RESUMEN
Recent discoveries have highlighted the importance of transcription in cellular transformation. Transcription factors have a crucial role as nuclear targets that convert mitogenic signals from oncogenes into changes in gene expression.
Asunto(s)
Oncogenes , Transducción de Señal/genética , Factores de Transcripción/genética , Transcripción Genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Núcleo Celular/metabolismo , Datos de Secuencia MolecularRESUMEN
Measurement of the plasma free amino acids by column chromatography (AutoAnalyzer) in 32 patients with primary gout showed statistically significant increases or decreases in several components when compared with the spectrum in 18 control subjects, but the absolute amounts involved were small and the mean total plasma amino acid concentrations in both groups were the same. In the urine all major amino acid components, notably glutamine, serine, threonine, and leucine, were lower in our gouty than in our nongouty subjects, as were also the corresponding renal clearance ratios. These deficits could be reproduced by restricting dietary protein, so appear to be due largely to the some-what reduced mean dietary protein intake of our gouty subjects. However, the low renal clearance of glutamine, the most striking and consistent of the deficits in urinary amino acids noted, could not be accounted for by dietary or other relevant factors, and is interpreted as indicating increased tubular reabsorption of glutamine in primary gout. This interpretation was supported by the results of glutamine loading. The possible compensatory relationship of the abnormality in renal handling of glutamine to the deficiency in renal production of ammonia previously reported is discussed.
Asunto(s)
Aminoácidos/sangre , Glutamina/sangre , Glutamina/orina , Gota/metabolismo , Aminoacidurias Renales , Adolescente , Adulto , Anciano , Amoníaco/biosíntesis , Autoanálisis , Cromatografía , Proteínas en la Dieta , Gota/sangre , Gota/orina , Humanos , Riñón/metabolismo , Túbulos Renales/fisiopatología , Leucina/orina , Masculino , Persona de Mediana Edad , Serina/orina , Treonina/orinaRESUMEN
Mitochondrial fatty acid beta-oxidation is important for energy production, which is stressed by the different defects found in this pathway. Most of the enzyme deficiencies causing these defects are well characterized at both the protein and genomic levels. One exception is carnitine palmitoyltransferase I (CPT I) deficiency, of which until now no mutations have been reported although the defect is enzymatically well characterized. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Here we report the first delineation of the molecular basis of hepatic CPT I deficiency in a new case. cDNA analysis revealed that this patient was homozygous for a missense mutation (D454G). The effect of the identified mutation was investigated by heterologous expression in yeast. The expressed mutant CPT IA displayed only 2% of the activity of the expressed wild-type CPT IA, indicating that the D454G mutation is the disease-causing mutation. Furthermore, in patient's fibroblasts the CPT IA protein was markedly reduced on immunoblot, suggesting that the mutation renders the protein unstable.
Asunto(s)
Carnitina O-Palmitoiltransferasa/deficiencia , Isoenzimas/deficiencia , Errores Innatos del Metabolismo Lipídico/genética , Secuencia de Aminoácidos , Transporte Biológico , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/fisiología , Consanguinidad , Secuencia de Consenso , Ácidos Dicarboxílicos/orina , Ácidos Grasos/metabolismo , Femenino , Humanos , Hipoglucemia/etiología , Lactante , Isoenzimas/genética , Isoenzimas/fisiología , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/orina , Hígado/enzimología , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la EspecieRESUMEN
We report a patient with severe infantile carnitine palmitoyltransferase II (CPT II) deficiency who died at the age of 3 months. Genetic analysis of the CPT2 gene revealed that the patient was homozygous, and her parents were heterozygous, for a R503C missense mutation. Heterozygosity for R503C, without a second mutation, has previously been reported in symptomatic patients from two families, one with the mild adult myopathic form and one with malignant hyperthermia. In contrast, the R503C heterozygous parents of the patient were entirely asymptomatic, suggesting that additional genetic and/or environmental factors must have contributed to the occurrence of symptoms in previously reported carriers. Our findings indicate that the mutation R503C should be added to the handful of mutations associated with the severe phenotype when present in the homozygous state or combined with another severe mutation.
