RESUMO
A temporary elevation of serum alkaline phosphatase has been described in young children who have no evidence of liver or bone disease. This phenomenon has been termed benign hyperphosphatasemia of infancy. Its occurrence is described in three children undergoing chemotherapy for acute lymphoblastic leukemia and lymphoma. All three children were in remission and in the consolidation or maintenance phase of their therapy when the hyperphosphatasemia occurred. All children were also receiving methotrexate (IM and IV), oral 6-mercaptopurine, and oral sulfamethoxazole/trimethoprim. Although these agents are associated with hepatotoxicity, other liver transaminases (ALT, AST) remained at normal concentrations, and there was an elevation only in the bone isoenzyme of alkaline phosphatase, thus making hepatic toxicity an unlikely etiology for the hyperphosphatasemia. No alteration in chemotherapy was necessary for resolution of the elevated alkaline phosphatase in these children.
Assuntos
Fosfatase Alcalina/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Osso e Ossos/enzimologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de RemissãoRESUMO
PURPOSE: We describe a 3-year-old boy with widespread, metastatic Ewing sarcoma and an unusual translocation, involving chromosomes 21 and 22. MATERIALS AND METHODS: Cytogenetic studies were performed on a biopsy of the primary tumor. These included GTG banding and fluorescence in situ hybridization. RESULTS: A balanced translocation between chromosomes 21 and 22 was noted with translocation breakpoints at bands 21q22 and 22q12. CONCLUSIONS: The t(21;22) translocation represents a new cytogenetic abnormality that may be associated with Ewing sarcoma. Its prognostic significance, if any, remains to be determined.
Assuntos
Cromossomos Humanos Par 21 , Cromossomos Humanos Par 22 , Sarcoma de Ewing/genética , Translocação Genética , Pré-Escolar , Humanos , MasculinoRESUMO
We describe a case of aplastic anemia in an 8-year-old girl which was diagnosed 8 months after initiation of ethosuximide as treatment for absence seizures. Blood counts had been previously monitored and were normal. The patient successfully underwent allogeneic bone marrow transplantation. Only 8 cases of ethosuximide-associated aplastic anemia have been reported, and in only one of these reports, was ethosuximide used as a single antiepileptic agent. This rare, but potentially fatal complication of ethosuximide raises the question of whether routine monitoring of blood counts during ethosuximide therapy is useful and should be undertaken.
Assuntos
Anemia Aplástica/induzido quimicamente , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/efeitos adversos , Anemia Aplástica/terapia , Contagem de Células Sanguíneas/efeitos dos fármacos , Transplante de Medula Óssea , Criança , Monitoramento de Medicamentos , Etossuximida/administração & dosagem , Feminino , Humanos , Assistência de Longa DuraçãoRESUMO
Hepatocyte-directed production of urokinase-type plasminogen activator (uPA) in transgenic mice is hepatotoxic. Infrequently, hepatocytes arise that do not express uPA, due to physical loss of transgene DNA, and these cells clonally repopulate the entire liver within 3 months of birth. Surprisingly, hepatic tumors appear in these mice beginning at 8 months of age despite the fact that uPA is not oncogenic or genotoxic. Analysis of the transgene locus reveals that tumors arise only from a particular subclass of transgene-deficient cells in which the entire transgene array, and possibly a significant amount of flanking DNA, is deleted. Considering that all transgene-deficient regenerative nodules undergo extensive replication but only a subset gives rise to tumors, we propose that loss of genomic DNA, not mitogenesis per se, is a primary carcinogenic determinant in this model of hepatocarcinogenesis.
