We report the unique finding of a satellited X chromosome in a woman with Turner syndrome and a m... more We report the unique finding of a satellited X chromosome in a woman with Turner syndrome and a mosaic karyotype 45,X/46,X,mar(X)(sat,QFQ55),var(21)(sat,QFQ55). In PHA-stimulated lymphocytes and in lymphoblast culture, the satellited X chromosome was consistently late replicating. The translocated nucleolus organizer region (NOR) genes in the stalk of the satellite, however, remained transcriptionally active, and an unusual, late-replicating band was seen at the distal end of Xp. Analysis of fibroblast clones containing the satellited X chromosome suggests that the mar(X) is relatively stable.
American Journal of Obstetrics and Gynecology, Dec 1, 2005
(IUHSCT) is a promising therapy that may circumvent many of the morbidities and limitations of po... more (IUHSCT) is a promising therapy that may circumvent many of the morbidities and limitations of postnatal BMT.
American Journal of Obstetrics and Gynecology, Dec 1, 2007
Smoking during pregnancy is associated with alterations in neonatal growth. Previous studies have... more Smoking during pregnancy is associated with alterations in neonatal growth. Previous studies have demonstrated the additional contribution of maternal genotype to the reduction in birth weight. We sought to investigate the association between maternal smoking and infant growth and the influence of CYP1A1 and GSTT1. STUDY DESIGN: This analysis of neonatal growth outcomes was part of a larger study of maternal inflammatory response with smoking during pregnancy. We evaluated birth weight, length, and head circumference from 169 neonates. Neonates were grouped by maternal smoking status which was determined by cotinine concentrations. Analysis included the use of t-test and linear regression. RESULTS: The mean maternal age and BMI of the cohort was 23.5Ϯ4.8 years and 25.1Ϯ6.2 kg/m2. That rate of smoking in the cohort was 30%. Birth weight was approximately 200g less among neonates of women who smoked but did not reach statistical significance (pϭ0.06). Length was decreased among neonates of smokers (pϭ0.001). Head circumference was not different (pϭ0.14). Maternal cotinine concentrations correlated with fetal (cord) concentrations (r2ϭ0.34, pϽ0.01). Maternal cotinine concentration was negatively associated with birth weight and fetal length (pϭ0.05, pϽ0.01) using backward multivariable linear regression including maternal age, BMI, race, and gestational age at delivery. Fetal cotinine was associated with length but not weight (pϭ0.014, pϭ0.5). The prevalence of CYP1A1 wildtype was 75% and for GSTT present was 63%. There was no difference in genotypes by smoking status. In addition, there was no difference in birth weight or length by genotype and there was no additional influence on birth weight or length in addition to smoking status. CONCLUSION: The results of our study corroborate many other studies by demonstrating reduction in birth weight and birth length among neonates of women who smoked during pregnancy. Metabolic genotypes, specifically CYP1A1 and GSTT1, however, did not have any affect on measures of growth in this specific patient population.
International journal of gynaecology and obstetrics, 1993
generates anxiety, it is nevertheless perceived as necessaq for the successful outcome of the pre... more generates anxiety, it is nevertheless perceived as necessaq for the successful outcome of the pregnancy. Conclusion: Early mechanical transvaginal embryo reduction performed at 7 weeks of amenorrhea, leaving two embryos is, in our opinion, a simple and safe procedure with no affect on remaining fetuses. It is necessary when there are four or more embryos and it should also be proposed for triplets. In these circumstances, patients saw reduction as a necessary procedure.
