RESUMEN
BACKGROUND: Smoking prevalence is declining at a slower rate in rural than urban settings in the United States (U.S.), and known predictors of smoking do not readily account for this trend difference. Given that socioeconomic and psychosocial determinants of health disparities accumulate in rural settings and that life-course disadvantages are often greater in women than men, we examined whether smoking trends are different for rural and urban men and women. METHOD: We used yearly cross-sectional data (nâ¯=â¯303,311) from the U.S. National Survey on Drug Use and Health (NSDUH) from 2007 through 2014 to compare cigarette smoking trends in men and women across rural and urban areas. Current smoking status was modelled using logistic regression controlling for confounding risk factors. RESULTS: Regression derived graphs predicting unadjusted prevalence estimates and 95% confidence bands revealed that whereas the smoking trends of rural men, urban men, and urban women significantly declined from 2007 to 2014, the trend for rural women was flat. Controlling for demographic, socioeconomic and psychosocial predictors of smoking did not explain rural women's significantly different trend from those of the other three groups. CONCLUSION: Rural women lag behind rural men, urban men and urban women in decreasing smoking, a health disparity finding that supports the need for tobacco control and regulatory policies and interventions that are more effective in reducing smoking among rural women.
Asunto(s)
Población Rural/estadística & datos numéricos , Fumar/epidemiología , Productos de Tabaco/estadística & datos numéricos , Uso de Tabaco/tendencias , Población Urbana/estadística & datos numéricos , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Factores Sexuales , Fumar/tendencias , Factores Socioeconómicos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Rural areas of the United States have a higher smoking prevalence than urban areas. However, no recent studies have rigorously examined potential changes in this disparity over time or whether the disparity can be explained by demographic or psychosocial characteristics associated with smoking. The present study used yearly cross sectional data from the National Survey on Drug Use and Health from 2007 through 2014 to examine cigarette smoking trends in rural versus urban areas of the United States. The analytic sample included 303,311 respondents. Two regression models were built to examine (a) unadjusted rural and urban trends in prevalence of current smoking and (b) whether differences remained after adjusting for demographic and psychosocial characteristics. Results of the unadjusted model showed disparate and diverging cigarette use trends during the 8-year time period. The adjusted model also showed diverging trends, initially with no or small differences that became more pronounced across the 8-year period. We conclude that differences reported in earlier studies may be explained by differences in rural versus urban demographic and psychosocial risk factors, while more recent and growing disparities appear to be related to other factors. These emergent differences may be attributable to policy-level tobacco control and regulatory factors that disproportionately benefit urban areas such as enforcement of regulations around the sale and marketing of tobacco products and treatment availability. Strong federal policies and targeted or tailored interventions may be important to expanding tobacco control and regulatory benefits to vulnerable populations including rural Americans.
