate redistribution of P-selectin to the cell surface followed by reinternalization. Immunohistochemical staining showed that endothelial cells on human fatty streak lesions expressed increased levels of P-selectin compared with nonlesion areas. These studies suggest that P-selectin may play an important role in early recruitment of mononuclear cells to the subendothelium in human atherosclerosis and that oxidized lipoproteins may contribute to the increased expression of this molecule by increasing intracellular stores and causing redistribution to the cell surface.


Asunto(s)
Lipoproteínas LDL/farmacología , Selectina-P/metabolismo , Aorta/citología , Aorta/efectos de los fármacos , Aorta/metabolismo , Arteriosclerosis/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Fraccionamiento Químico , AMP Cíclico/fisiología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Inmunohistoquímica , Lípidos/farmacología , Selectina-P/biosíntesis , Selectina-P/fisiología
14.
Cancer ; 78(11): 2421-6, 1996 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-8941014

RESUMEN

BACKGROUND: Second primary malignancies have been described in patients with both solid tumors and hematologic malignancies. However, an association between renal cell carcinoma and lymphoid malignancies has rarely been described. Eight patients with both disorders are described and possible explanations for the association are reviewed. METHODS: A retrospective review of records from patients with renal cell carcinoma, lymphoma, leukemia, or myeloma discharged from the University of California at Los Angeles between July 1, 1993 and June 30, 1995 was performed. Renal cell carcinoma was diagnosed in 186 patients, whereas 405 had a lymphoid malignancy. Eight patients with both disorders were identified. RESULTS: In four of the eight patients, the renal cell carcinoma was diagnosed prior to their hematologic malignancy, whereas in the remaining four patients, the lymphoid malignancy was diagnosed first. Renal cell carcinoma is observed in the general population in 12.5 persons per 100,000 and hematologic malignancies in 31.8 per 100,000. The number of cases of lymphoid malignancies expected in the 186 renal cell carcinoma patients is lower than the 4 cases actually observed (P < 0.01). Likewise, the number of renal tumors expected in the 405 patients with hematologic malignancies is fewer than the 4 cases observed (P < 0.01). CONCLUSIONS: The incidence of renal cell carcinoma and lymphoid malignancy occurring in the same patient is higher than that expected in the general population. This association cannot be explained by treatment-related development of a second malignancy. A common genetic mutation or an immunomodulatory role of the first malignancy predisposing to the second are possibilities but further investigation is warranted.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Linfoma , Neoplasias Primarias Secundarias , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapia , Resultado Fatal , Femenino , Enfermedad de Hodgkin , Humanos , Neoplasias Renales/patología , Neoplasias Renales/terapia , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma/patología , Linfoma/terapia , Linfoma de Células B/patología , Linfoma de Células B/terapia , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/terapia , Linfoma de Células T/patología , Linfoma de Células T/terapia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Estudios Retrospectivos , Macroglobulinemia de Waldenström/patología , Macroglobulinemia de Waldenström/terapia
15.
Arterioscler Thromb Vasc Biol ; 16(7): 831-42, 1996 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8673557

RESUMEN

Recent data support the hypothesis that the fatty streak develops in response to specific phospholipids contained in LDL that become trapped in the artery wall and become oxidized as a result of exposure to the oxidative waste of the artery wall cells. The antioxidants present within both LDL and the microenvironments in which LDL is trapped function to prevent the formation of these biologically active, oxidized lipids. Enzymes associated with LDL and HDL (eg, platelet activating factor acetylhydrolase) or with HDL alone (eg, paraoxonase) destroy these biologically active lipids. The regulation and expression of these enzymes are determined genetically and are also significantly modified by environmental influences, including the acute-phase response or an atherogenic diet. The balance of these multiple factors leads to an induction or suppression of the inflammatory response in the artery wall and determines the clinical course.


Asunto(s)
Arteriosclerosis/etiología , Peroxidación de Lípido , Animales , Arterias/metabolismo , Arteriosclerosis/genética , Humanos , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Fosfolípidos/metabolismo
16.
Am J Cardiol ; 76(9): 18C-23C, 1995 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-7572682

RESUMEN

The earliest lesion in the development of an atherosclerotic plaque is the fatty streak. This chronic inflammatory reaction results from a sequence of events that begins with the trapping of low density lipoprotein (LDL) in the subendothelial space of the artery wall. The trapped LDL is seeded with oxidative species released by the overlying endothelium, and lipid oxidation is initiated within the LDL particle. Some of the lipids that result lead to the activation of NFkB-like transcription factors that cause the expression of genes whose protein products mediate monocyte binding, monocyte chemotaxis into the subendothelial space, and conversion into macrophages. At least 1 major gene modulates the oxidation of LDL lipids and/or the biologic response to these lipids. The inverse relation between high density lipoprotein (HDL) and atherosclerotic events may in part be due to enzymes associated with HDL that destroy the biologically active lipids generated in LDL.


