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1.
ESMO Open ; 9(4): 102385, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38387111

RESUMEN

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Resistencia a Antineoplásicos , Fulvestrant , Piperazinas , Piridinas , Humanos , Fulvestrant/uso terapéutico , Fulvestrant/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Piperazinas/uso terapéutico , Piperazinas/farmacología , Femenino , Piridinas/uso terapéutico , Piridinas/farmacología , Resistencia a Antineoplásicos/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Pronóstico , Anciano , Adulto , Ácidos Nucleicos Libres de Células , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Mutación
2.
J Inherit Metab Dis ; 25(1): 41-6, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11999979

RESUMEN

We report the result of enzymatic and molecular analyses, using cultured lymphocyte fractions (cultivated monocytes), of six Japanese patients (from five families) and one Italian patient with fructose-1,6-bisphosphatase (FBPase) deficiency. Enzymatic analysis demonstrated FBPase deficiency in all seven patients, including the Italian patient whose fructose-1,6-bisphosphatase activity has been reported to be normal in leukocytes but deficient in liver. Molecular analysis of the FBPase gene identified pathogenic mutations in only 8 among the total 12 alleles of six families. We have thus demonstrated the validity of using cultured monocytes as a secure and noninvasive alternative to liver biopsy for accurate diagnosis of FBPase deficiency.


Asunto(s)
Deficiencia de Fructosa-1,6-Difosfatasa/diagnóstico , Fructosa-Bifosfatasa/genética , Hígado/enzimología , Monocitos/enzimología , Alelos , Células Cultivadas , Niño , Femenino , Fructosa-Bifosfatasa/metabolismo , Humanos , Lactante , Hígado/patología , Linfocitos/citología , Masculino , Monocitos/citología , Mutagénesis Insercional
3.
Rinsho Ketsueki ; 42(3): 216-7, 2001 Mar.
Artículo en Japonés | MEDLINE | ID: mdl-11345785

RESUMEN

A 4-year-old boy with ALL received low-dose ara-C (50 mg/m2/day, bolus). After 10 fractions of ara-C, he developed an erythematous rash predominantly on the palms and soles, mimicking acral erythema except for the absence of pain. Chemotherapy was interrupted and the rash disappeared in four days. A similar rash occurred again just after the second cycle of ara-C had been started. Co-administration of dexamethasone improved the rash rapidly, thus allowing the chemotherapy to be continued, and suggesting the beneficial effect of corticosteroids. Although skin toxicity induced by low-dose ara-C is very rare and usually occurs after continuous infusion, it should also be borne in mind when considering bolus infusion.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Citarabina/efectos adversos , Erupciones por Medicamentos/etiología , Antimetabolitos Antineoplásicos/administración & dosificación , Preescolar , Citarabina/administración & dosificación , Erupciones por Medicamentos/tratamiento farmacológico , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico
4.
J Chromatogr B Biomed Sci Appl ; 746(1): 75-82, 2000 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-11048742

RESUMEN

Children with fructose-1,6-diphosphatase (FDPase) deficiency often experience life threatening episodes such as ketotic hypoglycemia. We report here a rapid, simplified and sensitive method to analyze glycerol-3-phosphate (G3P) and glycerol in urine, that can be used to detect FDPase deficiency. We used the urease/direct preparation and gas chromatography-mass spectrometry in the selected-ion monitoring mode, enabling detection of G3P and glycerol level in normal controls. Using this approach, FDPase deficiency can be more easily diagnosed and differentiated from glycerol kinase deficiency or glycerol infusion patients. To date, diagnosis has been essentially based on the assay of enzymes in the liver. The proposed non-invasive method provides a clinically significant diagnostic tool that may help prevent episodic attacks.


