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T Hassold

Publications and source records attributed to T Hassold.

At least 19 recordsLinked to original sources
PubMed2004

Cytological studies of meiotic recombination in human males.

We combined immunostaining and fluorescence in situ hybridization (FISH) methodology to directly examine meiotic exchanges in over 2,000 pachytene stage spermatocytes from 25 individuals. Our results indicate that, on average, there are about 50 exchanges per cell and that, with the exception of the acrocentric chromosomes, all chromosome arms harbor at least one exchange. We also identified significant among-individual variation in the mean number of exchanges, with an approximate 20% difference between individuals with "low" and those with "high" exchange frequencies.

Adaptor Proteins, Signal Transducing↗
PubMed2001

To err (meiotically) is human: the genesis of human aneuploidy.

Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

Aneuploidy↗
PubMed2000

Down syndrome: genetic recombination and the origin of the extra chromosome 21.

Despite the clinical importance of trisomy 21, we have been ignorant of the causes of meiotic nondisjunction of chromosome 21. Recently, however, genetic mapping studies of trisomy 21 families have led to the identification of the first molecular correlate of human nondisjunction; i.e. altered levels and positioning of meiotic recombinational events. Specifically, increases in 0 exchange events or in distal-only or pericentromeric exchanges are significantly increased in trisomy 21-generating meioses. These observations have led to the idea that chromosome 21 nondisjunction requires 'two hits': first, the establishment in prophase I of a 'vulnerable' bivalent and second, abnormal processing of the bivalent at metaphase I or II.

Chromosomes, Human, Pair 21↗
PubMed2000

Counting cross-overs: characterizing meiotic recombination in mammals.

Until recently, most of our understanding of meiotic recombination has come from studies of lower eukaryotes. However, over the past few years several components of the mammalian meiotic recombination pathway have been identified, and new molecular and cytological approaches to the analysis of mammalian meiosis have been developed. In this review, we discuss recent advances in three areas: the application of new techniques to study genome-wide levels of recombination in individual meioses; studies analyzing temporal aspects of the mammalian recombination pathway; and studies linking the genesis of human trisomies to alterations in meiotic exchange patterns.

Animals↗
PubMed2000

Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidization.

Vascular smooth muscle cells (VSMCs) at capacitance arteries of hypertensive individuals and animals undergo marked age- and blood pressure-dependent polyploidization and hypertrophy. We show here that VSMCs at capacitance arteries of rat models of hypertension display high levels of Akt1/PKB protein and activity. Gene transfer of Akt1 to VSMCs isolated from a normotensive rat strain was sufficient to abrogate the activity of the mitotic spindle cell-cycle checkpoint, promoting polyploidization and hypertrophy. Furthermore, the hypertrophic agent angiotensin II induced VSMC polyploidization in an Akt1-dependent manner. These results demonstrate that Akt1 regulates ploidy levels in VSMCs and contributes to vascular smooth muscle polyploidization and hypertrophy during hypertension.

Angiotensin II↗
PubMed1999

Prevalence of developmental and inflammatory lesions in nonmolar first-trimester spontaneous abortions.

The management of patients with first-trimester spontaneous abortions is handicapped by two problems: difficulty in recognizing conceptions that abort because of abnormal karyotypes and an incomplete understanding of what causes abortions with normal karyotypes. Our goals in this study were to define features useful in distinguishing normal from abnormal karyotype and to identify pathological processes contributing to abortions with a normal karyotype. The study population consisted of 668 well-characterized first-trimester spontaneous abortions derived from a larger study of 1,054 consecutively karyotyped spontaneous abortions. Clinical factors increased in specimens with normal karyotype were maternal age younger than 20 years (P=.0003) and autoimmune markers (P=.0474). Developmental features associated with abnormal karyotype were developmental stage less than 6 weeks (P=.0017), hydropic villi greater than 1 mm (P=.0004), and villi with two or more dysmorphic features (P=.0001). Developmental stage greater than 11.5 weeks was increased with normal karyotype (P=.0001). Histological features increased in specimens with a normal karyotype were chronic intervillositis (P=.0003), increased perivillous fibrin deposition with intermediate trophoblast (P=.0006), decidual plasma cells (P=.0040), deciduitis without plasma cells (P=.0660), and chronic villitis (P=.1581). Overall, 19% of samples with a normal karyotype versus 8% with abnormal karyotype had one or more of these findings (P < .0001). Autoimmune markers, chronic intervillositis, and increased perivillous fibrin with intermediate trophoblast all had positive predictive values greater than 85% for normal karyotype, whereas dysmorphic villi had a positive predictive value of 90% for abnormal karyotype. Patients with recurrent spontaneous abortion and normal karyotype were more likely to have one or more of the histological features listed above (31%) than patients with normal karyotype and no prior abortions (13%) and patients with recurrent abortion and abnormal karyotype (11%).

Abortion, Spontaneous↗
PubMed1998

FISH studies of the sperm of fathers of paternally derived cases of trisomy 21: no evidence for an increase in aneuploidy.

