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ABSTRACT: STUDY QUESTION: Are human trophectoderm (TE) cells committed or still able to develop into inner cell mass (ICM) cells? SUMMARY ANSWER: Human full blastocyst TE cells still have the capacity to develop into ICM cells expressing the pluripotency marker NANOG, thus they are not yet committed. WHAT IS KNOWN ALREADY: Human Day 5 full blastocyst TE cells express the pluripotency markers POU5F1, SOX2 and SALL4 as well as the TE markers HLA-G and KRT18 but not yet CDX2, therefore their developmental direction may not yet be definite. STUDY DESIGN, SIZE, DURATION: The potency of human blastocyst TE cells was investigated by determining their in vitro capacity to develop into a blastocyst with ICM cells expressing NANOG; TE cells were isolated either by aspiration under visual control or after labeling with fluorescent 594-wheat germ agglutinin. Further on, aspirated TE cells were also labeled with fluorescent PKH67 and repositioned in the center of the original embryo. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human preimplantation embryos were used for research after obtaining informed consent from IVF patients. The experiments were approved by the Local Ethical Committee and the 'Belgian Federal Committee on medical and scientific research on embryos in vitro'. Outer cells were isolated and reaggregated by micromanipulation. Reconstituted embryos were analyzed by immunocytochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: Isolated and reaggregated TE cells from full human blastocysts are able to develop into blastocysts with ICM cells expressing the pluripotency marker NANOG. Moreover, the majority of the isolated TE cells which were repositioned in the center of the embryo do not sort back to their original position but integrate within the ICM and start to express NANOG. LIMITATIONS, REASONS FOR CAUTION: Owing to legal and ethical restrictions, manipulated human embryos cannot be transferred into the uterus to determine their totipotent capacity. The definitive demonstration that embryos reconstructed with TE cells are a source of pluripotent cells is to obtain human embryonic stem cell 'like' line(s), which will allow full characterization of the cells. WIDER IMPLICATIONS OF THE FINDINGS: Our finding has important implications in reproductive medicine and stem cell biology because TE cells have a greater developmental potential than assumed previously. STUDY FUNDING/COMPETING INTEREST(S): Scientific Research Foundation-Flanders (FWO-Vlaanderen) and Research Council (OZR) of the Vrije Universiteit Brussel. None of the authors declared a conflict of interest.
Human Reproduction 12/2012; · 4.47 Impact Factor
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ABSTRACT: Carriers of reciprocal translocations (rcp) are known to be at risk for reproductive difficulties. Preimplantation genetic diagnosis (PGD) is one of the options these carriers have to try in order to fulfil their desire to have a child. In the present study, we retrospectively looked at the results of 11 years (1997-2007) of PGD for rcp in our center to improve the reproductive counseling of these carriers. During this period 312 cycles were performed for 69 male and 73 female carriers. The mean female age was 32.8 years, the mean male age 35.8 years. Most carriers were diagnosed with a translocation because of fertility problems or recurrent miscarriages, and most of them opted for PGD to avoid these problems. In 150 of the 312 cycles, embryo transfer (ET) was feasible and 40 women had a successful singleton or twin pregnancy. This gives a live birth delivery rate of 12.8% per started cycle and of 26.7% per cycle with ET. Owing to the large number of abnormal embryos, PGD cycles for rcp often lead to cancellation of ET, explaining the low success rate when expressed per cycle with oocyte pick-up. Once ET was feasible, the live birth delivery rate was similar to that of PGD in general at our center. PGD is therefore an established option for specific reciprocal translocation carriers.