Asunto(s)
Fructosa-Bifosfatasa/orina , Cromatografía de Gases y Espectrometría de Masas/métodos , Errores Innatos del Metabolismo/diagnóstico , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Errores Innatos del Metabolismo/orina , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Ureasa/metabolismo
5.
J Biochem ; 127(3): 373-82, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10731708

RESUMEN

Fructose-1,6-bisphosphatase (FBPase) is a key gluconeogenic enzyme. The data herein show that both the enzyme activity and mRNA level of the human FBPase gene are enhanced by 9-cis retinoic acid (9cRA) and all-trans retinoic acid (atRA) as well as by 1,25-dihydroxyvitamin D3 (VD3) in human promyelocytic HL60 cells and normal monocytes in peripheral blood, which were used as an alternative source to liver for the DNA diagnosis of FBPase deficiency. To understand the molecular mechanism of this enhancing action, the 2.4 kb 5'-regulatory region of the human FBPase gene was isolated and sequenced. Using luciferase reporter gene assays, a 0.5 kb FBPase basal promoter fragment was found to confer induction by VD3, 9cRA, and atRA that was mediated by the vitamin D3 receptor (VDR), retinoid X receptor (RXR), and retinoic acid receptor (RAR). Within this region, a direct repeat sequence, 5'-TAACCTttcTGAACT-3' (-340 to -326), which functions as a common response element for VD3, 9cRA, and atRA, was identified. The results of electrophoretic mobility shift assays indicated that VDR-RXR and RAR-RXR heterodimers bind this response element. Collectively, these observations indicate that VD3 and RA are important modulators of the expression of the human FBPase gene in monocytic cells.


Asunto(s)
Colecalciferol/metabolismo , Fructosa-Bifosfatasa/genética , Regiones Promotoras Genéticas , Elementos de Respuesta/genética , Tretinoina/metabolismo , Northern Blotting , Cicloheximida/farmacología , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Células HL-60 , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Monocitos , Unión Proteica , Inhibidores de la Síntesis de la Proteína/farmacología , Análisis de Secuencia de ADN , Transfección
6.
J Pediatr Hematol Oncol ; 21(5): 384-8, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10524451

RESUMEN

PURPOSE: CD44 is an adhesion molecule expressed on a variety of cells, and its level correlates with the metastatic potential of malignant tumors. Serum concentrations of soluble CD44 (sCD44) are elevated in various cancers. The purpose of this study was to measure the serum concentrations of CD44 in pediatric patients with acute leukemia. PATIENTS AND METHODS: Fourteen pediatric patients with acute leukemia were studied. The authors measured the serum concentration of sCD44 by enzyme-linked immunosorbent assay before and after therapy. The concentrations were compared with those of 15 control healthy children and 10 patients with bacterial infections. RESULTS: The mean serum concentration of sCD44 at presentation was significantly higher in patients than in control subjects, but decreased to a normal range in complete remission after chemotherapy. There was no difference in sCD44 concentrations between patients with acute lymphocytic leukemia and those with acute myeloid leukemia. Serum concentrations of sCD44 did not correlate with lactic dehydrogenase concentrations or bone marrow nucleated cell counts and only weakly with peripheral leukocyte count. sCD44 levels in patients with bacterial infections were similar to those of control subjects. CONCLUSION: Serum concentration of sCD44 may reflect disease status in pediatric patients with acute leukemia and might be a useful tumor marker in these patients.


Asunto(s)
Antígenos CD/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores de Hialuranos/sangre , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Antibióticos Antineoplásicos/administración & dosificación , Asparaginasa/administración & dosificación , Infecciones Bacterianas/sangre , Infecciones Bacterianas/inmunología , Biomarcadores de Tumor/sangre , Niño , Preescolar , Citarabina/administración & dosificación , Ensayo de Inmunoadsorción Enzimática , Humanos , Lactante , Leucemia Mieloide Aguda/inmunología , Metotrexato/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Prednisolona/administración & dosificación , Valores de Referencia , Inducción de Remisión , Vincristina/administración & dosificación
7.
J Chromatogr B Biomed Sci Appl ; 731(1): 97-103, 1999 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-10491994

RESUMEN

In a neonatal-screening pilot study for inherited disorders in organic acid and amino acid metabolism, we analyzed butyrated acylcarnitines and amino acids in blood spots of more than 20,000 newborns by electrospray tandem mass spectrometry. In order to screen urea cycle disorders, we performed multiple scanning functions with additional stable isotope-labelled internal standards, since such reported functions as neutral loss of m/z 102 or 109 for butyrated amino acids were not sufficient. Arginine levels were measured with arginine-13C6. Hypocitrullinemia for the screening of some urea cycle disorders was detectable by measurement with synthesized citrulline-d6, although we did not find any such disorders. In the acylcarnitine analysis, we found a patient with propionic acidemia, who has been treated effectively. The increasing false positive rate due to the use of pivalic acid-containing antibiotics in the diagnosis of isovaleric acidemia was a problem in Japan.