Asunto(s)
Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/genética , Homocigoto , Errores Innatos del Metabolismo/fisiopatología , Mutación Missense , Arginina , Cisteína , Exones , Resultado Fatal , Ácidos Grasos/metabolismo , Femenino , Humanos , Lactante , Errores Innatos del Metabolismo/genética , Mitocondrias/metabolismo , Oxidación-Reducción , Índice de Severidad de la EnfermedadRESUMEN
Mouse Hoxb-4 (Hox-2.6) is a homeobox gene that belongs to a family which also includes Hoxa-4, Hoxc-4, and Hoxd-4 and that is related to the Deformed gene in Drosophila melanogaster. We have determined the sequence of 1.2 kb of 5' flanking DNA of mouse Hoxb-4 and by nuclease S1 and primer extension experiments identified two transcription start sites, P1 and P2, 285 and 207 nucleotides upstream of the ATG initiator codon, respectively. We have shown that this region harbors two independent promoters which drive CAT expression in several different cell lines with various efficiencies, suggesting that they are subject to cell-type-specific regulation. Through detailed mutational analysis, we have identified several cis-regulatory elements, located upstream and downstream of the transcription start sites. They include two cell-type-specific negative regulatory elements, which are more active in F9 embryonal carcinoma cells than in neuroblastoma cells (regions a and d at -226 to -186 and +169 to +205, respectively). An additional negative regulatory element has been delimited (region b between +22 and +113). Positive regulation is achieved by binding of HoxTF, a previously unknown factor, to the sequence GCCATTGG (+148 to +155) that is essential for efficient Hoxb-4 expression. We have also defined the minimal promoter sequences and found that they include two 12-bp initiator elements centered around each transcription start site. The complex architecture of the Hoxb-4 promoter provides the framework for fine-tuned transcriptional regulation during embryonic development.
Asunto(s)
Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Genes Homeobox , Proteínas de Homeodominio/genética , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Animales , Secuencia de Bases , Sitios de Unión , Ratones , Datos de Secuencia Molecular , ARN Mensajero/genética , Mapeo Restrictivo , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Transcripción GenéticaRESUMEN
We have identified oncogene-responsive sequences in the human c-fos promoter that mediate induction of transcription by several nonnuclear oncoproteins and the tumor promoter TPA. These sequences are regulated in a cell-specific manner. (i) In NIH 3T3 cells, the CArG box of the c-fos promoter is sufficient to mediate activation by oncogenes. (ii) In contrast, in HeLa cells, additional flanking sequences are also required, including the outer arm of the serum response element and the FAP site. We also show that the serum response factor, which binds to the CArG box, activates transcription in vivo in NIH 3T3 cells but not in HeLa cells. Finally, we present evidence that the intracellular level of the c-Fos protein could be a major determinant of cell-specific regulation of these oncogene-responsive elements of the c-fos promoter.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Genes ras , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fos/genética , Proto-Oncogenes , Secuencia de Bases , Células HeLa , Humanos , Datos de Secuencia Molecular , Mutación/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Recombinantes de Fusión/biosíntesis , Secuencias Reguladoras de Ácidos Nucleicos/genética , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Incubation of a rat adipose tissue homogenate causes a time and temperature dependent activation of glycogen synthetase (UDP glucose:glycogen 4-alpha-glucosyltransferase) and simultaneous inactivation of phosphorylase (1,4-alpha-D-glucan: orthophosphate alpha-glucosyltransferase, EC 2.4.1.1). Activation of glycogen synthetase at 15 and 23 degrees C was preceded by a lag period. The duration of the lag period could not be correlated with significant changes in phosphorylase activity. Addition of glucose and methylxanthines caused an increase in the rates of glycogen synthetase activation and phosphorylase inactivation. The effect on glycogen synthetase activation was mainly on the linear phase. Addition of AMP inhibited phosphorylase inactivation and accelerated glycogen synthetase activation. Addition of muscle phosphorylase alpha caused a prolongation of the lag period which lasted until phosphorylase alpha activity had decreased to the level originally present in the preparation. It is concluded that in adipose tissue activation of glycogen synthetase is not dependent on prior inactivation of phosphorylase and that other factors should be looked for to explain the lag period preceding glycogen synthetase activation.