Assuntos
Rearranjo Gênico , Neoplasias Hepáticas Experimentais/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Alanina Transaminase/sangue , Albuminas/genética , Animais , Divisão Celular , DNA/biossíntese , Deleção de Genes , Regeneração Hepática , Camundongos , Camundongos TransgênicosRESUMO
We previously demonstrated that expression of an albumin-urokinase-type plasminogen activator (Alb-uPA) fusion construct in transgenic mice resulted in elevated plasma uPA concentration, hypofibrinogenemia, and neonatal hemorrhaging. Two lines of Alb-uPA mice were established in which only one half of the transgenic pups died at birth; surprisingly, plasma uPA concentrations in survivors gradually returned to normal by 2 months of age. The basis for this phenomenon is DNA rearrangement within hepatocytes that affects the transgene tandem array and abolishes transgene expression. Transgene-deficient cells selectively proliferate relative to surrounding liver, and this process culminates in replacement of the entire liver by clonal hepatic nodules derived from transgene-deficient progenitor cells. In some cases as few as two nodules can reconstitute over 90% of liver mass, highlighting the remarkable regenerative capacity of individual liver cells.
Assuntos
Deleção Cromossômica , Regeneração Hepática , Ativadores de Plasminogênio/genética , Albumina Sérica/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Sequência de Bases , Núcleo Celular/ultraestrutura , Replicação do DNA , Precursores Enzimáticos/fisiologia , Expressão Gênica , Fígado/patologia , Fígado/fisiologia , Fígado/ultraestrutura , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Ativadores de Plasminogênio/análise , RNA Mensageiro/análise , RNA Mensageiro/genética , Albumina Sérica/análise , Ativador de Plasminogênio Tipo Uroquinase/análise , alfa-Fetoproteínas/análise , alfa-Fetoproteínas/genéticaRESUMO
Spontaneous intestinal and intra-abdominal bleeding was observed in a high percentage of newborn transgenic mice carrying the murine urokinase-type plasminogen activator (uPA) gene linked to the albumin enhancer/promoter. These hemorrhagic events were directly related to transgene expression in the liver and the development of high plasma uPA levels. Two lines were established from surviving founder mice that displayed multigenerational transmission of the bleeding phenotype. Fatal hemorrhaging developed between 3 and 84 hr after birth in about half of the transgenic offspring of these lines; transgenic pups that did not bleed nevertheless passed the phenotype to their young. The phenotypic variability could not be explained by differences in transgene expression. All transgenic neonates were severely hypofibrinogenemic and displayed loss of clotting function that extended beyond the risk period for bleeding. These mice provide a means of studying the pathophysiology of plasminogen hyperactivation and evaluating therapeutic protocols designed to prevent bleeding.
Assuntos
Hemorragia Gastrointestinal/genética , Hormônio do Crescimento/genética , Fígado/enzimologia , Ativadores de Plasminogênio/genética , Precursores de Proteínas/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Animais , Sequência de Bases , Northern Blotting , Fibrinogênio/análise , Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Sondas de Oligonucleotídeos , Fenótipo , Contagem de Plaquetas , RNA/genética , RNA/isolamento & purificação , RNA Mensageiro/genética , Mapeamento por RestriçãoRESUMO
The murine urokinase-type plasminogen activator (uPA) gene has been isolated from a BALB/c liver DNA cosmid library and its nucleotide sequence established. The gene is organized into 11 exons comprising 34.7% of the 6710 base pair (bp) region spanning the interval between the presumed transcription initiation and polyadenylation sites. The transcription initiation site is flanked by common RNA polymerase II promoter elements, including a TATA box and a potential transcription factor Sp1 binding site. A large polypurine tract of the structure (AG)22(AGGG)16(AG)28 is located 79 bp upstream of the 5'-terminus. It was highly sensitive to the single-strand-specific nuclease S1, suggesting a non-B-DNA conformation of unknown significance. Consistent with the well-documented influence of adenosine cyclic 3',5'-phosphate (cAMP) on uPA gene expression, there is a dodecanucleotide homologous to proposed regulatory sequences identified in other cAMP-modulated genes. Comparison of the murine uPA gene to the previously described porcine and human uPA genes revealed an unusually high degree of evolutionary (interspecies) sequence conservation that was not limited to exons but included introns and flanking sequences as well.