Asunto(s)
Disparidades en el Estado de Salud , Población Rural/estadística & datos numéricos , Fumar/epidemiología , Fumar/tendencias , Población Urbana/estadística & datos numéricos , Adolescente , Adulto , Anciano , Estudios Transversales , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Mercadotecnía , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Población Rural/tendencias , Factores Socioeconómicos , Productos de Tabaco , Estados Unidos/epidemiología , Población Urbana/tendenciasAsunto(s)
Antineoplásicos/farmacología , Células de la Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Leucemia Mieloide Aguda/patología , Quinazolinas/farmacología , Tretinoina/farmacología , Células de la Médula Ósea/citología , Sinergismo Farmacológico , Gefitinib , Células HL-60 , HumanosRESUMEN
Recurrent chromosomal translocations involving the RAR alpha locus on chromosome 17 are the hallmark of acute promyelocytic leukemia (APL). The RAR alpha gene fuses to variable partners (PML, PLZF, NPM, NuMA and STAT5B: X genes) leading to the expression of APL-specific fusion proteins with identical RAR alpha moieties. To analyse whether the variable X moiety could affect the activity of the fusion protein in vivo, we generated and characterized, on a comparative basis, NPM/RAR alpha transgenic mice (TM) in which the fusion gene is expressed under the control of a human Cathepsin G (hCG) minigene. We compared the features of the leukemia observed in these TM with those in hCG-PML/RAR alpha and hCG-PLZF/RAR alpha TM. In all three transgenic models, leukemia developed after a variably long latency, with variable penetrance. However, the three leukemias displayed distinct cytomorphological features. hCG-NPM/RAR alpha leukemic cells resembled monoblasts. This phenotype contrasts with what was observed in the hCG-PML/RAR alpha TM model in which the leukemic phase was characterized by the proliferation of promyelocytic blasts. Similarly, hCG-PLZF/RAR alpha TM displayed a different phenotype where terminally differentiated myeloid cells predominated. Importantly, the NPM/RAR alpha oncoprotein was found to localize in the nucleolus, unlike PML/RAR alpha and PLZF/RAR alpha, thus possibly interfering with the normal function of NPM. Similarly to what was observed in human APL patients, we found that NPM/RAR alpha and PML/RAR alpha, but not PLZF/RAR alpha leukemia, was responsive to all-trans retinoic acid (ATRA) or As2O3 treatments. Taken together, our results underscore the critical relevance of the X moiety in dictating the biology of the disease and the activity of the APL fusion oncoprotein.
Asunto(s)
Proteínas de Unión al ADN/genética , Fusión Génica , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Receptores de Ácido Retinoico/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Animales , Antineoplásicos/farmacología , Catepsina G , Catepsinas/genética , Catepsinas/fisiología , Proliferación Celular , Transformación Celular Neoplásica , Humanos , Factores de Transcripción de Tipo Kruppel , Ratones , Ratones Transgénicos , Fenotipo , Proteína de la Leucemia Promielocítica , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Receptor alfa de Ácido Retinoico , Serina Endopeptidasas/genética , Serina Endopeptidasas/fisiología , Translocación Genética , Tretinoina/farmacologíaRESUMEN
The t(15;17)(q22;q21) translocation is tightly linked to the APL phenotype, and the resultant PML-RAR fusion can be demonstrated in 98% of APL cases. Rare variant translocations have been reported, the majority of which on detailed analysis represent cryptic PML-RAR fusions. However, a handful of APL cases have been described with different genotypes. These include the t(11;17)(q23;q21) that produces the PLZF-RAR fusion, t(5;17)(q35;q21) that forms NPM-RAR, t(11;17)(q13;q21) that generates NUMA-RAR, and der(17) that creates STAT5b-RAR. In this review we will discuss these variant translocations, and discuss the insights that we have gained from their study.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 17 , Leucemia Promielocítica Aguda/genética , Translocación Genética , HumanosRESUMEN
A novel method for joint detection of association caused by linkage disequilibrium (LD) and estimation of both recombination fraction and linkage disequilibrium parameters was compared to several existing implementations of the transmission/disequilibrium test (TDT) and modifications of the TDT in the simulated genetic isolate data from Genetic Analysis Workshop 12. The first completely genotyped trio of affected child and parents was selected from each family in each replicate so that the TDT tests are valid tests of linkage and association, rather than being only valid as tests for linkage. In general, power to detect LD using the genome-wide scan markers was inadequate in the individual replicate samples, but the power was better when analyzing several SNP markers in candidate gene 1.