European journal of human genetics: EJHG 11/2011; 20(4):376-80. · 3.56 Impact Factor
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ABSTRACT: This study provides an overview of 13 years of experience of preimplantation genetic diagnosis (PGD) for Huntington's disease (HD) at three European PGD centres in Brussels, Maastricht and Strasbourg. Information on all 331 PGD intakes for HD, couples' reproductive history, PGD approach, treatment cycles and outcomes between 1995 and 2008 were collected prospectively. Of 331 couples for intake, 68% requested direct testing and 32% exclusion testing (with a preponderance of French couples). At the time of PGD intake, 39% of women had experienced one or more pregnancies. A history of pregnancy termination after prenatal diagnosis was observed more frequently in the direct testing group (25%) than in the exclusion group (10%; P=0.0027). PGD workup was based on two approaches: (1) direct testing of the CAG-triplet repeat and (2) linkage analysis using intragenic or flanking microsatellite markers of the HTT gene. In total, 257 couples had started workup and 174 couples (70% direct testing, 30% exclusion testing) completed at least one PGD cycle. In total, 389 cycles continued to oocyte retrieval (OR). The delivery rates per OR were 19.8%, and per embryo transfer 24.8%, resulting in 77 deliveries and the birth of 90 children. We conclude that PGD is a valuable and safe reproductive option for HD carriers and couples at risk of transmitting HD.
European journal of human genetics: EJHG 11/2011; 20(4):368-75. · 3.56 Impact Factor
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ABSTRACT: Robertsonian translocation carriers are at increased risk for infertility, spontaneous abortions, or chromosomally unbalanced offspring. Reproductive counseling of these carriers is challenging. We performed a retrospective analysis of all prenatal diagnoses from Robertsonian translocation carriers during the time period January 1, 1992 through December 31, 2007. Data on the carriers and the results of their prenatal analyses were retrieved as well as data on their previous pregnancies. We identified 28 female and 20 male carriers of Robertsonian translocations and results on 79 prenatal samples were obtained. Among female carriers, 10.3% of chorionic villus sampling and 5.9% of amniocentesis results were unbalanced, whereas for male carriers, this was 3.6% and 0%, respectively. When considering all pregnancies involving carriers, 52.7% of those to female carriers and 61.8% of those to male carriers led to the birth of a healthy child. Male carriers in whom the translocation was ascertained because of infertility or recurrent miscarriages appear to be at higher risk, whereas carriers in whom ascertainment was because of a family history are at lower risk. We conclude that pregnancies of Robertsonian translocation carriers are at increased risk for chromosomal imbalance, and prenatal chromosomal testing should be discussed. More than half of the pregnancies led to the birth of a healthy child, but prediction of which couples will be successful in obtaining a pregnancy with or without assisted reproductive technologies and/or embryo selection remains difficult. The reason for ascertainment of the translocation should be taken into account when counseling these couples. The possibility of preimplantation genetic diagnosis should also be discussed with the couples.
American Journal of Medical Genetics Part A 09/2011; 155A(10):2381-5. · 2.39 Impact Factor
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ABSTRACT: To investigate whether the incidence of chromosomally abnormal blastomeres is related to the type of pituitary suppression used in ovarian stimulation.
Retrospective study.
Tertiary referral center.
The study involved 694 consecutive cycles; 320 belonged to agonist group and 374 to antagonist group, of patients' ≤ 37 years of age who underwent preimplantation genetic screening between October 1, 1992 until December 31, 2006. All of them (and their partners) had normal karyotyping results. Only the data of patients who had at least one embryo biopsy were analyzed.
Preimplantation genetic screening (PGS).
The primary outcome measure was detection of abnormal blastomeres on the total number of embryos analyzed.
The total abnormal ratio was statistically similar between the embryos of the two study groups (49.9 ± 28.1 vs. 50.2 ± 26.6). Likewise, a multivariate (linear regression) analysis indicated that the total abnormality ratio was not influenced by the type of stimulation when simultaneously adjusting for age, rank of trials, indication for preimplantation genetic screening, total gonadotropin amount, number of cumulus-oocyte complexes, and number of two pronuclear oocytes embryos. No difference was observed in ongoing pregnancy rates between agonists and antagonists (26.6% vs. 23.3%, respectively).
Based on our findings there is no difference in the proportion of abnormal blastomeres either when using gonadotropin-releasing hormone (GnRH) agonist, or antagonist protocol.
