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Biomedical subjects

G Barkai

Publications and source records attributed to G Barkai.

At least 19 recordsLinked to original sources
PubMed2003

Frequency and clinical consequences of extremely high maternal serum PAPP-A levels.

A multicentre study was carried out to determine the frequency and clinical consequences of extremely high maternal serum pregnancy-associated plasma protein (PAPP)-A. There was a total of 79 pregnancies with PAPP-A exceeding 5.0 multiples of the gestation-specific median in a series of 46 776 pregnancies tested (0.2%) at the 7 collaborating centres. Five pregnancies were lost to follow-up, one miscarried and one with Noonan's syndrome was terminated. Of the remaining 72 that ended in a live birth, one infant had gastroschisis and five pregnancies had obstetric complications: pre-eclampsia, pregnancy-induced hypertension, gestational diabetes and two with growth retardation. Among women with high PAPP-A and no complications or adverse outcomes, there was no evidence of a substantial change in the levels of other Down syndrome markers or the extent of nuchal translucency. Three analytical methods were used to assay PAPP-A and yielded different frequencies of extremely high levels (0.05%, 0.4% and 0.6%) possibly owing to cross-reaction with another substance. We conclude that women with high PAPP-A can be reassured that there is no reason to suppose that the outcome of pregnancy will differ from those with normal levels, provided other markers are normal. If, as more centres move their Down syndrome screening practice to the first trimester, additional cases emerge with Noonan's syndrome or gastroschisis and raised PAPP-A, this advice will need to be modified.

Adult↗
PubMed2002

Association between anorexia nervosa and the hsKCa3 gene: a family-based and case control study.

Familial and twin studies have suggested that anorexia nervosa (AN) is a multifactorial disorder with a substantial genetic contribution. The hSKCa3 potassium channel gene, which contains polymorphic CAG repeats in the coding region and is involved in the regulation of neuronal activity, may be a candidate gene for AN because alleles with longer repeats have been found to be associated with mental disorders. Forty Israeli AN family trios were genotyped for the hSKCa3 CAG repeat polymorphism using the haplotype relative risk (HRR) method. The distribution of alleles transmitted to the patients was found to be significantly different from that of the non-transmitted parental alleles, with the longer alleles being over-represented in the patients (Wilcoxon rank test, P = 0.008). The transmission disequilibrium test (TDT) revealed that longer (>19) repeat alleles were preferentially transmitted to AN patients (McNemar's chi(2) = 10.31, P = 0.0013). These results were corroborated by comparing the distribution of alleles between patients and healthy controls (Mann-Whitney test, P = 0.005). Our study suggests that the longer repeat alleles of the hSKCa3 gene may contribute to the genetic susceptibility to AN.

Adolescent↗
PubMed2001

Studies on sperm chromosomes in patients with severe male factor infertility undergoing assisted reproductive technology treatment.

The aim of the study was to determine the rate of chromosome abnormalities in testicular sperm after intracytoplasmic sperm injection due to severe male factor infertility. The study groups included patient with non-obstructive azoospermia (n=9), obstructive azoospermia (n=10), Klinefelter's syndrome (n=5) and normal controls (n=6, groups I-VI, respectively). The mean serum levels of FSH 17.5+/-8.2 (P<0.05), 3.5+/-2.6, 29.8+/-13.0 (P<0.05) and 3.1+/-0.4 mIU/ml, respectively. The rates of chromosome abnormalities were 19.6% (P<0.001), 8.2% (P<0.001), 6.3 and 1.6%, respectively. Chromosomes X and Y were significantly more involved in the aneuploidy than chromosome 18 in groups I and II. The present findings demonstrate a linkage between gonadal failure (high serum FSH levels) and sperm chromosome abnormalities. Our findings may explain the increased incidence of perinatal sex chromosome abnormalities found in severe male factor patients. Patients with non-mosaic Klinefelter's syndrome have comparable risk for sex chromosomes aneuploidy as the rest of the patients with azoospermia. Therefore, genetic screening during pregnancy or before embryo replacement should be carefully considered in severe male factor patient following in vitro fertilization (IVF).