Asunto(s)
Espectrometría de Masas/métodos , Errores Innatos del Metabolismo/diagnóstico , Tamizaje Neonatal/métodos , Calibración , Humanos , Recién Nacido , Japón , Proyectos Piloto , Estándares de Referencia , Reproducibilidad de los Resultados
8.
Ann Neurol ; 45(5): 624-32, 1999 May.
Artículo en Inglés | MEDLINE | ID: mdl-10319885

RESUMEN

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder characterized by dysmyelination of the central nervous system (CNS) caused by mutations involving the proteolipid protein gene (PLP). In addition to point and frameshift mutations in the coding region, duplications involving the entire PLP have been recognized recently as a major genetic abnormality causing PMD. We devised an interphase fluorescence in situ hybridization (FISH) assay to establish an efficient screening test for PLP duplication. Thirteen patients from 11 Japanese PMD families were determined to have PLP duplications. This molecular diagnostic FISH test also readily detected female carriers. Molecular analysis revealed that the size of the duplication and location of the breakpoints showed striking variation. Fiber FISH demonstrated that the duplication is tandem in nature. Haplotype analysis indicated an intrachromosomal origin for the duplication. These results suggest that an unequal sister chromatid exchange in male meiosis is likely to be the major mechanism leading to the formation of the duplication. Patients with the duplication commonly present with a mild PMD phenotype. Two patients with an exceptionally severe clinical phenotype carried large duplications, suggesting that either the larger duplicated segment incorporates additional dosage-sensitive genes or that the location of the duplication junction may affect the phenotype.


Asunto(s)
Esclerosis Cerebral Difusa de Schilder/genética , Duplicación de Gen , Proteína Proteolipídica de la Mielina/genética , Adolescente , Alelos , Niño , Preescolar , Mapeo Cromosómico , Femenino , Haplotipos , Humanos , Hibridación Fluorescente in Situ , Masculino , Fenotipo
9.
J Pediatr Hematol Oncol ; 20(5): 463-6, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9787320

RESUMEN

PURPOSE: Essential thrombocythemia and agnogenic myeloid metaplasia as one form of idiopathic myelofibrosis are myeloproliferative disorders and are quite rare in children. A patient with essential thrombocythemia that transformed to "adult-type" agnogenic myeloid metaplasia is described. PATIENTS AND METHODS: A routine examination of an 8-year-old girl with bronchial asthma showed thrombocytosis. Essential thrombocythemia was diagnosed 2 years later. During a 3-year follow-up without treatment, transition of the essential thrombocythemia to agnogenic myeloid metaplasia was noticed. The patient had an excellent response to interferon (IFN)-alpha therapy. CONCLUSION: This case is unique because of the availability of premorbid hematologic data and the natural progression of essential thrombocythemia to agnogenic myeloid metaplasia. Whether IFN-alpha therapy can prevent the progression of idiopathic myelofibrosis to leukemia has not yet been determined.