Fertility and sterility 02/2011; 95(2):563-7. · 3.97 Impact Factor
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ABSTRACT: In this report, we present the derivation and characterization of 15 hESC lines established at the Vrije Universiteit Brussel, Belgium in collaboration with the Universitair Ziekenhuis Brussel, Belgium, using surplus in vitro fertilization embryos and embryos carrying monogenic disorders donated for research. Four lines were derived from blastocyst-stage embryos presumed to be genetically normal, and 11 hESC lines were obtained from embryos shown to carry genetic mutations by preimplantation genetic diagnosis. All the lines express markers of pluripotency as determined by immunocytochemistry and RT-PCR, and formed teratomas when injected into SCID mice. All VUB hESC lines, except for VUB17, are reported in the European hESC registry and are available upon request after signing a Material Transfer Agreement from the VUB (contact person: Prof. Dr. Karen Sermon; Karen.Sermon@uzbrussel.be).
In Vitro Cellular & Developmental Biology - Animal 03/2010; 46(3-4):300-8. · 1.31 Impact Factor
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ABSTRACT: Human embryonic stem cells (hESC) have the capacity to differentiate in vivo and in vitro into cells from all three germ lineages. The aim of the present study was to investigate the effect of specific culture conditions on the differentiation of hESC into lung epithelial cells.
Undifferentiated hESC, grown on a porous membrane in hESC medium for four days, were switched to a differentiation medium for four days; this was followed by culture in air-liquid interface conditions during another 20 days. Expression of several lung markers was measured by immunohistochemistry and by quantitative real-time RT-PCR at four different time points throughout the differentiation and compared to appropriate controls.
Expression of CC16 and NKX2.1 showed a 1,000- and 10,000- fold increase at day 10 of differentiation. Other lung markers such as SP-C and Aquaporin 5 had the highest expression after twenty days of culture, as well as two markers for ciliated cells, FOXJ1 and beta-tubulin IV. The results from qRT-PCR were confirmed by immunohistochemistry on paraffin-embedded samples. Antibodies against CC16, SP-A and SP-C were chosen as specific markers for Clara Cells and alveolar type II cells. The functionality was tested by measuring the secretion of CC16 in the medium using an enzyme immunoassay.
These results suggest that by using our novel culture protocol hESC can be differentiated into the major cell types of lung epithelial tissue.
Respiratory research 11/2009; 10:105. · 3.36 Impact Factor
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ABSTRACT: The major objective of this study was to determine whether the embryo biopsy procedure might cause growth restriction or affect health outcome of children.
Auxological data and physical findings were compared at birth and age 2 for 102 children (70 singletons and 32 twins) born after PGD/PGS and 102 matched children born after intracytoplasmic sperm injection (ICSI) in a prospective study.
No statistically significant differences regarding weight, height and head circumference standard deviation scores (SDS) at birth and at age two years were observed. At two years of age the mean BMI SDS tended to be lower in PGD/PGS children (p=0.058). PGD/PGS babies had been more often breastfed (p=0.013), but mostly during a shorter time. The prevalence of major as well as minor congenital anomalies, hospital admissions and surgical interventions was similar.
Children born after embryo biopsy applied in PGD/PGS present similar prenatal and postnatal growth and health outcome in the first two years of life compared to ICSI children. Up till now, PGD and PGS appear not to be associated with a higher risk for health problems.
Early human development 11/2009; 85(12):755-9. · 2.12 Impact Factor
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ABSTRACT: Recently, we demonstrated that single blastomeres of a 4-cell stage human embryo are able to develop into blastocysts with inner cell mass and trophectoderm. To further investigate potency at the 4-cell stage, we aimed to derive pluripotent human embryonic stem cells (hESC) from single blastomeres.
Four 4-cell stage embryos were split on Day 2 of preimplantation development and the 16 blastomeres were individually cultured in sequential medium. On Day 3 or 4, the blastomere-derived embryos were plated on inactivated mouse embryonic fibroblasts (MEFs).
Ten out of sixteen blastomere-derived morulae attached to the MEFs, and two produced an outgrowth. They were mechanically passaged onto fresh MEFs as described for blastocyst ICM-derived hESC, and shown to express the typical stemness markers by immunocytochemistry and/or RT-PCR. In vivo pluripotency was confirmed by the presence of all three germ layers in the teratoma obtained after injection in immunodeficient mice. The first hESC line displays a mosaic normal/abnormal 46, XX, dup(7)(q33qter), del(18)(q23qter) karyotype. The second hESC line displays a normal 46, XY karyotype.