Asunto(s)
Tejido Adiposo/enzimología , Glucógeno Sintasa/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Fosforilasa Fosfatasa/metabolismo , Adenosina Monofosfato/farmacología , Adenosina Trifosfato/farmacología , Animales , Cafeína/farmacología , Activación Enzimática , Glucosa/farmacología , Masculino , Ratas , Temperatura , Xantinas/farmacologíaRESUMEN
The correlation between blood glucose levels, the concentration of glycogen, the activities of glycogen synthase and phosphorylase and their respective kinases and phosphatases was examined in liver of rat fetuses between day 18 of gestation and one day after birth. Between day 18 and 21 there is a rapid increase in the concentration of glycogen and in the activity of synthase a and a much slower increase in the activity of phosphorylase a. The activity of the respective kinases increased rapidly during this period and reached maximum on day 21. The activity of synthase phosphatase and phosphorylase phosphatase increased after day 18, to reach a maximum on day 19 and 20, respectively, but decreased again towards day 21. The possibility that the changes in glycogen concentration and enzyme activities were related to an effect of glucose or AMP on the respective phosphatases was considered. It was found that the Km of phosphorylase phosphatase for glucose in the prenatal period was 5--7 mM, as in the adult. Since the level of blood glucose during this period was constant (2.8 mM), an effect of glucose on phosphatase activity seems unlikely. AMP concentration increased between day 18 and 21 from 6--15 nmol/g. In view of the low level of phosphorylase a activity during this period, the increase in AMP concentration is not considered to be important in the regulation of glycogen breakdown at this time. Immediately after birth blood glucose levels dropped to 5 mg/dl. This was accompanied by a rapid decrease in glycogen concentration and in the activity of glycogen synthase and a rise in phosphorylase activity. Blood glucose levels returned to the initial level within 1 h after birth, whereas the changes in glycogen concentration and enzyme activities continued for at least 3 h after birth. On day 22 all parameters examined had reached the level found in adult rat liver. It is suggested that the rapid changes observed immediately after birth are due to an effect of gypoglycemia mediated by hormones and cannot be ascribed to direct effects of metabolites on the enzyme systems involved.
Asunto(s)
Glucógeno Sintasa/metabolismo , Glucógeno Sintasa-D Fosfatasa/metabolismo , Glucógeno Hepático/metabolismo , Hígado/enzimología , Fosfoproteínas Fosfatasas/metabolismo , Fosforilasa Fosfatasa/metabolismo , Fosforilasas/metabolismo , Animales , Animales Recién Nacidos , Femenino , Feto , Edad Gestacional , Cinética , Embarazo , RatasRESUMEN
Several trimethylsilyl derivatives were found to be ligands of acetylcholinesterase (acetylcholine acetylhydrolase, EC 3.1.1.7): trimethylsilylethyl acetate (III) and trimethylsilylmethyl acetate (V) are substrates of the enzyme, whereas trimethylsilylethanol (VIII) is a competitive inhibitor. The silicon compounds have kinetic parameters similar to those of their carbon analogues, except for trimethylsilylmethyl acetate, which is a substrate of acetylcholinesterase, whereas its carbon analogue is not susceptible to enzymic hydrolysis.
Asunto(s)
Inhibidores de la Colinesterasa/metabolismo , Silicio/metabolismo , Compuestos de Trimetilsililo/metabolismo , Unión Competitiva , Cinética , Compuestos de Trimetilsililo/farmacologíaRESUMEN
Sand rats (Psammomys obesus) maintained on a diet providing a free choice between laboratory chow and salt bush (Atriplex halimus) were classified into four groups differing in extent of the diabetic syndrome: A, normoglycemic-normoinsulinemic; B, normoglycemic-hyperinsulinemic; C, hyperglycemic-hyperinsulinemic; or D, hyperglycemic with reduced insulin levels. The metabolic pattern of these groups was characterized by measuring the uptake of fatty acid-labeled, very-low-density lipoprotein-borne triglycerides (VLDL-TG) and [3H]-2-deoxyglucose (2-DOG) into muscle and adipose tissues; incorporation of [14C]alanine into glycogen in vivo; gluconeogenesis from lactate, pyruvate, and alanine in hepatocytes; the effect of insulin on glycogen synthesis from glucose; the oxidation of albumin-bound [1-14C]palmitate and [14C]glucose in strips of soleus muscle; activities of muscle and adipose tissue lipoprotein lipase; and activities of rate-limiting enzymes of glycolysis, gluconeogenesis, and fatty acid synthesis in liver. In group A, uptake of VLDL-TG and activity of lipoprotein lipase were higher in adipose tissue and lower in muscle than in albino rats. In the liver, gluconeogenesis and the activity of phosphoenolpyruvate carboxykinase, as well as lipid synthesis and the activity of NADP-malate dehydrogenase, were higher than in albino rats, whereas activity of pyruvate kinase was lower. In group B, uptake of VLDL-TG by adipose tissue and muscle and lipoprotein lipase activity were similar or higher than in group A. Uptake of 2-DOG by muscle and adipose tissue and activity of liver phosphoenolpyruvate carboxykinase were lower than in group A. In groups C and D, uptake of VLDL-TG and lipoprotein lipase activity in muscle were further increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus/metabolismo , Obesidad , Tejido Adiposo/metabolismo , Factores de Edad , Alanina/metabolismo , Animales , Arvicolinae , Glucemia/análisis , Radioisótopos de Carbono , Dieta , Ácidos Grasos/metabolismo , Gluconeogénesis , Glucosa/metabolismo , Hiperglucemia/etiología , Insulina/sangre , Lipoproteínas VLDL/metabolismo , Músculos/metabolismo , Oxidación-Reducción , Triglicéridos/metabolismoRESUMEN