Objectives: The detection of an increased nuchal translucency (NT) or nuchal fold (NF) measuremen... more Objectives: The detection of an increased nuchal translucency (NT) or nuchal fold (NF) measurement is associated with an increased risk of common aneuploidies. Only rarely is it associated with other types of chromosome abnormalities. We report the prenatal finding of an increased NF in a fetus with an interstitial 4p deletion. Methods: Standard karyotype analysis was followed by FISH with research generated BAC probes to precisely map the 4p deletion. Results: The karyotype of the fetus was determined to be 46,XX,del(4)(p15.2p16.1) by G-banding analysis and was refined to 46,XX,del(4) (p15.1p15.32) after FISH analysis. The breakpoints were narrowed to 150 kb regions on each side. The deletion is approximately 14.5 Mb, containing approximately 47 genes. Conclusions: We report a case of an increased NF measurement associated with a 4p deletion. A literature review revealed a previous case of a 4p deletion in a fetus with an increased NT. Since chromosome deletions are rarely associated with an increased NT or NF, we believe it is significant that a 4p deletion has now been found in two unrelated cases. We mapped the deletion with BAC probes, generating a list of possible candidate genes involved in the pathogenesis of increased nuchal skin folds.
In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of... more In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of congenital disorders. Our objective was to determine the optimal time in gestation for IUHSCT in a canine model. Methods: IUHSCT was performed in day 31-50 (term 63) fetal canines with CD34+ cells isolated from paternal bone marrow at doses of 0.09-3.4 × 10 9 CD34+ cells/kg and T cells (CD3+/CD5+) from paternal blood at 0.11-1.1 × 10 9 cells/kg. Engraftment was assayed using PCR-based chimerism analysis (SRY gene detection for female recipients, and unique microsatellite loci for both sexes). Results: Microchimerism and chimerism were present in multiple recipients across most gestational ages at transplant. Maximal engraftment was obtained in hematopoietic tissues in transplants performed at 42 days. At extremes of recipient gestational age, minimal to no engraftment was seen. Conclusion: Fetal age at the time of IUHSCT plays an important role in achieving engraftment in our canine model.
Objectives: To explore the advantages and limitations of comparative genomic hybridization to BAC... more Objectives: To explore the advantages and limitations of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of a fetus with anomalies and a chromosome abnormality. Methods: We used karyotype analysis, FISH and array CGH to investigate an unbalanced chromosome rearrangement. Results: We report a case of a fetus with ultrasound anomalies at 11 weeks' gestation and an unbalanced chromosome translocation [46,XX,der(13)t(2; 13)(p25.1;q32)pat]. Initially, a chromosome 13 deletion was reported from G-banded chromosome analysis and 13q subtelomere FISH. The involvement of chromosome 2 was determined after a balanced translocation was identified in the father, 46,XY,t(2; 13)(p25.1;q32). Array CGH confirmed the fetal abnormality as partial trisomy of the short arm chromosome 2 and partial monosomy of the long arm of chromosome 13. The abnormalities identified by ultrasound studies and autopsy appear to be most consistent with 13q deletion syndrome. Conclusions: Array CGH successfully identified a subtle unbalanced chromosome complement in a fetus with multiple ultrasound anomalies. If array CGH had been performed along with the fetal karyotype, the cryptic partial trisomy 2 could have been identified in a more timely manner to assist in the prenatal counseling of this family.
Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation ... more Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation were detected from 200 consecutive first-trimester chorionic villus samples (CVS) analysed. The mosaicism was similar in the two cases, but the pregnancy outcome was different. In both cases, the direct metaphases from the CVS were 46,XY. Culture metaphases were mos46,XY/47,XY, + 7; the trisomy 7 was seen in 34 per cent of cells from case 1 and 53 per cent from case 2. A sonogram at 15; weeks revealed fetal death in utero in case 1, and the patient declined amniocentesis. The fetal tissue failed to grow in culture, but the placental cultured cells were 47,XY, + 7 in 28 (100 per cent) cells analysed. In the second case, all the amniotic fluid cells were 46,XY and the pregnancy resulted in a normal male with a 46,XY karyotype in the cord blood and foreskin fibroblast cultures. The term placenta was mosaic with 13/163 (8 per cent) trisomy 7 cells. Extensive cytogenetic studies on the placenta for the first time confirmed trisomy 7 mosaicism confined to the villus cultures.
evidence of graft-versus-host disease (GVHD). Conclusion: Canine IUHSCT is a useful model to inve... more evidence of graft-versus-host disease (GVHD). Conclusion: Canine IUHSCT is a useful model to investigate the role of donor T cells in engraftment and GVHD. IUHSCT at early gestational ages with high doses of donor T cells in the graft yields microchimerism in multiple tissues without GVHD.