We report the successful derivation and characterization of two hESC lines from single blastomeres of four split 4-cell stage human embryos. These two hESC lines were derived from distinct embryos, proving that at least one of the 4-cell stage blastomeres is pluripotent.
Human Reproduction 08/2009; 24(11):2709-17. · 4.47 Impact Factor
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ABSTRACT: Preimplantation genetic screening is being scrutinized, as recent randomized clinical trials failed to observe the expected significant increase in live birth rates following fluorescence in situ hybridization (FISH)-based screening. Although these randomized clinical trials are criticized on their design, skills or premature stop, it is generally believed that well-designed and well-executed randomized clinical trials would resolve the debate about the potential benefit of preimplantation genetic screening. Since FISH can analyze only a limited number of chromosomal loci, some of the embryos transferred might be diagnosed as 'normal' but in fact be aneuploid for one or more chromosomes not tested. Hence, genome-wide array comparative genome hybridization screening enabling aneuploidy detection of all chromosomes was thought to be a first step toward a better design. We recently showed array screening indeed enables accurate determination of the copy number state of all chromosomes in a single cell. Surprisingly, however, this genome-wide array screening revealed a much higher frequency and complexity of chromosomal aberrations in early embryos than anticipated, with imbalances in a staggering 90% of all embryos. The mitotic error rate in cleavage stage embryos was proven to be higher than the meiotic aneuploidy rate and as a consequence, the genome of a single blastomere is not representative for the genome of the other cells of the embryo. Hence, potentially viable embryos will be discarded upon screening a single blastomere. This observation provides a biological basis for the failure of the randomized clinical trials to increase baby-take-home rates using FISH on cleavage stage embryos.
Human Reproduction 08/2009; 24(11):2679-82. · 4.47 Impact Factor
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ABSTRACT: Carriers of Robertsonian translocations are at increased risk for infertility, repeated miscarriage and aneuploid offspring. In the present study, 10 years of experience with preimplantation genetic diagnosis (PGD) for Robertsonian translocations is reviewed and these data are used to improve the reproductive counselling in the carriers.
A retrospective analysis was performed of all requests and cycles for PGD for Robertsonian translocations at our centre between January 1997 and December 2006. Data on the characteristics of the couples and on the PGD cycles were retrieved from the medical records. These data were recorded for the whole group and according to the sex of the carrier.
A total of 111 couples made a request for PGD in our centre, of which 76 had at least one PGD cycle. In the PGD cycles embryo transfer could take place in 66.1% of the cycles with oocyte pick-up and positive hCG was found in 42.7% of the cycles with embryo transfer. The live born delivery rate was 20.2% per cycle with oocyte retrieval and 30.5% per cycle with embryo transfer.
With a live birth delivery rate of 32.9% per couple, PGD is considered a good option for these couples, especially when there is a coexisting fertility problem. PGD reduces the risk of miscarriage and allows couples to have a healthy child within a relatively short time span compared with spontaneous pregnancies. However, for young, fertile couples, the chances of having a healthy child after a number of spontaneous pregnancies, should not be ignored.
Human Reproduction 07/2009; 24(9):2365-71. · 4.47 Impact Factor
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ABSTRACT: Male infertility is a worldwide problem, keeping many researchers puzzled. Besides environmental factors, much attention is paid to single gene defects. In this view, the sex chromosomes are particularly interesting since men only have a single copy of these chromosomes. The involvement of the Y chromosome in male infertility is obvious since the detection of Yq microdeletions. The role of the X chromosome, however, remains less understood.
Articles were obtained by searching PubMed until December 2008. A first search attempted to identify genes located on the X chromosome potentially important for spermatogenesis. A second part of the study was focused on those genes for which the role has already been studied in infertile patients.
Multiple genes located on the X chromosome are expressed in testicular tissues. The function of many genes, especially the cancer-testis genes, has not been studied so far. There were striking differences between mouse and human genes. In the second part of the study, the results of mutation analyses of seven genes (AR, SOX3, USP26, NXF2, TAF7L, FATE and AKAP4) are described. Except for AR, no infertility causing mutations have, thus far, been described. It cannot be excluded that some of the observed changes should be considered as risk factors for impaired spermatogenesis.