Aneuploidy↗
PubMed2001

Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice.

Stem cell homing into the bone microenvironment is the first step in the initiation of marrow-derived blood cells. It is reported that human severe combined immunodeficient (SCID) repopulating cells home and accumulate rapidly, within a few hours, in the bone marrow and spleen of immunodeficient mice previously conditioned with total body irradiation. Primitive CD34(+)CD38(-/low)CXCR4(+) cells capable of engrafting primary and secondary recipient mice selectively homed to the bone marrow and spleen, whereas CD34(-)CD38(-/low)Lin(-) cells were not detected. Moreover, whereas freshly isolated CD34(+)CD38(+/high) cells did not home, in vivo stimulation with granulocyte colony-stimulating factor as part of the mobilization process, or in vitro stem cell factor stimulation for 2 to 4 days, potentiated the homing capabilities of cytokine-stimulated CD34(+)CD38(+) cells. Homing of enriched human CD34(+) cells was inhibited by pretreatment with anti-CXCR4 antibodies. Moreover, primitive CD34(+)CD38(-/low)CXCR4(+) cells also homed in response to a gradient of human stromal cell-derived factor 1 (SDF-1), directly injected into the bone marrow or spleen of nonirradiated NOD/SCID mice. Homing was also inhibited by pretreatment of CD34(+) cells with antibodies for the major integrins VLA-4, VLA-5, and LFA-1. Pertussis toxin, an inhibitor of signals mediated by Galpha(i) proteins, inhibited SDF-1-mediated in vitro transwell migration but not adhesion or in vivo homing of CD34(+) cells. Homing of human CD34(+) cells was also blocked by chelerythrine chloride, a broad-range protein kinase C inhibitor. This study reveals rapid and efficient homing to the murine bone marrow by primitive human CD34(+)CD38(-/low)CXCR4(+) cells that is integrin mediated and depends on activation of the protein kinase C signal transduction pathway by SDF-1.

ADP-ribosyl Cyclase↗
PubMed2001

Karyotype of the abortus in recurrent miscarriage.

OBJECTIVE: To assess the chromosomal aberrations in the abortus in recurrent miscarriage and the live birth rate after a euploid or aneuploid miscarriage. DESIGN: Retrospective analysis. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One hundred sixty-seven patients with 3 to 16 miscarriages before 20 weeks. INTERVENTION(S): Material collected at curettage from 167 abortuses was analyzed by standard G-banding techniques. MAIN OUTCOME MEASURE(S): The incidence of aberrations and the outcome of the subsequent pregnancy were assessed according to the embryonic karyotype. RESULT(S): In this study 125 specimens were successfully karyotyped. Of these, 29% (36 of 125) had chromosome aberrations; 94% of the aberrations were aneuploidy, and 6% were structural. The most prevalent anomalies were chromosome 16, 18, and 21 trisomies, triploidy, and monosomy X. After an aneuploid miscarriage, there was a 68% subsequent live birth rate (13 of 19) compared to the 41% (16 of 39) rate after a euploid abortion. CONCLUSION(S): The low (29%) incidence of aberrations indicates that alternative mechanisms may be responsible for the majority of recurrent miscarriages. These figures provide a basis for assessing the efficacy of therapy for recurrent miscarriage. If further studies confirm that patients with karyotypically abnormal fetuses have a good prognosis, an informed decision can be made as to whether further investigations and treatment should be undertaken.

Abortion, Habitual↗
PubMed2001

Sperm chromosome abnormalities in men with severe male factor infertility who are undergoing in vitro fertilization with intracytoplasmic sperm injection.