The glycogen concentration and the activities of glycogen synthetase and phosphorylase were assayed in endometrial tissue obtained during curettage. Tissues were obtained during different phases of the menstrual cycle from women investigated because of menometrorrhagia or sterility. The glycogen concentration was less than 2 mg/g wet wt in specimens from days 1-15 and increased 10-fold during the early secretory phase. The total activities of glycogen synthetase and phosphorylase were increased 1.5- and 2-fold, respectively, during the secretory phase compared to those during the first half of the cycle. The activities of the active forms (a form) of these enzymes did not show significant changes during the menstrual cycle. The largest difference between the proliferative and secretory phases was in the activity of glycogen synthetase phosphatase, which was virtually inactive in tissues obtained on days 1-15 and increased almost 20-fold during the secretory part of the cycle. In tissues obtained from cases of sterility, the activities of glycogen synthetase and phosphorylase were significantly reduced only during the early secretory phase. Glycogen concentration throughout the menstrual cycle and enzyme activities during the midsecretory and premenstrual phase were similar in cases of sterility and other pathologies.
Asunto(s)
Endometrio/metabolismo , Glucógeno Sintasa/metabolismo , Glucógeno Sintasa-D Fosfatasa/metabolismo , Glucógeno/metabolismo , Menstruación , Fosfoproteínas Fosfatasas/metabolismo , Adulto , Femenino , Humanos , Infertilidad Femenina/metabolismo , Cinética , Menorragia/metabolismo , Metrorragia/metabolismo , Persona de Mediana EdadRESUMEN
A male with pseudohypoparathyroidism presented with several hormonal abnormalities. He was clinically euthyroid with no palpable goiter, His serum T4, total T3, T3 Sephadex retention, and 131I uptake were normal. However, elevated basal TSH levels and exaggerated TSH responses to TRH which normalized during the administration of thyroid extract suggested reduced thyroidal reserve. Despite these finding the 131I uptake increased after exogeneous TSH, and the T3 level rose after TRH. Basal testosterone levels and response to hCG were normal however, gonadotropins were elevated and there was an exaggerated response after LRH treatment. Both LH and FSH levels were suppressed by testosterone propionate. The patient demonstrated intermittent basal hyperprolactinemia and impaired PRL responsiveness after metolopramide, chlorpromazine, and insulin administration. There was, however, an intact response to TRH. Basal PRL, TSH, and LH levels decreased after the administration of L-dopa and bromocriptine. Although the precise mechanism underlying these finding is unknown, the elevated basal levels of TSH, LH, and FSH and the exaggerated responses to their respective releasing hormones suggest the presence of partial degree of end-organ resistance to these pituitary trophic hormones. Together with the resistance to PTH, this may imply a common defect, presumably at a postreceptor level. However, hyporesponsiveness of PRL to metoclopramide and chlorpromazine and normal responsiveness to TRH suggest that an abnormality of dopamine tone also exists in pseudohypoparathyroidism.
Asunto(s)
Adenohipófisis/fisiopatología , Seudohipoparatiroidismo/fisiopatología , Testículo/fisiopatología , Glándula Tiroides/fisiopatología , Adolescente , Niño , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina , Humanos , Hormona Luteinizante/sangre , Masculino , Prolactina/sangre , Tirotropina/sangre , Hormona Liberadora de TirotropinaRESUMEN
Fibronectins (FNs) are extracellular glycoproteins consisting of dimers or multimers of similar but not identical subunits. The subunit differences result from variations in internal primary sequence due to alternative splicing in at least 2 regions of the pre-mRNA. The complete amino acid sequence of mature human cellular FN has been reported recently from cDNA cloning and sequencing. The same approach has now enabled us to deduce, for the first time, that FN has a 26 amino acid signal peptide and that it undergoes proteolytic processing at its N-terminus to eliminate a 5 amino acid pro-sequence (Ser-Lys-Ser-Lys-Arg). The signal sequence matches the consensus format, while this pro-sequence is a distinctive, very hydrophilic and basic peptide.