Asunto(s)
Genotipo , Desequilibrio de Ligamiento , Modelos Genéticos , Adulto , Análisis de Varianza , Niño , Mapeo Cromosómico/estadística & datos numéricos , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Escala de Lod , Masculino , Polimorfismo de Nucleótido Simple , Carácter Cuantitativo HeredableAsunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 17/genética , Proteínas de Unión al ADN/genética , Leucemia Monocítica Aguda/genética , Proteínas de Neoplasias/genética , Proto-Oncogenes , Receptores de Ácido Retinoico/genética , Factores de Transcripción , Translocación Genética , Adulto , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 17/ultraestructura , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Proteína de la Leucemia Mieloide-Linfoide , Proteínas de Fusión Oncogénica/genética , Receptor alfa de Ácido RetinoicoRESUMEN
The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the genes for nucleophosmin (NPM) and the retinoic acid receptor alpha (RARalpha). Two NPM-RAR molecules are expressed as a result of alternative RNA splicing. Both contain RARalpha sequences that encode the DNA binding, heterodimerization, and ligand activation domains of RARalpha. This study was designed to test the ability of these fusion proteins to act as transcriptional activators of retinoic acid responsive promoters. The NPM-RAR fusion proteins bind to retinoic acid response element sequences as either homodimers or as heterodimers with RXR. Transcription of retinoic acid-inducible promoters is activated by the fusion proteins in the presence of retinoic acid. The level of transactivation induced by the NPM-RAR fusions differs from the level of transactivation induced by wild-type RARalpha in both a promoter and cell specific fashion, and more closely parallels the pattern of activation of the PML-RAR fusion than wild-type RARalpha. In addition, NPM-RAR decreases basal transcription from some promoters and acts in a dominant-negative fashion when co-transfected with wild-type RARalpha. Both NPM-RAR and PML-RAR interact with the co-repressor protein SMRTe in a manner that is less sensitive than RARalpha to dissociation by retinoic acid. Retinoic acid induces binding of the co-activator protein RAC3. These data indicate that the NPM-RAR fusion proteins can modulate expression of retinoid-responsive genes in a positive or negative manner, depending on context of the promoter, and lend support to the hypothesis that aberrant transcriptional activation underlies the APL phenotype. (Blood. 2000;95:2683-2690)
Asunto(s)
Cromosomas Humanos Par 17 , Cromosomas Humanos Par 5 , Regulación Neoplásica de la Expresión Génica , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Humanos , Proteínas Represoras/genética , Transcripción Genética , Células Tumorales CultivadasAsunto(s)
Cromatina/metabolismo , Regulación Leucémica de la Expresión Génica , Leucemia/genética , Proto-Oncogenes , Acetilación , Antineoplásicos/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Cromatina/ultraestructura , Proteínas Cromosómicas no Histona/fisiología , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de Histona Desacetilasas , N-Metiltransferasa de Histona-Lisina , Histonas/química , Histonas/fisiología , Humanos , Leucemia/metabolismo , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Modelos Genéticos , Proteína de la Leucemia Mieloide-Linfoide , Proteínas de Neoplasias/fisiología , Conformación de Ácido Nucleico , Nucleosomas/ultraestructura , Proteínas de Fusión Oncogénica/fisiología , Procesamiento Proteico-Postraduccional , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Recombinantes de Fusión/fisiología , Electricidad Estática , Factores de Transcripción/fisiología , Translocación Genética , Tretinoina/farmacología , Tretinoina/uso terapéuticoRESUMEN
Retinoic acid receptor alpha (RARalpha) is the target of several chromosomal translocations associated with acute promyelocytic leukemias (APLs). These rearrangements fuse RARalpha to different partner genes creating the chimeric proteins: PML-RARalpha, PLZF-RARalpha, and NPM-RARalpha. Although the vast majority of APLs respond to retinoic acid therapy, those associated with PLZF-RARalpha are resistant. We have used retroviruses to express PML-RARalpha, PLZF-RARalpha, NPM-RARalpha, RARalpha403 (a dominant negative mutant of RARalpha), and wild-type RARalpha in murine bone marrow progenitors and found that all of these constructs blocked differentiation and led to the immortalization of myeloid progenitors. This cellular transformation is specific to an alteration of the RARalpha pathway because overexpression of RARbeta, RARgamma, or RXRalpha did not result in similar growth perturbations. Pharmacological doses of RA induced differentiation and inhibited proliferation of cells transformed with either of the APL fusion genes, including PLZF-RARalpha, whereas physiological retinoic acid concentrations were sufficient to reverse the phenotype of cells transformed with wild-type RARalpha. The cellular responses to retinoic acid were accompanied by a sharp decrease in the amount of the RARalpha-fusion proteins expressed in the cells. Our findings suggest that the oncogenicity of RARalpha-fusion proteins results from their nature to behave as unliganded RARalpha in the presence of physiological concentrations of retinoic acid.