OBJECTIVE: To investigate the potential paternal contribution to the risk of fetal chromosomal anomalies after intracytoplasmic sperm injection (ICSI). DESIGN: Spermatozoa isolated from testicular tissue and ejaculated specimens of consenting patients undergoing testicular biopsy and ICSI were analyzed for chromosomes X, Y, and 18 by FISH. SETTING: Assisted reproductive technology program. PATIENT(S): Consenting patients undergoing testicular biopsy and ICSI, severe oligozoospermic patients, and normal fertile donors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rate of chromosome abnormalities in testicular sperm with regard to the type of azoospermia and ejaculated sperm compared to healthy men. RESULT(S): The mean serum levels of FSH in the groups with nonobstructive azoospermia (n = 9), obstructive azoospermia (n = 10), severe oligozoospermia (n = 9), and the normal donors (n = 6) were 17.5 +/- 8.2 (P<.05), 3.5 +/- 2.6, 14.6 +/- 3.5 (P<.05), and 3.1 +/- 0.4 IU/mL, respectively. The corresponding rates of sperm chromosome abnormalities among these groups were 19.6% (P<.001), 8.2% (P<.001), 13.0% (P<.001), and 1.6%, respectively. The corresponding rates of disomy among these groups were 7.8% (12 of 153 spermatozoa), 4.9% (18 of 367), 6.2% (109 of 1,751), and 1% (5 of 500 spermatozoa), respectively. Errors in chromosomes X and Y were significantly more common than in chromosome 18. CONCLUSION(S): The present findings demonstrate a linkage between gonadal failure (high serum FSH levels) and the occurrence of sperm chromosome aneuploidies. Our findings may explain the increased incidence of sex chromosome abnormalities found after IVF in the severe male factor patient population. Genetic screening during pregnancy or before embryo replacement should be considered carefully.

Aneuploidy↗
PubMed2001

Comparative genomic hybridization analysis of radiation-associated and sporadic meningiomas.

Ionizing irradiation to the skull is a known risk factor for meningioma development. To gain insight into the molecular mechanisms that underlie radiation-associated meningioma (RAM), we characterized the somatic genetic alterations in 16 RAMs by using comparative genomic hybridization and compared the pattern of alterations with 17 nonradiation-associated meningiomas (non-RAM). Most tumors (29/33;87.9%) displayed at least one DNA copy number alteration, and 11 out of 33 (33%) exhibited four or more changes. The mean number of DNA copy number changes was similar in RAMs (2.4+/-1.9) and in non-RAMs (2.5+/-1.9). The most common DNA losses were noted in chromosome 22 (56.2% in RAM, and 47% in non-RAM) and chromosome 1 (37.5% in RAM and 35.3% in non-RAM), with no significant differences between the two groups. Noteworthy, gain in DNA copy number of chromosomes 8 and 12 was detected in two RAM tumors only. In conclusion, no significant differences were noted between RAMs and non-RAMs regarding the number of genetic changes and the extent and frequency of chromosomes 1 and 22 losses. These preliminary data suggest that the tumorogenic pathways of meningioma formation are similar, regardless of previous skull irradiation.

Adult↗
PubMed2001

Prolactin (PRL)-releasing peptide stimulates PRL secretion from human fetal pituitary cultures and growth hormone release from cultured pituitary adenomas.