Asunto(s)
Fibronectinas/biosíntesis , Péptidos/análisis , Precursores de Proteínas/análisis , Secuencia de Aminoácidos , ADN/análisis , Fibronectinas/análisis , Fibronectinas/genética , Humanos , Precursores de Proteínas/genética , ARN Mensajero/análisisRESUMEN
OBJECTIVE: To investigate whether the reported association between insulin resistance and hypertension in spontaneously hypertensive rats (SHR) is a primary defect or a secondary phenomenon in hypertension. DESIGN: Comparisons of glucose metabolism between three groups of hypertensive rats: deoxycorticosterone (DOCA)-salt hypertensive rats; two-kidney, one clip renovascular hypertensive (RVH) rats; SHR; and their respective control groups. There was also an additional group of weight-matched SHR and respective Wistar-Kyoto (WKY) controls. METHODS: A trace amount of 3H-deoxyglucose (3H-DOG) was administered in vivo to evaluate its plasma half-life and tissue uptake. In vitro adipose tissue segments were incubated with 14C-glucose and increasing doses of insulin. RESULTS: Compared with age-matched WKY rats, SHR had significantly higher insulin levels, longer plasma half-life and lower 3H-DOG uptake by heart and striated muscle. Plasma glucose levels and incorporation of 14C-glucose into CO2, triglycerides and glycogen by adipose tissue in response to increasing insulin concentrations was similar for both groups of SHR and WKY rats. No differences were found between hypertensive rats and controls in either the DOCA or RVH groups. CONCLUSION: Evidence of insulin resistance in spontaneous, but not secondary, rat hypertension indicates that the resistance is a primary rather than a secondary event in hypertension.
Asunto(s)
Desoxicorticosterona/efectos adversos , Hipertensión Renovascular/fisiopatología , Hipertensión/fisiopatología , Resistencia a la Insulina/fisiología , Sodio en la Dieta/efectos adversos , Animales , Glucemia/metabolismo , Hipertensión/inducido químicamente , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Some neurons possess dendritic persistent inward current, which is activated during depolarization. Dendrites can be stably depolarized, i.e. they are bi-stable if the net current is inward. A proper method to show the existence of dendritic bi-stability is putting the neuron into the electric field to induce transmembrane potential changes along the dendrites. Here we present analytical and computer simulation of the bi-stable dendrite in the d.c. field. A prominent jump to a depolarization plateau can be seen in the soma upon initial hyperpolarization of its membrane. If a considerable portion of dendrites are parallel to the field it is impossible to switch off the depolarization plateau by changing the direction and the strength of the electric field. There is nothing similar in neurons with ohmic dendrites. The results of the simulation conform to the experimental observations in turtle motoneurons [Hounsgaard J. and Kiehn O. (1993) J. Physiol., Lond. (in press)]; comparison of the theoretical and the experimental results makes semi-quantitative estimation of some electrical parameters of dendrites possible. We propose modifications of the experiment which enable one to measure dendritic length constants and other parameters of stained neurons.
Asunto(s)
Dendritas/fisiología , Campos Electromagnéticos , Electrofisiología , Potenciales de la Membrana/fisiología , Modelos Biológicos , Neuronas/fisiologíaRESUMEN
This study was carried out to compare iodine-123 metaiodobenzylguanidine ([I123I]MIBG) and technetium-99m-methylene diphosphonate bone scans (99mTc-MDP) in the detection of skeletal involvement by neuroblastoma. Forty-four children with neuroblastoma underwent both [123I] MIBG and 99mTc-MDP scans within a 4-wk period; bone marrow examination also was performed; all these investigations were done both at diagnosis and at follow-up. At diagnosis, four children with Stage 4 disease had normal [123I]MIBG scans but abnormal 99mTc-MDP scans, while at follow-up there were four children with negative [123I]MIBG studies who later died from disseminated neuroblastoma. All eight scans are considered false-negative. In 24 children, the [123I]MIBG revealed more extensive disease with 161 positive sites while the 99mTc-MDP scan showed only 100 positive sites; 34 of these sites were common to both studies. This study shows that underassessment of skeletal involvement by neuroblastoma occurred using [123I]MIBG scans and that one cannot therefore substitute [123I]MIBG for 99mTc-MDP bone scans in the staging of neuroblastoma.