Asunto(s)
Interferón-alfa/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/etiología , Trombocitosis/complicaciones , Niño , Femenino , Humanos , Trombocitosis/fisiopatología
10.
Am J Hum Genet ; 61(4): 852-61, 1997 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9382095

RESUMEN

Fructose-1,6-bisphosphatase (FBPase) deficiency is an autosomal recessive inherited disorder and may cause sudden unexpected infant death. We reported the first case of molecular diagnosis of FBPase deficiency, using cultured monocytes as a source for FBPase mRNA. In the present study, we confirmed the presence of the same genetic mutation in this patient by amplifying genomic DNA. Molecular analysis was also performed to diagnose another 12 Japanese patients with FBPase deficiency. Four mutations responsible for FBPase deficiency were identified in 10 patients from 8 unrelated families among a total of 13 patients from 11 unrelated families; no mutation was found in the remaining 3 patients from 3 unrelated families. The identified mutations included the mutation reported earlier, with an insertion of one G residue at base 961 in exon 7 (960/961insG) (10 alleles, including 2 alleles in the Japanese family from our previous report [46% of the 22 mutant alleles]), and three novel mutations--a G-->A transition at base 490 in exon 4 (G164S) (3 alleles [14%]), a C-->A transversion at base 530 in exon 4 (A177D) (1 allele [4%]), and a G-->T transversion at base 88 in exon 1 (E30X) (2 alleles [9%]). FBPase proteins with G164S or A177D mutations were enzymatically inactive when purified from E. coli. Another new mutation, a T-->C transition at base 974 in exon 7 (V325A), was found in the same allele with the G164S mutation in one family (one allele) but was not responsible for FBPase deficiency. Our results indicate that the insertion of one G residue at base 961 was associated with a preferential disease-causing alternation in 13 Japanese patients. Our results also indicate accurate carrier detection in eight families (73%) of 11 Japanese patients with FBPase deficiency, in whom mutations in both alleles were identified.


Asunto(s)
Deficiencia de Fructosa-1,6-Difosfatasa/genética , Fructosa-Bifosfatasa/genética , Mutación Puntual , Sustitución de Aminoácidos , Secuencia de Bases , Células Cultivadas , Preescolar , Femenino , Fructosa-Bifosfatasa/metabolismo , Tamización de Portadores Genéticos , Humanos , Lactante , Recién Nacido , Japón , Hígado/enzimología , Masculino , Mutagénesis Sitio-Dirigida , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple
11.
Eur J Clin Pharmacol ; 51(5): 399-406, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9049582

RESUMEN

We conducted a single and repeat oral dose study of YM17E, a novel inhibitor of acyl coenzyme A (CoA): cholesterol acyltransferase, in healthy male volunteers to evaluate the pharmacokinetic profile, tolerability and effect of the drug on serum cholesterol. In the single administration study, YM17E was administered after a meal to two groups of subjects (each containing six subjects taking the drug and three taking placebo) receiving 3, 60 and 300 mg or 15, 60 and 450 mg YM17E, respectively. Plasma concentrations of unchanged drug following single oral administration at 3-300 mg after a meal increased with increasing dose. In contrast, plasma concentrations after administration of 450 mg were almost the same as after 300 mg. Unchanged YM17E was not detected in urine after single administration, suggesting that it was excreted via the bile or urine after metabolism. Five active metabolites (M1, M2-a, M2-b, M3 and M4) were observed in plasma at concentrations comparable to those of unchanged YM17E. Their plasma concentrations increased in a slightly greater than dose-dependent manner from 3 to 300 mg. The effect of food was studied in an open crossover design with a 1-week washout period. Twelve subjects received 150 mg YM17E in both the fasted and post-prandial states. The AUC and Cmax after fasting were closely similar to those after a meal, showing that bioavailability was not affected by food intake. In the repeated oral dose study, the subjects received test drug at 150 mg or 300 mg (n = 6 each) or placebo (n = 3) twice a day (after breakfast and after dinner) for 7 days. On days 1 and 7, the subjects received YM17E once a day (after breakfast) for evaluation of pharmacokinetic properties. After repeated oral administration of 150 mg b.d., plasma concentrations reached steady state by day 5 (mean Cmin 48.6 ng.ml-1). After repeated administration of 300 mg b.d., plasma concentrations prior to each daily morning dose increased up to the 5th day (mean Cmin 166.6 ng.ml-1) and then tended to decrease until the 7th day. No significant signs, symptoms or changes in serum cholesterol levels were observed during the single and repeated oral dose studies at 150 mg b.d. Although statistical analysis was not conducted because of the small number of subjects, all subjects receiving repeated oral administration of 300 mg twice daily showed a 25% decrease in serum cholesterol level on day 7, but also the simultaneous occurrence of diarrhoea.