In situ hybridization using a series of alphoid DNA probes has demonstrated the origin of two sma... more In situ hybridization using a series of alphoid DNA probes has demonstrated the origin of two small accessory mosaic marker chromosomes ascertained from 1079 amniocenteses. These markers appeared to be de novo, derived from acrocentric chromosomes, and identical by traditional cytogenetic staining (G, Q, C, AgNOR, Hoechst‐distamycin). Molecular characterization showed that one marker had originated from chromosome 14, the other from chromosome 22. Clinical outcome in both cases was normal.
American journal of medical genetics, Jan 10, 1997
We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a s... more We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a second trimester fetus with the karyotype of 46,XX, inv dup del (7)(pter-q36::q36-q21.2:) pat. Both a large duplication (q21.2-q36) and a small deletion (within q36) were confirmed by FISH studies. DNA analysis on the family showed that the abnormal chromosome was derived from a single paternal homolog. A mechanism is proposed in light of this finding. The phenotype at autopsy was consistent with reported cases of similar duplications in chromosome 7 in that hydrocephalus, a depressed nasal bridge, low set ears, microretrognathia and a short neck were present.
American Journal of Obstetrics and Gynecology, Apr 1, 2004
Chimerism can be achieved in a canine model of in utero bone marrow transplantation with &amp... more Chimerism can be achieved in a canine model of in utero bone marrow transplantation with > or =1 x 10(8) CD34(+) haploidentical donor cells per kilogram without graft-versus-host disease. In utero bone marrow transplantation was performed by ultrasound-guided intraperitoneal infusion in 30- to 41-day-old canines with CD34(+) selected cells from paternal bone marrow at doses of 1.3 x 10(8) to 2.5 x 10(10) CD34(+) cells/kg. A method for marking control littermates was developed with intraperitoneal ethiodol. Postnatal studies included histologic, fluorescent in situ hybridization canine Y probe, and polymerase chain reaction-based chimerism analyses. Term survival was 86% to 100% for transplantations > or =34 days versus 14% and 43% at 30 and 31 days. Microchimerism (<1%) was demonstrated in tissues from 4 informative litters that included thymus, liver, skin, spleen, and intestine. Neither gestational age nor donor CD34 cell dosage altered the level of engraftment in these experiments. There was no evidence of graft-versus-host disease. In utero bone marrow transplantation in a canine model achieves microchimerism with high CD34(+) cell doses.
We report on monozygotic (MZ) twins who were discordant for phenotypic sex and U11rich-Turner syn... more We report on monozygotic (MZ) twins who were discordant for phenotypic sex and U11rich-Turner syndrome (UTS). The nonviable female was hydropic with cystic hygromas, ventricular septa1 defect, bicuspid aortic valve, polysplenia, intestinal malrotation, and small ovaries. The male was phenotypically normal. The monochorionic, diamniotic placenta had hydropic changes limited to the UTS infant's side. Skin samples from the infants and blood from their parents were obtained for cytogenetic and molecular analysis. Karyotypes of the twins were 45,X and 46,XY. Quinacrine polymorphisms on 7 chromosomes and RFLP analysis at 8 loci showed complete identity. MZ twins discordant for phenotypic sex have been described previously. Most of these show evidence of mosaicism in a 45,X patient with a normal 46,XY cell line, and a normal 46,XY male. While the issue of mosaicism in our case cannot be fully resolved, no mosaicism was found in 50 cells analyzed cytogenetically from each culture or by PCR analysis of a Y-specific sequence. The twins probably originated from either postzygotic nondisjunction or anaphase lag, followed or accompanied by twinning. The discordant placental morphology suggests an embryonic origin of at least part of the placental mesenchymal core.
Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 ... more Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0.3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10.3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15.3 per cent) were mosaic for a marker chromosome. Ninety-five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype-phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian-Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40.4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.
Proceedings of the National Academy of Sciences of the United States of America, Oct 10, 1995
In many vertebrate and invertebrate cells, inositol 1,4,5-trisphospate production induces a bipha... more In many vertebrate and invertebrate cells, inositol 1,4,5-trisphospate production induces a biphasic Ca2+ signal. Mobilization of Ca2+ from internal stores drives the initial burst. The second phase, referred to as storeoperated Ca2+ entry (formerly capacitative Ca2+ entry), occurs when depletion of intracellular Ca2+ pools activates a non-voltage-sensitive plasma membrane Ca2+ conductance. Despite the prevalence of store-operated Ca2+ entry, no vertebrate channel responsible for store-operated Ca2+ entry has been reported. trp (transient receptor potential), a Dro
An unstable ring chromosome 21 detected through prenatal studies was associated at birth with an ... more An unstable ring chromosome 21 detected through prenatal studies was associated at birth with an apparently normal male phenotype. At 14 months of age, examination indicated only minor developmental delay. The majority of cells examined from amniocyte, fibroblast, and lymphocyte cultures contained an asymmetrical dicentric ring 21 chromosome which was larger than a normal chromosome 21. This ring is presumed to be a duplication for most of chromosome 21 and a deletion of part of the terminal regions. The karyotype is described as mos45,XY,-21/46,XY,r(21)(p13q22.3). The child is monosomic for part of the sub-band 21q22.3 in every cell and trisomic for the remainder of the chromosome in most of his cells. The terminal deletion does not appear to have been severely detrimental to the phenotype and the effective trisomy present in many cells studied was insufficient to cause the Down syndrome.
We report the unique finding of a satellited X chromosome in a woman with Turner syndrome and a m... more We report the unique finding of a satellited X chromosome in a woman with Turner syndrome and a mosaic karyotype 45,X/46,X,mar(X)(sat,QFQ55),var(21)(sat,QFQ55). In PHA-stimulated lymphocytes and in lymphoblast culture, the satellited X chromosome was consistently late replicating. The translocated nucleolus organizer region (NOR) genes in the stalk of the satellite, however, remained transcriptionally active, and an unusual, late-replicating band was seen at the distal end of Xp. Analysis of fibroblast clones containing the satellited X chromosome suggests that the mar(X) is relatively stable.
American Journal of Obstetrics and Gynecology, Dec 1, 2005
(IUHSCT) is a promising therapy that may circumvent many of the morbidities and limitations of po... more (IUHSCT) is a promising therapy that may circumvent many of the morbidities and limitations of postnatal BMT.
American Journal of Obstetrics and Gynecology, Dec 1, 2007
Smoking during pregnancy is associated with alterations in neonatal growth. Previous studies have... more Smoking during pregnancy is associated with alterations in neonatal growth. Previous studies have demonstrated the additional contribution of maternal genotype to the reduction in birth weight. We sought to investigate the association between maternal smoking and infant growth and the influence of CYP1A1 and GSTT1. STUDY DESIGN: This analysis of neonatal growth outcomes was part of a larger study of maternal inflammatory response with smoking during pregnancy. We evaluated birth weight, length, and head circumference from 169 neonates. Neonates were grouped by maternal smoking status which was determined by cotinine concentrations. Analysis included the use of t-test and linear regression. RESULTS: The mean maternal age and BMI of the cohort was 23.5Ϯ4.8 years and 25.1Ϯ6.2 kg/m2. That rate of smoking in the cohort was 30%. Birth weight was approximately 200g less among neonates of women who smoked but did not reach statistical significance (pϭ0.06). Length was decreased among neonates of smokers (pϭ0.001). Head circumference was not different (pϭ0.14). Maternal cotinine concentrations correlated with fetal (cord) concentrations (r2ϭ0.34, pϽ0.01). Maternal cotinine concentration was negatively associated with birth weight and fetal length (pϭ0.05, pϽ0.01) using backward multivariable linear regression including maternal age, BMI, race, and gestational age at delivery. Fetal cotinine was associated with length but not weight (pϭ0.014, pϭ0.5). The prevalence of CYP1A1 wildtype was 75% and for GSTT present was 63%. There was no difference in genotypes by smoking status. In addition, there was no difference in birth weight or length by genotype and there was no additional influence on birth weight or length in addition to smoking status. CONCLUSION: The results of our study corroborate many other studies by demonstrating reduction in birth weight and birth length among neonates of women who smoked during pregnancy. Metabolic genotypes, specifically CYP1A1 and GSTT1, however, did not have any affect on measures of growth in this specific patient population.