It can be concluded that, so far, the mutation analysis of X-linked genes in humans, presumed to be crucial for spermatogenesis or sperm quality, has been disappointing. Other approaches to learn more about male infertility are necessary.
Human Reproduction Update 07/2009; 15(6):623-37. · 9.23 Impact Factor
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ABSTRACT: Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for patients at risk of transmitting an inherited disease such as myotonic dystrophy type 1(DM1) to their offspring. In this paper, the clinical application of preimplantation diagnosis for DM1 upon request to children born is described in a large cohort of risk couples. PGD could be offered to all 78 couples opting for PGD regardless of the triplet repeat size. The incidence of major complications was minimalised following a careful assessment in affected DM1 females anticipating possible cardiological, obstetrical and anaesthetical problems. A live-birth delivery rate per cycle with oocyte retrieval of 20% was the outcome. Forty-eight of the 49 children born are in good health and have normal psychomotor development.
European journal of human genetics: EJHG 05/2009; 17(11):1403-10. · 3.56 Impact Factor
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ABSTRACT: Embryo biopsy is an essential but invasive procedure to perform preimplantation genetic diagnosis (PGD) or preimplantation genetic screening (PGS). The major objective of this study was to determine whether embryo biopsy might cause post-natal growth restriction.
We compared growth data and physical findings at birth and 2 years for singletons born either after PGD/PGS (n = 70), ICSI (n = 70) or natural conception (NC) (n = 70). Children were matched for gender, maternal educational level, mother tongue and birth order.
No significant differences were found between the three groups regarding weight, height and head circumference standard deviation scores (SDS) at birth and at age 2 years, although the PGD/PGS children tended to have a lower birthweight compared with the NC children. At 2 years, the mean BMI SDS in PGD/PGS children was significantly lower compared with NC children (P = 0.005). PGD/PGS children were more frequently born after Caesarian section than ICSI children, but had no more congenital malformations, hospital admissions and surgical interventions compared with ICSI and NC children.
Singleton children at age 2 years born after embryo biopsy applied in PGD/PGS present a similar post-natal linear growth compared with ICSI and NC children. PGD/PGS singletons appear not to be at higher risk for congenital malformations and surgical interventions during the first 2 years of life. To date, there have been no observable detrimental effects of the PGD/PGS procedure on children.
Human Reproduction 01/2009; 24(2):470-6. · 4.47 Impact Factor
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ABSTRACT: Two European centres report on human leukocyte antigen (HLA) typing of preimplantation embryos for haematopoietic stem cell (HSC) transplantation: 'UZ Brussel' in Brussels and 'Genoma' in Rome. Both centres have 6 years' experience with technical and clinical aspects of this type of genetic analysis on single blastomeres.
Both centres apply a similar technique for preimplantation HLA typing using short tandem repeats linked to the HLA locus in multiplex PCR for haplotyping.
At present, a conclusive HLA diagnosis could be assured in 92.8% and 90.3% of the embryos at UZ Brussel and at Genoma, respectively. The implantation rates were 32.4% and 28.2%, respectively, and the birth rates per cycle were 9.4% and 18.6%, respectively. The HLA programme at UZ Brussel and at Genoma resulted in the birth of 9 babies and 3 successful HSC transplantations, and 42 babies and 7 successful HSC transplantations, respectively, so far.
Drastic embryo selection for preimplantation HLA typing (in theory 1/4 for HLA, 1/8 for HLA in combination with sexing for X-linked recessive diseases, 3/16 for HLA in combination with autosomal recessive disorders) resulted overall in the birth of 51 babies (15.9% live birth rate per started cycle) in two European centres.
Human Reproduction 01/2009; 24(3):732-40. · 4.47 Impact Factor
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ABSTRACT: Cultured human embryonic stem (hES) cells have a known predisposition to aneuploidy of chromosomes 12, 17 and X. We studied 17 hES cell lines by array-based comparative genomic hybridization (aCGH) and found that the cells accumulate other recurrent chromosomal abnormalities, including amplification at 20q11.21 and a derivative chromosome 18. These genomic changes have a variable impact at the transcriptional level.