The hypothalamic peptide PRL-releasing peptide (PrRP) has recently been cloned and identified as a ligand of an orphan pituitary receptor that stimulates in vitro PRL secretion. PrRP also induces PRL release in rats in vivo, especially in normal cycling females. However, no information on the effects of PrRP in the human is available. To elucidate the role of PrRP in regulating human anterior pituitary hormones, we used human PrRP-31 in primary cultures of human pituitary tissues, including fetal (20--27 weeks gestation) and normal adult pituitaries, as well as PRL- and GH-secreting adenomas. PrRP increased PRL secretion from human fetal pituitary cultures in a dose-dependent manner by up to 35% (maximal effect achieved with 10 nM), whereas TRH was slightly more potent for PRL release. Coincubation with estradiol resulted in enhanced fetal PRL response to PrRP, and GH release was only increased in the presence of estradiol. Although PRL secretion from PRL-cell adenomas was not affected by PrRP, PrRP induced PRL release from cultures of a GH-cell adenoma that cosecreted PRL. PrRP enhanced GH release in several GH-secreting adenomas studied by 25--27%, including GH stimulation in a mixed PRL-GH-cell tumor. These results show for the first time direct in vitro effects of PrRP-31 on human pituitary cells. PrRP is less potent than TRH in releasing PRL from human fetal lactotrophs and is unable to release PRL from PRL-cell adenomas in culture, but stimulated GH from several somatotroph adenomas. Thus, PrRP may participate in regulating GH, in addition to PRL, in the human pituitary.

Adenoma↗
PubMed2001

Fetal hemoglobin-expressing nucleated red blood cell frequencies in pregnancies with intrauterine growth restriction.

The objective of this study was to examine whether there is a difference in the frequency of fetal erythroblasts in maternal blood in pregnancies with intrauterine growth restriction (IUGR) as compared with normal pregnancies. Nucleated red blood cells (NRBC) were isolated from nine pregnant women with ultrasonically diagnosed IUGR (estimated fetal weight less than the 10th percentile for gestational age) and 11 women with appropriately grown fetuses. The frequency of fetal hemoglobin-expressing NRBC (FHE-NRBC) in maternal blood was evaluated by triple density centrifugation and anti-CD71+ magnetic cell sorting, followed by indirect immunocytochemistry for the detection of gamma-chain fetal hemoglobin. The number of FHE-NRBC in 10 ml maternal blood in the IUGR group was higher than in the control group (454.5 vs 56.7, p<0.05). This difference was even more pronounced when FHE-NRBC frequency was calculated relative to the total CD71+ population of cells. There were 118.9 FHE-NRBC per 10(5) CD71+ cells in IUGR pregnancies as compared with 11.5 cells in the control group (p<0.01). There was no difference in the total mean number of CD71+ mononuclear cells between the two groups. The observed increase in the frequency of fetal cells in the maternal circulation found in IUGR pregnancies may be a result of an increase in total NRBC in the fetal circulation or rather of abnormalities in placental structure. This phenomenon may assist in identifying pregnancies at risk for this complication early in the course of the pregnancy, even before actual growth restriction presents itself ultrasonically.

Adult↗
PubMed2001

The association between sporadic somatic parental aneuploidy and chromosomally abnormal placentae in habitual abortions.

To determine whether there is a correlation between the proportion of aneuploid cells in peripheral lymphocytes and the karyotype of the abortus in recurrent miscarriage. 40 couples with recurrent miscarriage and their abortuses were cytogenetically analyzed according to the analysis of 60 cells per proband. Women were divided into two groups according to the proportion of chromosomally abnormal cells in the abortus. Chromosomal analysis was performed using G-banding with trypsin-Giemsa in parental peripheral blood and in the abortus. 20 of the 40 abortuses had a chromosomally abberant karyotype. 65% of parents aborting an embryo with with an increased proportion of chromosomally aberrant cells, had more than 10% aneuploid cells in their peripheral lymphocytes. However, only 12.5% of couples aborting an embryo with chromosomally normal cells had increased rates of aneuploidy. An increased proportion of aneuploid cells was found in the lymphocytes of recurrently aborting couples who repeatedly abort chromosomally abnormal fetuses. Mitotic instability in the lymphocytes may indicate a predisposition to instability at meiosis leading to a chromosomal abberations in the embryo and its subsequent abortion.

Abortion, Habitual↗
PubMed2000

Molecular cytogenetic studies in three patients with partial trisomy 2p, including CGH from paraffin-embedded tissue.