Asunto(s)
Transformación Celular Neoplásica/genética , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/fisiología , Proteínas de Fusión Oncogénica/fisiología , Receptores de Ácido Retinoico/biosíntesis , Animales , Diferenciación Celular , Células Cultivadas , Vectores Genéticos/genética , Células Madre Hematopoyéticas/patología , Humanos , Ratones , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Receptores de Ácido Retinoico/genética , Proteínas Recombinantes de Fusión/fisiología , Receptor alfa de Ácido Retinoico , Retroviridae/genética , Eliminación de Secuencia , Transfección , Ensayo de Tumor de Célula MadreRESUMEN
The (8;21) translocation, found in 12% of acute myeloid leukemia (AML), creates the chimeric fusion product, AML1-ETO. Previously, we demonstrated that the ETO moiety recruits a transcription repression complex that includes the histone deacetylase (HDAC1) enzyme. Here, we used inhibitors of HDAC1 to study the pathophysiology of AML1-ETO. Both the potent inhibitor, trichostatin (TSA), and the well-known but less specific inhibitor, phenylbutyrate (PB), could partially reverse ETO-mediated transcriptional repression. PB was also able to induce partial differentiation of the AML1-ETO cell line, Kasumi-1. With the intention of developing a clinically useful protocol, we combined PB with a number of other agents that induced differentiation and apoptosis of Kasumi-1 cells. In summary, transcriptional repression mediated by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and relief of repression using agents such as PB (alone or in combination) may prove to be therapeutically useful.
Asunto(s)
Proteínas de Unión al ADN/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Leucemia Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas , Factores de Transcripción/química , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacos , Células 3T3 , Enfermedad Aguda , Animales , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Humanos , Ácidos Hidroxámicos/farmacología , Leucemia Mieloide/enzimología , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patología , Ratones , Fenilbutiratos/farmacología , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Recombinantes de Fusión/metabolismo , Translocación Genética , Células Tumorales CultivadasRESUMEN
The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-most-frequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1/ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR/mSin3/HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1/ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.
Asunto(s)
Proteínas de Unión al ADN/genética , Histona Desacetilasas/metabolismo , Leucemia Mieloide/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas , Proteínas Represoras/metabolismo , Proteínas de Saccharomyces cerevisiae , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Translocación Genética , Enfermedad Aguda , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Cartilla de ADN , Proteínas de Unión al ADN/metabolismo , Histona Desacetilasas/genética , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/química , Co-Represor 1 de Receptor Nuclear , Unión Proteica , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Represoras/química , Proteínas Represoras/genética , Transcripción Genética/genéticaRESUMEN
BACKGROUND: Isolated thrombosis of the deep cerebral venous system is very rare and is associated with a poor prognosis. Antithrombin III (AT III) deficiency is a disorder of hypercoagulability associated with deep venous thrombosis and recurrent pulmonary emboli. We report a case of an 18-year-old man who presented with spontaneous thrombosis of the deep cerebral veins and straight dural sinus as the initial presentation of a previously undiagnosed AT III deficiency. METHODS: The patient was managed using direct endovascular infusion of the fibrinolytic agent urokinase followed by intravenous heparin. RESULTS: The technique was successful in establishing patency of the deep cerebral venous system. The patient experienced a good clinical outcome. CONCLUSIONS: Direct endovascular thrombolysis is a potentially effective management strategy for isolated thrombosis of the deep cerebral venous system.