Asunto(s)
Neoplasias Óseas/secundario , Radioisótopos de Yodo , Yodobencenos , Neuroblastoma/secundario , Medronato de Tecnecio Tc 99m , 3-Yodobencilguanidina , Médula Ósea/patología , Neoplasias Óseas/diagnóstico por imagen , Niño , Preescolar , Reacciones Falso Negativas , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estadificación de Neoplasias/métodos , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/patología , CintigrafíaRESUMEN
We describe four cases with several findings of Fanconi anemia (FA), but without hypersensitivity to DNA cross-linking that is the distinguishing characteristic of FA. Two of the cases are male and female sibs of Hispanic origin, age 6 years and 11 months, respectively. Both have short stature, failure to thrive, absent thumbs, short palpebral fissures, and skin pigmentation abnormalities. The girl also has developmental "dysplasia" of her hips. Presently, both siblings are hematologically normal. Elevated baseline chromosome breakage was observed in the boy, but not in the girl. Neither sib showed elevated diepoxybutane (DEB)-induced chromosomal breakage. In a subsequent pregnancy, prenatal studies showed slightly elevated baseline and DEB induced chromosome breakage (greater than normal, but lower than the established range for FA). The fetus had intrauterine growth retardation and an absent right thumb. A review of cases referred to the International Fanconi Anemia Registry for DEB testing showed one additional case with similar findings. That patient, a girl, of Caucasian English ancestry, age 14 years, had short stature, a history of failure to thrive, skin pigmentation abnormalities, absent right thumb, hypoplastic left thumb, and hydrocephalus that resolved spontaneously. Elevated baseline chromosome breakage was observed in skin fibroblasts but not in lymphocytes. We postulate that these cases represent a previously undescribed autosomal recessive syndrome. These and other previously reported cases provide evidence for alternative genetic mechanisms that may result in developmental anomalies similar to those seen in FA.
Asunto(s)
Anomalías Múltiples/genética , Rotura Cromosómica , Anemia de Fanconi/complicaciones , Anomalías Múltiples/inmunología , Anomalías Múltiples/fisiopatología , Niño , Preescolar , Femenino , Retardo del Crecimiento Fetal/diagnóstico por imagen , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/fisiopatología , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/fisiopatología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/fisiopatología , Humanos , Lactante , Masculino , Embarazo , Síndrome , UltrasonografíaRESUMEN
We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2 1/2, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46, XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed.
Asunto(s)
Anomalías Múltiples/genética , Síndrome del Cromosoma X Frágil/genética , Anomalías Múltiples/fisiopatología , Animales , Preescolar , Labio Leporino , Fisura del Paladar , Atresia Esofágica , Síndrome del Cromosoma X Frágil/fisiopatología , Humanos , Masculino , Fístula Traqueoesofágica , Repeticiones de TrinucleótidosRESUMEN
A 63-year-old man developed an asymptomatic pleural effusion following the administration of 500 gm of procainamide hydrochloride over a six-month period. The diagnosis was initially suggested by the finding of lupus erythematosus cells in the pleural fluid. Lupus erythematosus cells and antinuclear antibodies appeared in the blood two months later and remained for a period of six months. The diagnosis was corroborated by the presence of antibodies to denatured DNA, but not to native DNA.
Asunto(s)
Lupus Eritematoso Sistémico/inducido químicamente , Neutrófilos , Derrame Pleural/citología , Procainamida/efectos adversos , Anticuerpos Antinucleares/análisis , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Procainamida/uso terapéuticoRESUMEN
Studies of peripheral blood, bone marrow, and spleen cells from three patients with hairy-cell leukemia were performed. Two of the three patients had well-organized cytoplasmic, ribosome-lamellar inclusions in their leukemic cells. Blast transformation and 3H-thymidine incorporation of lymphocytes seemed to fall within normal ranges when the findings were related to the absolute numbers of lymphocytes. The enzymatic markers demonstrated in hairy cells-strong acid phosphatase activity in endoplasmic reticulum and lysosomes, marked alpha-naphthyl acetate esterase reaction, and weak beta-glucuronidase activity-as well as their phagocytosis of latex particles, indicate a common origin with monocytes or histiocytes. No decisive results were obtained by immunofluorescence. Evaluation of the significance of the formation by hairy cells of mouse erythrocyte rosettes, as well as the presence of the typical hair-like projections, may require additional knowledge concerning the membrane of these cells.