Asunto(s)
Colesterol/sangre , Compuestos de Fenilurea/farmacocinética , Esterol O-Aciltransferasa/antagonistas & inhibidores , Esterol O-Aciltransferasa/sangre , Administración Oral , Adulto , Estudios Cruzados , Femenino , Interacciones Alimento-Droga , Humanos , Masculino , Compuestos de Fenilurea/efectos adversos , Método Simple Ciego
12.
J Pediatr ; 129(6): 909-12, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8969735

RESUMEN

We describe a girl with hypothyroidism and blocking-type thyrotropin receptor antibodies that developed after chemotherapy and irradiation of the neck region for neuroblastoma. Results of thyroid studies before treatment were normal. Twenty months after completion of treatment, the girl had hypothyroidism with high titers of blocking-type thyrotropin receptor antibodies, antithyroglobulin, and antiperoxidase antibodies.


Asunto(s)
Anticuerpos/sangre , Enfermedades Autoinmunes/etiología , Neoplasias de Cabeza y Cuello/complicaciones , Hipoparatiroidismo/etiología , Neuroblastoma/complicaciones , Peroxidasa/inmunología , Radioterapia/efectos adversos , Receptores de Tirotropina/inmunología , Tiroglobulina/inmunología , Enfermedades Autoinmunes/inmunología , Unión Competitiva/efectos de la radiación , Preescolar , Terapia Combinada , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Hipoparatiroidismo/inmunología , Metástasis Linfática , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/radioterapia , Peroxidasa/efectos de la radiación , Receptores de Tirotropina/efectos de la radiación , Tiroglobulina/efectos de la radiación , Factores de Tiempo
13.
Pediatr Res ; 39(4 Pt 1): 680-4, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8848345

RESUMEN

Acylcarnitines in amniotic fluid samples were analyzed for the prenatal diagnosis of propionic acidemia, methylmalonic aciduria, isovaleric acidemia, and glutaric aciduria by electrospray tandem mass spectrometry. Although the levels of the specific acylcarnitine between affected and unaffected cases showed an overlap, the ratios of propionylcarnitine to 4-carbon acylcarnitine levels for propionic acidemia and methylmalonic aciduria, those of isovalerylcarnitine to propionylcarnitine for isovaleric acidemia, and those of glutarylcarnitine to propionylcarnitine for glutaric aciduria type I were shown to be reliable indicators in the prenatal diagnosis. In addition, it is suggested that the combination of the ratios of glutarylcarnitine, isovaleryl-carnitine, and hexanoylcarnitine to propionylcarnitine may be useful for the prenatal diagnosis of glutaric aciduria type II.


Asunto(s)
Acetilcarnitina/metabolismo , Acidosis/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Líquido Amniótico/metabolismo , Enfermedades Fetales/diagnóstico , Diagnóstico Prenatal , Acidosis/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Femenino , Enfermedades Fetales/metabolismo , Humanos , Espectrometría de Masas , Embarazo
14.
Pediatr Neurol ; 13(4): 346-8, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8771174

RESUMEN

A patient with Zellweger syndrome, who manifested marked dilatation of the lateral ventricles, observed at 34 weeks gestation by fetal ultrasonography, is reported. Postnatal magnetic resonance imaging revealed marked colpocephaly and hypogenesis of the posterior part of the corpus callosum. However, pachygyria was limited to the perisylvian regions. Biochemical diagnosis was based on increased serum very-long-chain fatty acids, 2-hydroxysebacic aciduria, and the detection of the ghosts of peroxisomal membrane in cultured fibroblasts. The patient was classified as belonging to group B of this syndrome by complementation study.


