Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics.
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Acute myeloid leukemia (AML) is a heterogeneous group of diseases. Normal cytogenetics (CN) constitutes the single largest group, while trisomy 8 (+8) as a sole abnormality is the most frequent trisomy. How trisomy contributes to tumorigenesis is unknown. We used oligonucleotide-based DNA microarrays to study global gene expression in AML+8 patients with +8 as the sole chromosomal abnormality and AML-CN patients. CD34(+) cells purified from normal bone marrow (BM) were also analyzed as a representative heterogeneous population of stem and progenitor cells. Expression patterns of AML patients were clearly distinct from those of CD34(+) cells of normal individuals. We show that AML+8 blasts overexpress genes on chromosome 8, estimated at 32% on average, suggesting gene-dosage effects underlying AML+8. Systematic analysis by cellular function indicated up-regulation of genes involved in cell adhesion in both groups of AML compared with CD34(+) blasts from normal individuals. Perhaps most interestingly, apoptosis-regulating genes were significantly down-regulated in AML+8 compared with AML-CN. We conclude that the clinical and cytogenetic heterogeneity of AML is due to fundamental biological differences. (+info)
Maternal sex chromosome non-disjunction: evidence for X chromosome-specific risk factors.
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Human trisomy is attributable to many different mechanisms and the relative importance of each mechanism is highly chromosome specific. The association between altered recombination and maternal non-disjunction is well documented: reductions in recombination have been reported for maternal meiosis I (MI) errors involving chromosomes 15, 16, 18 and 21 and increased recombination has been reported for meiosis II (MII) errors involving chromosome 21. We therefore investigated maternal X chromosome non-disjunction, to determine whether the effects of recombination are unique to the X chromosome or similar to any of the autosomes thus far studied. We genotyped 45 47,XXX females and 95 47,XXY males of maternal origin. Our results demonstrate that 49% arose during MI, 29% during MII and 16% were postzygotic events; a further 7% were meiotic but could not be assigned as either MI or MII because of recombination at the centromere. Among the MI cases, a majority (56%) had no detectable transitions and so absent recombination is an important factor for X chromosome non-disjunction. However, similar to trisomy 15 and unlike trisomy 21, we observed a significant increase in the mean maternal age of transitional MI errors compared with nullitransitional cases. In our studies of MII errors, recombination appeared normal and there was no obvious effect of maternal age, distinguishing our results from MII non-disjunction of chromosomes 18 or 21. Thus, surprisingly, the risk factors associated with both MI and MII non-disjunction appear to be different for virtually every chromosome that has been adequately studied. (+info)
Reverse flow in the umbilical vein in a case of trisomy 9.
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This report describes a case of reverse flow in the umbilical vein and ductus venosus during atrial contraction of a fetus at 12 weeks of gestation with increased nuchal translucency (9.1 mm). In addition, Doppler velocimetry detected high retrograde flow in the inferior vena cava. Cytogenetic analysis of chorionic villi revealed trisomy 9. We suggest that these findings may be a first trimester sign of chromosomal and cardiac abnormalities in the fetus. (+info)
Fetal heart rate in chromosomally abnormal fetuses.
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OBJECTIVES: To determine the effects of chromosomal defects on fetal heart rate at 10-14 weeks of gestation. METHODS: Fetal heart rate at 10-14 weeks of gestation in 1061 chromosomally abnormal fetuses was compared to that from 25,000 normal pregnancies. The chromosomally abnormal group included 554 cases of trisomy 21, 219 cases of trisomy 18, 95 of trisomy 13, 50 of triploidy, 115 of Turner syndrome and 28 of sex chromosome abnormalities other than Turner syndrome. RESULTS: In the normal group, fetal heart rate decreased from a mean value of 170 beats per minute (bpm) at 35 mm of crown-rump length to 155 bpm at 84 mm crown-rump length. In trisomy 21, trisomy 13 and Turner syndrome fetal heart rate was significantly higher, in trisomy 18 and triploidy the heart rate was lower and in other sex chromosome defects it was not significantly different from normal. Fetal heart rate was above the 95th centile of the normal range in 10%, 67% and 52% of fetuses with trisomy 21, trisomy 13 and Turner syndrome, respectively. The fetal heart rate was below the 5th centile in 30% of fetuses with triploidy and 19% of those with trisomy 18. CONCLUSIONS: Trisomy 21, trisomy 13 and Turner syndrome are associated with fetal tachycardia, whereas in trisomy 18 and triploidy there is fetal bradycardia. Inclusion of fetal heart rate in a first-trimester screening program for trisomy 21 by a combination of maternal age and fetal nuchal translucency thickness is unlikely to provide useful improvement in sensitivity. (+info)
Parental origin and mechanisms of formation of triploidy: a study of 25 cases.