International journal of gynaecology and obstetrics, 1993
generates anxiety, it is nevertheless perceived as necessaq for the successful outcome of the pre... more generates anxiety, it is nevertheless perceived as necessaq for the successful outcome of the pregnancy. Conclusion: Early mechanical transvaginal embryo reduction performed at 7 weeks of amenorrhea, leaving two embryos is, in our opinion, a simple and safe procedure with no affect on remaining fetuses. It is necessary when there are four or more embryos and it should also be proposed for triplets. In these circumstances, patients saw reduction as a necessary procedure.
Objectives: The detection of an increased nuchal translucency (NT) or nuchal fold (NF) measuremen... more Objectives: The detection of an increased nuchal translucency (NT) or nuchal fold (NF) measurement is associated with an increased risk of common aneuploidies. Only rarely is it associated with other types of chromosome abnormalities. We report the prenatal finding of an increased NF in a fetus with an interstitial 4p deletion. Methods: Standard karyotype analysis was followed by FISH with research generated BAC probes to precisely map the 4p deletion. Results: The karyotype of the fetus was determined to be 46,XX,del(4)(p15.2p16.1) by G-banding analysis and was refined to 46,XX,del(4) (p15.1p15.32) after FISH analysis. The breakpoints were narrowed to 150 kb regions on each side. The deletion is approximately 14.5 Mb, containing approximately 47 genes. Conclusions: We report a case of an increased NF measurement associated with a 4p deletion. A literature review revealed a previous case of a 4p deletion in a fetus with an increased NT. Since chromosome deletions are rarely associated with an increased NT or NF, we believe it is significant that a 4p deletion has now been found in two unrelated cases. We mapped the deletion with BAC probes, generating a list of possible candidate genes involved in the pathogenesis of increased nuchal skin folds.
In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of... more In utero hematopoietic stem cell transplantation (IUHSCT) is a promising therapy for a variety of congenital disorders. Our objective was to determine the optimal time in gestation for IUHSCT in a canine model. Methods: IUHSCT was performed in day 31-50 (term 63) fetal canines with CD34+ cells isolated from paternal bone marrow at doses of 0.09-3.4 × 10 9 CD34+ cells/kg and T cells (CD3+/CD5+) from paternal blood at 0.11-1.1 × 10 9 cells/kg. Engraftment was assayed using PCR-based chimerism analysis (SRY gene detection for female recipients, and unique microsatellite loci for both sexes). Results: Microchimerism and chimerism were present in multiple recipients across most gestational ages at transplant. Maximal engraftment was obtained in hematopoietic tissues in transplants performed at 42 days. At extremes of recipient gestational age, minimal to no engraftment was seen. Conclusion: Fetal age at the time of IUHSCT plays an important role in achieving engraftment in our canine model.