Asunto(s)
Deficiencia de Antitrombina III , Trastornos de la Coagulación Sanguínea/diagnóstico , Embolia y Trombosis Intracraneal/tratamiento farmacológico , Activadores Plasminogénicos/uso terapéutico , Terapia Trombolítica , Activador de Plasminógeno de Tipo Uroquinasa/uso terapéutico , Adulto , Trastornos de la Coagulación Sanguínea/complicaciones , Venas Cerebrales , Diagnóstico Diferencial , Humanos , Embolia y Trombosis Intracraneal/etiología , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Trombosis de los Senos Intracraneales/tratamiento farmacológico , Terapia Trombolítica/métodos , Tomografía Computarizada por Rayos XRESUMEN
All-trans retinoic acid (ATRA) induces differentiation of acute promyelocytic leukemic (APL) blasts from patients with t(15;17) APL. However, blasts from patients with the t(11;17) variant do not differentiate in response to ATRA. Our group has identified a variant of APL characterized by t(5;17) and expression of the NPM-RAR fusion gene product. From case reports it has been difficult to establish whether ATRA induces clinical responses in patients with this variant. In order to determine whether t(5;17) blasts differentiate with ATRA, we harvested mononuclear bone marrow cells from a patient with t(5;17) APL at time of relapse and cultured them in medium containing ATRA. Morphologic analysis of cytospins after 7 days of culture revealed that 60% of cells in the ATRA-treated culture had differentiated into mature neutrophilic forms, as opposed to less than 1% in the control culture. Seventy-three percent of cells acquired NBT positivity after exposure to ATRA, compared with 1% in the control culture. These results indicate that t(5;17) blasts retain the ability to terminally differentiate in response to retinoic acid.
Asunto(s)
Cromosomas Humanos Par 17 , Cromosomas Humanos Par 5 , Leucemia Promielocítica Aguda/patología , Translocación Genética , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Humanos , Leucemia Promielocítica Aguda/genéticaRESUMEN
We have studied an acute promyelocytic leukemia (APL) patient with a variant t(5;17)(q32;q12). This translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). Two alternatively spliced transcripts are expressed, which differ in 129 bases immediately upstream of the RARA sequence. The NPM sequences contained in the shorter NPM-RAR cDNA are identical to the NPM sequences contained in the NPM-ALK fusion gene expressed in t(2;5) lymphomas. The RARA sequences are the same as the RARA sequences found in the PML-RAR and PLZF-RAR fusion seen in t(15;17) and t(11;17) APL, respectively. Both NPM-RAR transcripts fuse NPM and RARA sequence in the same reading frame, to generate translation products of 57 kD and 62 kD. Both NPM-RAR proteins are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele. In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators. This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA.