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Triploidy is one of the most frequently observed chromosome abnormalities in spontaneous abortions in humans. The parental origin of the additional chromosome set is known to have a major impact on the phenotype of the foetuses and to result in differences in size and structure of the placenta. Early studies based on cytogenetic polymorphisms indicated a preponderant diandric origin of the triploidies; such detection method, however, is known to be prone to error. Other studies revealed a predominant digynic origin in cases with longer intrauterine survival. It is now thought that, to some extent, a detection bias in favour of cases with associated partial hydatidiform moles may account for the high incidences of diandric cases reported in some studies. Furthermore, depending on the gestational age of the cases analysed there may indeed be differences in the proportion of diandric and digynic triploidies. We investigated the parental origin and mechanisms of formation of triploidy in a group of 25 probands with gestational ages ranging from 8 to 37 weeks. DNA samples were extracted from foetal material and from blood samples of the parents, and were analysed using microsatellite markers. The parental origin of the triploidies was found to be maternal in 20 cases and paternal in 5. Regarding the digynic cases, an error at meiosis I was inferred in 10 cases, whereas in the other half an error occurred at meiosis II. All five diandric cases included in this study were found to be due to dispermy. No significant differences in the average maternal ages were found amongst the different subgroups of patients. (+info)
Ets transcription factors and targets in osteogenesis.
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Bone formation in vivo is a complex phenomenon whereby recruitment and replication of mesenchymal precursors of osteoblasts, differentiation into preosteoblasts, osteoblasts, and mature osteoblasts ultimately result in the accumulation and mineralization of the extracellular matrix. MC3T3-E1, a clonal osteoblastic cell line, was derived from mouse calvaria and undergoes an ordered and time dependent developmental sequence leading to formation of multilayered bone nodules over a 30 - 35 day period. This developmental pattern is characterized by the replication of preosteoblasts followed by growth arrest and expression of mature osteoblastic characteristics such as matrix maturation and eventual formation of multilayered nodules with a mineralized extracellular matrix. We have found that Ets1 is expressed in proliferating preosteoblastic cells whereas Ets2 is expressed by differentiating and mature osteoblasts. In addition, the expression of Ets1 can be induced in MC3T3-E1 and fetal rat calvaria cells by retinoic acid (RA) which is known to exert profound effects on skeletal growth and development, bone turnover, and induce specific cellular responses in bone cells. Thus the multiple functions of RA in bone cells are likely to be mediated in part by Ets1. Also, Ets2 transgenic mice develop multiple neurocranial, viserocranial, and cervical skeletal abnormalities. Significantly, these abnormalities are similar to the skeletal anomalies found in trisomy-16 mice and in humans with Down's syndrome, wherein the dosage of Ets2 is known to be increased. These results indicate that Ets2 has an important role in skeletal development and that Ets2 overexpression in transgenics is responsible for the genesis of the same type of skeletal abnormalities that are seen in Down's syndrome. Thus the genetic programs regulated by Ets1 and Ets2 may significantly affect the development and differentiation of osteoblasts, and in fact, Ets1 has been shown to interact with the 'quintessential' osteoblast transcription factor CbfA1. This review will examine in detail the role and possible targets of Ets1 and Ets2 in osteoblast differentiation and bone formation. (+info)
Oesophageal atresia in the South West of England.
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A retrospective anatomical and family study was made of 345 patients with oesophageal atresia who were born in the South West of England between 1942 and 1973. There were 186 males and 159 females. Twenty-one cases were stillborn. Eighty-five percent of the patients had a combination of oesophageal atresia with a tracheo-oesophageal fistula to the distal oesophageal segment, and 9 percent had atresia without a fistula. Fifty-five per cent of the patients had other congenital malformations and these tended to be multiple rather than single. Thirty-six per cent of singletons had unequivocal fetal growth retardation, and there is some evidence that nearly all cases have poor fetal growth. There appeared to be a maternal age effect, with an excess of mothers under 20 and over 35, and there was an unexplained excess of fathers employed in the Armed Forces. Ten per cent of the cases were illegitimate. There were 21 twins which is nearly three times the expected number; there were two pairs of twins concordant for oesophageal atresia, one being monozygotic and the other dizygotic. In one case there were two sibs with oesophageal atresia. Five out of 365 sibs had anencephaly. The blood group distributions of the patients and their mothers did not significantly differ from the expected distribution. Oesophageal atresia is aetiologically heterogenous. In this series there were at least five, and probably 10 cases of trisomy 18 and four cases of trisomy 21. Five mothers had overt diabetes, and there is some suggestion from other work that maternal diabetes or its treatment may be aetiologically important. Oesophageal atresia was part of a possibly recessively inherited malformation syndrome in two cases. A sibship with a case of rectal atresia, a case of Hirschprung's disease and a case of oesophageal atresia may represent the action of another recessive gene. It seems likely that oesophageal atresia is a rather non-specific consequence of several teratological processes. (+info)
Trisomy 13 and Rubinstein-Taybi syndrome.
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Initial diagnosis of Rubinstein-Taybi syndrome was made in an infant with a prominent nose and broad thumbs and first toes. However, due to the presence of other anomalies such as low-set, malformed ears, anti-mongoloid slant of the eyes, colobomata of the iris, and cleft palate, cytogenetic studies were carried out and the diagnosis of trisomy 13 was confirmed. Since, occasionally, trisomy 13 syndrome may mimic the Rubinstein-Taybi syndrome, cytogenetic studies should be considered in all patients with clinical diagnosis of Rubinstein-Taybi syndrome. (+info)