Nature Biotechnology 12/2008; 26(12):1361-3. · 29.50 Impact Factor
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Janine Reichenbach,
Hilde Van de Velde,
Martine De Rycke,
Cathérine Staessen,
Peter Platteau,
Patricia Baetens,
Tayfun Güngör,
Hulya Ozsahin,
Franziska Scherer,
Ulrich Siler,
Reinhard A Seger, Inge Liebaers
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ABSTRACT: Allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen (HLA)-identical donor is currently the only proven curative treatment for chronic granulomatous disease. Hematopoietic stem cell transplantation with alternative donors is associated with higher morbidity and mortality. Therefore, we performed in vitro fertilization and preimplantation HLA matching combined with female sexing for hematopoietic stem cell transplantation in chronic granulomatous disease. Ethical and psychological issues were considered carefully. We used in vitro fertilization with X-enriched spermatozoa followed by preimplantation genetic diagnosis to identify female HLA-genoidentical embryos in a family in need of a suitable donor for their boy affected with severe X-linked chronic granulomatous disease. Two preimplantation genetic diagnosis cycles were performed in the family. In the second cycle, 2 HLA-genoidentical female embryos were transferred and a singleton pregnancy was obtained, resulting in the birth of an unaffected girl at term. Because of insufficient cell numbers in the cord-blood source, conventional hematopoietic stem cell transplantation had to be performed at 12 months of age of the donor and 5 years of age of the recipient and resulted in complete stable donor chimerism and immunologic reconstitution up to 25 months post-hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation after in vitro fertilization and combined female sexing and HLA matching offers a new and relatively rapid therapeutic option for patients with X-linked primary immunodeficiency such as chronic granulomatous disease who need hematopoietic stem cell transplantation but lack an HLA-genoidentical donor.
PEDIATRICS 10/2008; 122(3):e778-82. · 4.47 Impact Factor
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ABSTRACT: Early mammalian blastomeres are thought to be flexible and totipotent allowing the embryo to overcome perturbations in its organization during preimplantation development. In the past, experiments using single blastomeres from 2-, 4- and 8-cell stage mammalian embryos have provided evidence that at least some of the isolated cells can develop into healthy fertile animals and therefore are totipotent. We investigated whether isolated blastomeres of human 4-cell stage embryos could develop in vitro into blastocysts with trophectoderm (TE) and inner cell mass (ICM).
Six 4-cell stage human embryos were split and the four blastomeres were cultured individually. The expression of NANOG, a marker for ICM cells, was analysed by immunocytochemistry.
The majority of the blastomere-derived embryos followed the normal pattern of development with compaction on Day 4 and cavitation on Day 5 and developed into small blastocysts with TE and ICM on Day 6 (n = 12). The four cells of one embryo were individually capable of developing into blastocysts with TE and ICM, and NANOG was expressed in the ICM.
Although based on a small number of embryos, we conclude that the blastomeres of a 4-cell stage human embryo are flexible and able to develop into blastocysts with ICM and TE.
Human Reproduction 09/2008; 23(8):1742-7. · 4.47 Impact Factor
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ABSTRACT: Human mitochondrial DNA (mt DNA) lesions can cause a heterogeneous group of mitochondrial degenerative disorders. We report on a 5-year-old patient suffering from the full-blown picture of Pearson syndrome. His symptoms started in the first year of life with failure to thrive, followed by chronic diarrhoea and lactic acidosis at 18 months of age. Analysis of mitochondrial DNA revealed large amounts of mt DNA molecules with a 2.7 kb deletion in all tissues examined. The diagnosis of Pearson syndrome was made initially in the absence of haematological disturbances. In the following months neutropenia, sideroblastic anaemia and hypoparathyroidism developed. Daily administration of dichloroacetate (DCA) and bicarbonate controls the lactic acidosis, while episodic treatments with filgastrim (Neupogen®) reverse episodes of severe neutropenia. Calcium and vitamin D supplementation compensate for the hypoparathyroidism. Chronic administration of DCA and supportive treatment for a long period help to stabilize patients with multiorgan dysfunction.
Clinical Genetics 06/2008; 51(5):338 - 342. · 3.13 Impact Factor