Asunto(s)
Cromosomas Humanos Par 17/ultraestructura , Cromosomas Humanos Par 5/ultraestructura , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Fosfoproteínas , Receptores de Ácido Retinoico/genética , Translocación Genética , Animales , Secuencia de Bases , Preescolar , Mapeo Cromosómico , ADN Complementario/genética , ADN de Neoplasias/genética , Femenino , Humanos , Leucemia Promielocítica Aguda/clasificación , Leucemia Promielocítica Aguda/metabolismo , Datos de Secuencia Molecular , Proteínas de Neoplasias/biosíntesis , Nucleoplasminas , Proteínas de Fusión Oncogénica/biosíntesis , Empalme del ARN , Ratas , Receptor alfa de Ácido Retinoico , Homología de Secuencia de Ácido Nucleico , Transactivadores/biosíntesis , Transactivadores/genética , Transcripción Genética/efectos de los fármacos , Tretinoina/farmacologíaRESUMEN
Acute promyelocytic leukemia (APML) almost always involves a chromosomal translocation t(15:17) that results in the fusion of the retinoic acid receptor alpha (RAR alpha) gene with a transcription factor gene called PML. Several cases of APML with t(11;17) have recently been described, involving fusion of the RAR alpha gene with a new zinc finger gene named PLZF. We report here a second non-classical translocation, t(5;17), with a rearranged RAR alpha gene in a child with APML. Based on restriction endonuclease analysis, the rearrangement of RAR alpha occurred within the second intron, the common breakpoint site for t(15;17). The leukemic cells in the bone marrow aspirate were a mixture of hypergranular and hypogranular bilobed promyelocytes. Although less than 1% abnormal promyelocytes were identified after induction therapy, cytogenetics revealed persistent t(5;17). Therefore, the child was treated with all-trans-retinoic acid (ATRA). There was no disease progression, and one marrow was interpreted as remission, with confirmation by cytogenetics which failed to reveal the translocation. However, disease reoccurred shortly after completion of ATRA. This poor response to ATRA may be an additional characteristic associated with non-classical translocations in APML. The identification of a second variant translocation involving the RAR alpha gene in APML suggests yet another RAR alpha rearrangement related to neoplastic myelopoiesis.
Asunto(s)
Cromosomas Humanos Par 17 , Leucemia Promielocítica Aguda/genética , Receptores de Ácido Retinoico/genética , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Preescolar , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 15 , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Etopósido/uso terapéutico , Femenino , Humanos , Cariotipificación , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/patología , Receptor alfa de Ácido Retinoico , Tioguanina/administración & dosificaciónRESUMEN
Patterns of infection were studied in 150 patients with aplastic anemia who were admitted to the Clinical Hematology Branch, National Institutes of Health, between January 1978 and December 1989 for immunosuppressive therapy. Sixty percent of the patients were males, 71% were white, their mean age was 33.6 years (median, 27.5; range, 1-75), and 83% had severe aplastic anemia. One hundred three patients developed 1 or more febrile episodes during the study period. The risk factors for developing a febrile episode included a low Absolute Neutrophil Count (ANC) and Absolute Monocyte Count (AMC) at admission and the presence of an indwelling central venous catheter (Hickman-Broviack or Port-A-Cath). A total of 289 febrile events were studied, including unexplained fever (FUO) in 89 (31%), microbiologically documented infection (MBDI) in 137 (47%), and clinically documented infection (CDI) in 63 patients (22%). Compared to documented infections (MBDI) or CDI), FUO events were associated with a higher frequency of rigors, signs and symptoms of serum sickness, and treatment regimens known to cause fevers. None of the FUO events had a fatal outcome, even if the antibiotic therapy was discontinued before day 7. Among CDI events, bacteria were the most commonly defined etiologic agent (67%), followed by fungi (23%), viruses (7%), and parasites (3%). The patterns of bacterial infections in patients with aplastic anemia were similar to those observed in patients with cancer-related neutropenia. Twenty-one patients (15%) developed invasive fungal infections (aspergillus, 11; candida, 7; and both, 3), which were fatal in 19 (90%). Fungal infections accounted for 30% of the secondary infectious events and for 55% of fatal infectious events. The only identifiable risk factors for developing a fungal infection were the degree of neutropenia and monocytopenia at initial admission or final evaluation. Invasive pulmonary aspergillosis developed despite empirical amphotericin B therapy and was associated with a high incidence of fatal pulmonary hemorrhage (10 of 13 patients [77%]). Infection was responsible for 36 (62%) of the deaths observed during the study period and hemorrhage alone for 4 (7%). However, 20 of the patients who died of infection had concomitant hemorrhage. No significant drop in ANC, AMC, or platelet count could be demonstrated during a fatal infectious event as compared to a nonfatal infectious event. Invasive fungal infections, predominantly with aspergillus and candida, emerged in our study as the major causes of mortality in patients with aplastic anemia. Without bone marrow recovery the prognosis associated with invasive mycoses was grave.