Asunto(s)
Imagen por Resonancia Magnética , Ultrasonografía Prenatal , Síndrome de Zellweger/diagnóstico , Femenino , Humanos , Recién Nacido , Embarazo , Síndrome de Zellweger/diagnóstico por imagen
15.
Rinsho Ketsueki ; 36(10): 1204-9, 1995 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-8531332

RESUMEN

We report a 3-year-old boy with acute myelogenous leukemia, who relapsed very early after peripheral blood stem cell transplantation (PBSCT). He was admitted with a tumor in maxillar sinus and hemorrhagic diathesis and was diagnosed as having acute myelogenous leukemia with t(8;21). He achieved complete remission with etoposide, cytosine arabinoside and mitoxantrone. After 8 courses of consolidation therapy and marrow ablative chemotherapy, he received PBSCT. G-CSF was given from day 0 because of severe infection. WBC and platelete counts rapidly increased, however, from day 20 platelet count spontaneously decreased. Concomitantly bone marrow examination revealed the presence of blastic cells. RT-PCR showed that the presence of AML 1/MTG 8 chimera mRNA in the cryopreserved PBSC samples. In vitro analysis also revealed that leukemic cells had G-CSF receptors and increased 3H-thymidine uptake in the presence of G-CSF. These findings strongly suggest that the reinfusion of leukemic cells in PBSC and the administration of G-CSF after PBSCT might be relevant to early relapse in this patient.


Asunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/etiología , Translocación Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Terapia Combinada , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Neoplasia Residual
16.
Biochem Biophys Res Commun ; 210(3): 797-804, 1995 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-7763253

RESUMEN

Fructose-1,6-bisphosphatase deficiency is an inheritable disorder of gluconeogenesis. Sequence analysis of the cDNA of the fructose-1,6-bisphosphatase mRNA isolated from monocytes from a girl with this disease and her consanguineous parents revealed that the patient and her parents were a homozygote and heterozygotes for an insertion of one G residue at G957GGGG961, respectively. This mutation resulted in translation of a truncated enzyme protein, and the mutant protein showed no fructose-1,6- bisphosphatase activity in an overexpression experiment in Escherichia coli. However, this mutation is located in a region of the amino acid sequence which is not well conserved among mammals. A mutagenized clone was prepared from the normal clone. The extents of substitutions and deletions of the amino acid sequence were predicted to be less in the mutagenized protein than in the mutant protein. This mutagenized clone also expressed no fructose-1,6-bisphosphatase activity, although both of two normal clones from control monocytes and a control liver sample expressed an apparently normal level of fructose-1,6-bisphosphatase activity. Thus, this mutation is concluded to be responsible for fructose-1,6-bisphosphatase deficiency in this patient.


Asunto(s)
Deficiencia de Fructosa-1,6-Difosfatasa/genética , Fructosa-Bifosfatasa/genética , Mutación , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Consanguinidad , Cartilla de ADN , Femenino , Deficiencia de Fructosa-1,6-Difosfatasa/enzimología , Tamización de Portadores Genéticos , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Núcleo Familiar , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/análisis , ARN Mensajero/biosíntesis
17.
Pediatr Nephrol ; 9(1): 78-80, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7742229

RESUMEN

A 4-year-old girl was diagnosed as having acute renal failure due to tubulointerstitial nephritis. The girl presented with remittent fever, vomiting and non-oliguric acute renal failure with sterile pyuria and tubular reabsorptive dysfunction. Ultrasound examination revealed that the kidneys were markedly enlarged with diffuse hyperechogenicity in the cortex when the abnormal renal function was present and were restored in size and echogenicity when the renal function normalised. A diagnosis of Yersinia pseudotuberculosis infection was based on a rise in haemagglutination titres against the organism.