Paternal nondisjunction accounts for approximately 5% of cases of trisomy 21. To test the hypothesis that, in some such cases, the fathers might be predisposed to meiotic nondisjunction, we utilized fluorescence in situ hybridization (FISH) to screen for aneuploidy in sperm. We analyzed sperm samples from ten males with a trisomy 21 offspring of paternal origin. Among these individuals, the overall frequency of disomy 21 was 0.15%, comparable to estimates of disomy 21 in the general male population. Furthermore, none of the ten fathers of trisomy 21 individuals had significantly elevated levels of disomic sperm. Thus, our results provide no evidence that the occurrence of a trisomy 21 conceptus of paternal origin imparts an increased risk of trisomy in subsequent pregnancies.

Aneuploidy↗
PubMed1998

Prevalence of the partial molar phenotype in triploidy of maternal and paternal origin.

Triploid partial moles are at risk for trophoblastic neoplasia, yet the prevalence, parent of origin, and evolution of the partial molar phenotype amongst all triploids remains controversial. We determined parental origin by polymerase chain reaction (PCR) analysis, stage of development by gross and histological criteria, and partial molar status according to strict diagnostic criteria for all triploids identified amongst 1,054 consecutively karyotyped spontaneous abortions. Triploidy was detected in 64 of 832 successfully karyotyped specimens. Complete data were collected in 59 cases. Diandric origin was found in 39 specimens, and 20 of these fulfilled all four criteria for partial mole (trophoblast hyperplasia, dimorphic population of large and small villi, villous hydrops greater than 0.5 mm, and irregular villous contour). We separated the 19 diandric triploids not fulfilling all criteria for partial mole into four groups: specimens of early developmental stage, which we believed represented developing ("early") partial moles (n = 3), cases of late developmental stage, which we believed represented involuting ("ancient") partial moles (n = 4), cases showing some but not all criteria for partial mole (n = 7), and specimens with few if any criteria suggestive of partial mole (n = 5). In triploids of digynic origin (n = 20), developmental stage was significantly lower, fetal tissue was more frequently identified, and all specimens showed well-preserved fetal red blood cells. Digynic triploids occasionally showed irregular contour, dimorphic villi, and a mild form of trophoblast hyperplasia but never showed hydropic degeneration and were never suspicious for partial mole.

Adult↗
PubMed1998

Determinants of villous trophoblastic hyperplasia in spontaneous abortions.

The diagnosis of complete and partial mole with its subsequent risk of trophoblastic malignancy relies on histologic criteria that are sometimes seen in nonmolar conceptuses. We performed karyotypic analysis on 1054 spontaneous abortions during a 43-month period. Villous trophoblastic hyperplasia was graded from 0 to 3 in successfully karyotyped cases of complete mole, triploidy, tetraploidy, monosomy X, trisomy, normal 46,XY, and normal 46,XX without contaminating maternal tissues (n = 649). Parental origin of the extra chromosome was analyzed by polymerase chain reaction in 64 trisomic cases. We also evaluated for each case the developmental stage, presence of uniformly hydropic villi, amnion, villous nucleated red blood cells, and fetal tissue. Villous trophoblastic hyperplasia was increased in spontaneous abortions with abnormal karyotype as a group and in the subgroup with trisomy compared with those of a normal karyotype. Hyperplasia and particularly high-grade hyperplasia (Grades 2-3), equivalent in severity to that seen in proliferative partial and complete moles was most frequent in a subgroup of trisomies involving chromosomes 7 (60% hyperplasia, with 30% of high grade), 15 (50% hyperplasia, 15% high grade), 21 (22% hyperplasia, 11% high grade), and 22 (13% hyperplasia, 4% high grade). Frequency of paternal origin for the extra chromosome in these four trisomies was similar in cases with and without hyperplasia There was a nonsignificant increase in female sex chromosomes with hyperplasia in both trisomic and normal conceptuses. Hyperplasia was more common in trisomic abortions of late stage (> 8.5 wk, P = .013), in those that lacked uniformly hydropic villi (P < .001), and in those that lacked fetal tissue (P = .204). This latter phenotype was particularly common with trisomies 15, 21, and 22.

Abortion, Spontaneous↗
PubMed1997

Early complete hydatidiform moles contain inner cell mass derivatives.

In four cases of early complete hydatidiform moles, confirmed to be androgenetic in origin by DNA studies, we have identified nonchorionic inner cell mass derived structures which are not commonly observed in specimens of later gestational age. These structures include nucleated red blood cells, endothelial cells, stromal macrophages, amnion and yolk sac. The latter four structures were confirmed by specific immunocytochemical stains. Recognition that such structures can accompany complete hydatidiform moles has both theoretical and practical significance. From a theoretical perspective, it demonstrates that the maternal genome is not required for the initiation of amniogenesis, development of the yolk sac, vasculogenesis, or hematopoiesis. From a practical perspective it emphasizes that complete hydatidiform moles, with their markedly increased risk of subsequent choriocarcinoma, cannot be excluded based on the finding of "fetal structures."

DNA↗
PubMed1997

Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

Chromosomes, Human, Pair 21↗
PubMed1996

Aneuploidy in germ cells: etiologies and risk factors.