Asunto(s)
Arteriosclerosis/etiología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Animales , Arteriosclerosis/genética , Arteriosclerosis/metabolismo , Endotelio Vascular/metabolismo , Matriz Extracelular/metabolismo , Humanos , Lipoproteínas HDL/fisiología , Lipoproteínas LDL/metabolismo , Macrófagos/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Monocitos/fisiología , FN-kappa B/metabolismo , Oxidación-Reducción , Fosfolipasas A/fisiología
17.
Arterioscler Thromb ; 14(3): 427-33, 1994 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8123647

RESUMEN

Treatment of rabbit aortic endothelial cells, human umbilical vein endothelial cells, and human aortic endothelial cells for 4 hours with minimally oxidized low-density lipoprotein (MM-LDL) induced the adhesion of monocytes but not neutrophils or lymphocytes to these cells. This induction was blocked by inhibitors of glycoprotein synthesis (cycloheximide and tunicamycin), and binding was abolished by treatment of cells with low levels of trypsin, suggesting that the binding molecule(s) is a protein. There was no increase in binding of antibodies to E-selectin, vascular cell adhesion molecule-1 (VCAM-1), or intercellular adhesion molecule-1 (ICAM-1) after treatment of cells with MM-LDL. Treatment of endothelial cells with Fab fragments of antibody to monocyte chemotactic protein-1 or to fibronectin did not block monocyte binding. Several sugars (lactose-1-phosphate, maltose-1-phosphate, and N-acetylglucosamine) inhibited monocyte binding to cells treated with MM-LDL, but binding was not blocked by mannose-6-phosphate, fructose-6-phosphate, glucose-1-phosphate, or glucose-6-phosphate. EDTA or EGTA treatment inhibited binding, which was restored by adding either calcium or magnesium. We conclude that the binding of monocytes to endothelial cells induced by a 4-hour treatment with MM-LDL is caused by a binding molecule(s) other than E-selectin, VCAM-1, or ICAM-1 and that carbohydrate chains on the monocytes or the endothelium play a role in binding.


Asunto(s)
Moléculas de Adhesión Celular/análisis , Endotelio Vascular/química , Lipoproteínas LDL/farmacología , Monocitos/fisiología , Adhesión Celular , Línea Celular , Quimiocina CCL2 , Factores Quimiotácticos/fisiología , Endotelio Vascular/efectos de los fármacos , Fibronectinas/fisiología , Humanos , Oxidación-Reducción
18.
J Clin Invest ; 92(1): 471-8, 1993 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8392092

RESUMEN

We have previously shown that minimally oxidized LDL (MM-LDL) activated endothelial cells to increase their interaction with monocytes but not neutrophils, inducing monocyte but not neutrophil binding and synthesis of monocyte chemotactic protein-1 and monocyte colony-stimulating factor (M-CSF). In the present studies we have examined the signaling pathways by which this monocyte-specific response is induced. Both induction of monocyte binding and mRNA levels for M-CSF by MM-LDL were not inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effects of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular cAMP levels. Agents which increased cAMP levels, including cholera toxin, pertussis toxin, dibutyryl cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NF kappa B, suggesting a role for this transcription factor in activation of monocyte-endothelial interactions. Although endothelial leukocyte adhesion molecule (ELAM) mRNA synthesis can be regulated by NF kappa B, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We present evidence that induction of neutrophil binding by LPS is actually suppressed by agents that elevated cAMP levels.


Asunto(s)
AMP Cíclico/farmacología , Endotelio Vascular/fisiología , Inflamación/patología , Leucocitos/citología , Lipoproteínas LDL/fisiología , Animales , Péptidos Catiónicos Antimicrobianos , Secuencia de Bases , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Técnicas In Vitro , Lipoproteínas LDL/química , Factor Estimulante de Colonias de Macrófagos/genética , Datos de Secuencia Molecular , FN-kappa B/metabolismo , Oligodesoxirribonucleótidos/química , Oxidación-Reducción , Proteínas/genética , ARN Mensajero/genética , Conejos , Sistemas de Mensajero Secundario , Transducción de Señal
20.
Gut ; 33(8): 1020-3, 1992 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1398224

RESUMEN

Helicobacter pylori is associated with an inflammatory reaction in the stomach and duodenum, yet the mechanism of this inflammatory infiltrate is unknown. The ability of Helicobacter pylori to secrete a factor that attracts leucocytes is investigated. Helicobacter pylori conditioned supernatant attracted neutrophils and monocytes with 50-100% of the activity of control chemotactic factor, 10(-8) M formyl-methionine-leucine-phenylalanine. Strains derived from individuals with ulcer or non-ulcer associated H pylori infections displayed similar chemotactic activity. Preliminary characterisation shows that the factor has a molecular weight of less than 3000, is heat stable, is acid resistant, and can be diluted at least 10-fold. Checkerboard analysis confirmed that the activity was chemotactic rather than chemokinetic. This chemotactic activity could play a role in the pathogenesis of Helicobacter pylori gastritis.


Asunto(s)
Factores Quimiotácticos/biosíntesis , Helicobacter pylori/metabolismo , Monocitos , Neutrófilos , Factores Quimiotácticos/análisis , Quimiotaxis de Leucocito , Humanos , Peso Molecular , N-Formilmetionina Leucil-Fenilalanina , Factores de Tiempo
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