Asunto(s)
Nefritis Intersticial/complicaciones , Infecciones por Yersinia pseudotuberculosis/complicaciones , Enfermedad Aguda , Lesión Renal Aguda/diagnóstico por imagen , Lesión Renal Aguda/etiología , Preescolar , Femenino , Pruebas de Hemaglutinación , Humanos , Riñón/diagnóstico por imagen , Nefritis Intersticial/diagnóstico por imagen , Ultrasonografía , Infecciones por Yersinia pseudotuberculosis/diagnóstico
18.
Acta Paediatr Jpn ; 36(4): 408-11, 1994 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7942005

RESUMEN

A 7 years 3 months old Japanese boy with familial thyroxine binding globulin (TBG) excess associated with growth hormone (GH) deficiency is reported. The patients height was 106.4 cm (-2.86 s.d.) and his bone age was 5 years and 3 months. He had no goiter and his developmental milestones were normal. The serum thyroid stimulating hormone (TSH) was 2.8 microU/mL, triiodothyronine (T3) 3.1 ng/mL, thyroxine (T4) 23.4 micrograms/dL and free T4 1.8 ng/dL. The serum TBG level was beyond 80.0 micrograms/mL, with normal TSH response to the thyrotropin-releasing hormone (TRH) test. Familial study revealed that his grandmother, mother, uncle, younger sister and younger brother had high TBG and T3 levels, thus an X-linked co-dominant transmission was suggested. The peak GH responses to insulin and clonidine hydrochloride were 5.8 and 8.2 ng/mL, respectively. The mean nocturnal GH concentration was 2.5 ng/mL. His growth velocity increased from 4.8 to 8.4 cm/year and his serum TBG levels decreased gradually after human growth hormone (hGH) treatment.


Asunto(s)
Hormona del Crecimiento/deficiencia , Proteínas de Unión a Tiroxina/metabolismo , Estatura , Niño , Hormona del Crecimiento/sangre , Hormona del Crecimiento/uso terapéutico , Humanos , Masculino , Triyodotironina/sangre
19.
Eur J Pediatr ; 153(8): 581-3, 1994 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7957405

RESUMEN

UNLABELLED: A 5-year-old boy with short stature, hepatomegaly and motor weakness due to hepatic phosphorylase kinase deficiency is described. Laboratory data showed mild hypoglycaemia and metabolic acidosis, hepatic dysfunction, and a low insulin-like growth factor-I level. Mild hypoglycaemia, marked ketosis and insufficient growth hormone secretion were revealed at night. Serum total and free carnitine levels were low and the acyl/total carnitine ratio was high. Urinary acylcarnitine profile using fast atom bombardment and tandem mass spectrometry showed increased excretion of acetylcarnitine and dicarboxylylcarnitines. These endocrinological and metabolic abnormalities and clinical symptoms were improved with uncooked cornstarch treatment. CONCLUSION: Uncooked cornstarch treatment may be helpful in hepatic phosphorylase deficiency.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno/dietoterapia , Hepatopatías/dietoterapia , Fosforilasa Quinasa/deficiencia , Almidón/uso terapéutico , Niño , Enfermedad del Almacenamiento de Glucógeno/metabolismo , Trastornos del Crecimiento/metabolismo , Humanos , Hepatopatías/metabolismo , Masculino
20.
J Nutr Sci Vitaminol (Tokyo) ; 40(3): 283-8, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7965217

RESUMEN

The relative proportions (% of total fatty acids) of odd-chain (15:0-29:0) and long-chain (22:0-30:0) saturated fatty acids in phospholipids of biotin-deficient rat lymphocytes were significantly increased as compared with biotin-supplemented rats, and the ratio of unsaturated fatty acids to saturated fatty acids in the former was significantly decreased mainly due to the reduced composition of polyunsaturated fatty acids in the omega-3, omega-6, and omega-9 pathway. The ratio of cis-vaccenic acid to palmitoleic acid in biotin-deficient rats was significantly lower than that in control rats, and was thought to be another important, but previously unreported indicator of biotin deficiency. These changes imply that the elongation and desaturation of unsaturated fatty acids are depressed in lymphocytes of biotin-deficient rats, and may contribute to the associated immunological dysfunction in biotin deficiency through abnormal prostaglandin metabolism and/or cell membrane functions.


Asunto(s)
Biotina/deficiencia , Ácidos Grasos/sangre , Linfocitos/metabolismo , Animales , Ácidos Grasos Monoinsaturados/sangre , Ácidos Grasos Insaturados/sangre , Masculino , Ácidos Oléicos/sangre , Fosfolípidos/sangre , Ratas , Ratas Wistar
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