Objectives: To explore the advantages and limitations of comparative genomic hybridization to BAC... more Objectives: To explore the advantages and limitations of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of a fetus with anomalies and a chromosome abnormality. Methods: We used karyotype analysis, FISH and array CGH to investigate an unbalanced chromosome rearrangement. Results: We report a case of a fetus with ultrasound anomalies at 11 weeks' gestation and an unbalanced chromosome translocation [46,XX,der(13)t(2; 13)(p25.1;q32)pat]. Initially, a chromosome 13 deletion was reported from G-banded chromosome analysis and 13q subtelomere FISH. The involvement of chromosome 2 was determined after a balanced translocation was identified in the father, 46,XY,t(2; 13)(p25.1;q32). Array CGH confirmed the fetal abnormality as partial trisomy of the short arm chromosome 2 and partial monosomy of the long arm of chromosome 13. The abnormalities identified by ultrasound studies and autopsy appear to be most consistent with 13q deletion syndrome. Conclusions: Array CGH successfully identified a subtle unbalanced chromosome complement in a fetus with multiple ultrasound anomalies. If array CGH had been performed along with the fetal karyotype, the cryptic partial trisomy 2 could have been identified in a more timely manner to assist in the prenatal counseling of this family.
Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation ... more Two cases of mosaic trisomy 7 confined to the cultured cells and not found in direct preparation were detected from 200 consecutive first-trimester chorionic villus samples (CVS) analysed. The mosaicism was similar in the two cases, but the pregnancy outcome was different. In both cases, the direct metaphases from the CVS were 46,XY. Culture metaphases were mos46,XY/47,XY, + 7; the trisomy 7 was seen in 34 per cent of cells from case 1 and 53 per cent from case 2. A sonogram at 15; weeks revealed fetal death in utero in case 1, and the patient declined amniocentesis. The fetal tissue failed to grow in culture, but the placental cultured cells were 47,XY, + 7 in 28 (100 per cent) cells analysed. In the second case, all the amniotic fluid cells were 46,XY and the pregnancy resulted in a normal male with a 46,XY karyotype in the cord blood and foreskin fibroblast cultures. The term placenta was mosaic with 13/163 (8 per cent) trisomy 7 cells. Extensive cytogenetic studies on the placenta for the first time confirmed trisomy 7 mosaicism confined to the villus cultures.
evidence of graft-versus-host disease (GVHD). Conclusion: Canine IUHSCT is a useful model to inve... more evidence of graft-versus-host disease (GVHD). Conclusion: Canine IUHSCT is a useful model to investigate the role of donor T cells in engraftment and GVHD. IUHSCT at early gestational ages with high doses of donor T cells in the graft yields microchimerism in multiple tissues without GVHD.
In situ hybridization using a series of alphoid DNA probes has demonstrated the origin of two sma... more In situ hybridization using a series of alphoid DNA probes has demonstrated the origin of two small accessory mosaic marker chromosomes ascertained from 1079 amniocenteses. These markers appeared to be de novo, derived from acrocentric chromosomes, and identical by traditional cytogenetic staining (G, Q, C, AgNOR, Hoechst‐distamycin). Molecular characterization showed that one marker had originated from chromosome 14, the other from chromosome 22. Clinical outcome in both cases was normal.
American journal of medical genetics, Jan 10, 1997
We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a s... more We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a second trimester fetus with the karyotype of 46,XX, inv dup del (7)(pter-q36::q36-q21.2:) pat. Both a large duplication (q21.2-q36) and a small deletion (within q36) were confirmed by FISH studies. DNA analysis on the family showed that the abnormal chromosome was derived from a single paternal homolog. A mechanism is proposed in light of this finding. The phenotype at autopsy was consistent with reported cases of similar duplications in chromosome 7 in that hydrocephalus, a depressed nasal bridge, low set ears, microretrognathia and a short neck were present.