A 2 1/2-day workshop on germ cell aneuploidy was convened September 11-13, 1995 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina to discuss current understandings of the etiology and origin of human aneuploidy, especially in regard to potential environmental causes, and to identify gaps in our research knowledge. The workshop was designed to facilitate interactions among research experts conducting studies on the fundamental biology of chromosomal movement and segregation, on aneuploidy as a human clinical problem, and on toxicological aspects of aneuploidy induction. Overview presentations provided perspectives on aneuploidy as a human clinical problem, the genetics of aneuploidy, and the issues of concern in toxicological testing and regulatory risk assessment. The four chairs introduced the topics for each of their workgroups, setting the stage for subsequent, in-depth discussions on (1) chromosome mover components, (2) altered recombination, (3) parental age effects, and (4) differential chromosome susceptibility. From these discussions, gaps in our research knowledge related to the role of the environment in the etiology of aneuploidy and associated molecular, cellular, and genetic processes involved were identified, and will be used to establish a research agenda for filling those gaps.

Aneuploidy↗
PubMed1996

Very early complete hydatidiform mole.

Recent trends toward early pregnancy ultrasound have led to evacuation of complete hydatidiform moles at a stage before the development of diffuse trophoblast hyperplasia and villous cavitation. Absence of these recognized diagnostic criteria can lead to misdiagnosis and subsequent trophoblastic neoplasia. The authors identified a case of very early complete hydatidiform mole (VECM) on review of a previous curettage specimen when the patient presented 4 weeks later with increasing human chorionic gonadotropin (HCC) titers and the typical histological features of complete mole on a subsequent curettage. DNA studies on this index case and three subsequent similar specimens confirmed the diagnosis of complete hydatidiform mole using polymerase chain reaction (PCR) amplification of eight microsatellite markers on microdissected maternal and villous tissue. VECM were compared with spontaneous abortions and elective terminations of a similar gestational age to develop diagnostic criteria. Five cardinal diagnostic features were identified: redundant bulbous terminal villi, hypercellular villous stroma, a labyrinthine network of vinous stromal canaliculi, focal cytotrophoblast and syncytiotrophoblast hyperplasia on both villi and the undersurface of the chorionic plate, and enlarged hyperchromatic implantation site trophoblast.

Adult↗
PubMed1996

Recombination and nondisjunction in humans and flies.

Recent studies of Drosophila and humans indicate that aberrant genetic recombination is an important component of nondisjunction in both species. In both, a proportion of nondisjunction is associated with failure to pair and/or recombine and in both, exchanges which are either too distal or too proximal increase the likelihood of malsegregation. In this review we provide two perspectives on these observations: first, a review of exchange and chromosome segregation in model organisms, focusing on Drosophila, and secondly an overview of nondisjunction in humans. This format allows us to describe the paradigms developed from studies of model organisms and to ask whether these paradigms apply to the human situation.

Animals↗
PubMed1995

Recombination and maternal age-dependent nondisjunction: molecular studies of trisomy 16.

Trisomy 16 is the most common human trisomy, occurring in > or = 1% of all clinically recognized pregnancies. It is thought to be completely dependent on maternal age and thus provides a useful model for studying the association of increasing maternal age and nondisjunction. We have been conducting a study to determine the parent and meiotic stage of origin of trisomy 16 and the possible association of nondisjunction and aberrant recombination. In the present report, we summarize our observations on 62 spontaneous abortions with trisomy 16. All trisomies were maternally derived, and in virtually all the error occurred at meiosis I. In studies of genetic recombination, we observed a highly significant reduction in recombination in the trisomy-generating meioses by comparison with normal female meioses. However, most cases of trisomy 16 had at least one detectable crossover between the nondisjoined chromosomes, indicating that it is reduced--and not absent--recombination that is the important predisposing factor. Additionally, our data indicate an altered distribution of crossing-over in trisomy 16, as we rarely observed crossovers in the proximal long and short arms. Thus, it may be that, at least for trisomy 16, the association between maternal age and trisomy is due to diminished recombination, particularly in the proximal regions of the chromosome.

Chromosome Mapping↗
PubMed1994

Nondisjunction of human acrocentric chromosomes: studies of 432 trisomic fetuses and liveborns.

The present report summarizes molecular studies on the parent and meiotic stage of origin of the additional chromosome in 432 fetuses or liveborns with an additional chromosome 13, 14, 15, 21, or 22. Our studies suggest that there is little variation in the origin of nondisjunction among the five acrocentric trisomies and that there is no association between the origin of nondisjunction and the likelihood of survival to term of the trisomic conceptus. The proportion of cases of paternal origin was similar among the five trisomies: 12% for trisomy 13, 17% for trisomy 14, 12% for trisomy 15, 9% for trisomy 21, and 11% for trisomy 22. The stage of nondisjunction was also similar among the five trisomies, with the majority of cases of maternal origin being due to nondisjunction at meiosis I, whereas for paternally derived cases, nondisjunction occurred primarily at meiosis II.

Adult↗