American Journal of Obstetrics and Gynecology, Apr 1, 2004
Chimerism can be achieved in a canine model of in utero bone marrow transplantation with &amp... more Chimerism can be achieved in a canine model of in utero bone marrow transplantation with > or =1 x 10(8) CD34(+) haploidentical donor cells per kilogram without graft-versus-host disease. In utero bone marrow transplantation was performed by ultrasound-guided intraperitoneal infusion in 30- to 41-day-old canines with CD34(+) selected cells from paternal bone marrow at doses of 1.3 x 10(8) to 2.5 x 10(10) CD34(+) cells/kg. A method for marking control littermates was developed with intraperitoneal ethiodol. Postnatal studies included histologic, fluorescent in situ hybridization canine Y probe, and polymerase chain reaction-based chimerism analyses. Term survival was 86% to 100% for transplantations > or =34 days versus 14% and 43% at 30 and 31 days. Microchimerism (<1%) was demonstrated in tissues from 4 informative litters that included thymus, liver, skin, spleen, and intestine. Neither gestational age nor donor CD34 cell dosage altered the level of engraftment in these experiments. There was no evidence of graft-versus-host disease. In utero bone marrow transplantation in a canine model achieves microchimerism with high CD34(+) cell doses.
We report on monozygotic (MZ) twins who were discordant for phenotypic sex and U11rich-Turner syn... more We report on monozygotic (MZ) twins who were discordant for phenotypic sex and U11rich-Turner syndrome (UTS). The nonviable female was hydropic with cystic hygromas, ventricular septa1 defect, bicuspid aortic valve, polysplenia, intestinal malrotation, and small ovaries. The male was phenotypically normal. The monochorionic, diamniotic placenta had hydropic changes limited to the UTS infant's side. Skin samples from the infants and blood from their parents were obtained for cytogenetic and molecular analysis. Karyotypes of the twins were 45,X and 46,XY. Quinacrine polymorphisms on 7 chromosomes and RFLP analysis at 8 loci showed complete identity. MZ twins discordant for phenotypic sex have been described previously. Most of these show evidence of mosaicism in a 45,X patient with a normal 46,XY cell line, and a normal 46,XY male. While the issue of mosaicism in our case cannot be fully resolved, no mosaicism was found in 50 cells analyzed cytogenetically from each culture or by PCR analysis of a Y-specific sequence. The twins probably originated from either postzygotic nondisjunction or anaphase lag, followed or accompanied by twinning. The discordant placental morphology suggests an embryonic origin of at least part of the placental mesenchymal core.
Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 ... more Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0.3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10.3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15.3 per cent) were mosaic for a marker chromosome. Ninety-five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype-phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian-Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40.4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.
Proceedings of the National Academy of Sciences of the United States of America, Oct 10, 1995
In many vertebrate and invertebrate cells, inositol 1,4,5-trisphospate production induces a bipha... more In many vertebrate and invertebrate cells, inositol 1,4,5-trisphospate production induces a biphasic Ca2+ signal. Mobilization of Ca2+ from internal stores drives the initial burst. The second phase, referred to as storeoperated Ca2+ entry (formerly capacitative Ca2+ entry), occurs when depletion of intracellular Ca2+ pools activates a non-voltage-sensitive plasma membrane Ca2+ conductance. Despite the prevalence of store-operated Ca2+ entry, no vertebrate channel responsible for store-operated Ca2+ entry has been reported. trp (transient receptor potential), a Dro
An unstable ring chromosome 21 detected through prenatal studies was associated at birth with an ... more An unstable ring chromosome 21 detected through prenatal studies was associated at birth with an apparently normal male phenotype. At 14 months of age, examination indicated only minor developmental delay. The majority of cells examined from amniocyte, fibroblast, and lymphocyte cultures contained an asymmetrical dicentric ring 21 chromosome which was larger than a normal chromosome 21. This ring is presumed to be a duplication for most of chromosome 21 and a deletion of part of the terminal regions. The karyotype is described as mos45,XY,-21/46,XY,r(21)(p13q22.3). The child is monosomic for part of the sub-band 21q22.3 in every cell and trisomic for the remainder of the chromosome in most of his cells. The terminal deletion does not appear to have been severely detrimental to the phenotype and the effective trisomy present in many cells studied was insufficient to cause the Down syndrome.
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Papers by Gail Stetten