We report on three cases of partial trisomy 2p in which the identification and exact localization of the duplicated chromosome segment was possible only by application of molecular cytogenetic techniques. These included fluorescence in situ hybridization by use of wcp2, N-myc, and subtelomeric 2p probes and comparative genomic hybridization with DNA isolated from blood samples, frozen fetal tendon, and formalin fixed, paraffin-embedded fetal lung tissue. Two of the cases concerned fetuses of gestational week 20 and 24 with duplication of nonoverlapping terminal (2pter-->p24) and more proximal (2p25-->p23) segments and with distinctly different phenotypes. The third case was due to a de novo inverted duplication of 2p25-->p23, with loss of the subtelomeric region of 2p. This 53-month-old girl was a Bloom syndrome carrier. The patient had prenatal growth failure, borderline microcephaly, dilated lateral horns of the cerebral ventricles, transient cortical blindness, myopia, muscle hypotonia, and dilatation of the left renal collecting system. Dermal cysts were found on the glabella, the soles of both feet, and the vocal cord, causing respiratory embarrassment. Previously reported cases of pure trisomy 2p are reviewed, in an attempt to correlate clinical findings to overlapping regions in 2p. These cases illustrate the effectiveness of molecular cytogenetic methods in resolving subtle chromosomal aberrations in order to coordinate more accurately a chromosome regionspecific phenotype.

Abortion, Induced↗
PubMed2000

Congenital diaphragmatic hernia in a family segregating a reciprocal translocation t(5;15)(p15.3;q24).

Congenital diaphragmatic hernia (CDH) is a relatively common malformation of unknown cause with high mortality due to hypoplasia of the lungs and pulmonary hypertension. We studied a family in which two fetuses had CDH, and two pregnancies resulted in first trimester missed abortions. Both fetuses with CDH had an apparently normal karyotype. In a subsequent pregnancy, fluorescent in situ hybridization analysis of amniocytes showed a balanced translocation 46,XY, t(5;15) (p15.3;q24) also present in the mother and in a normal child, suggesting that the diaphragmatic hernia in the first two fetuses was caused by a cryptic unbalanced translocation. This hypothesis is supported by a previous observation of CDH in a distal deletion of 15q as part of a multiple congenital anomalies syndrome. It is suggested that a gene distal to 15q21 is important for the normal development of the diaphragm.

Abortion, Induced↗
PubMed2000

Screening for fragile X syndrome in women of reproductive age.

We conducted a prospective intervention study of screening for fragile X syndrome in the general population. Antenatal and preconceptional screening were carried out in 9459 women aged between 19 and 44 with no known family history of fragile X syndrome. 80% were tested antenatally. 134 carriers were detected (a frequency of 1 in 70); 130 had a premutation (PM) and 4 had a full mutation (FM). Prenatal diagnosis was carried out in 108 concurrent or subsequent pregnancies among carriers involving 111 fetuses. Nine had an FM, a rate of 1 in 12; two of the affected embryos received the FM directly from the mother and in seven it was the result of expansion from a PM. In all cases with an FM the pregnancy was terminated. In PM carriers there was evidence of a selection against the mutated chromosome with a segregation ratio of 0.40. Owing to the high rate of premutated chromosomes in our population we conclude that screening for fragile X syndrome among women of reproductive age should be more widely available.

Adult↗
PubMed2000

Prenatal diagnosis of a novel COL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy.

Prenatal diagnosis was performed in a family where the father has osteogenesis imperfecta (OI) type I, with a novel mutation in the COL1A1 gene: a C to T change at position c3076 (c.3076C-->T) leading to a change of arginine at codon 848 to a stop codon (R848X). Prenatal diagnosis by chorionic villous sampling (CVS) was performed during the fourth pregnancy, and revealed that the fetus is a carrier of the same COL1A1 mutation. The possibility of phenotypic variability was discussed with the parents. They elected to carry the pregnancy to term, and a male child with mild OI was born. This is the first reported case where OI was diagnosed prenatally, and the parents opted to carry the pregnancy to term. It illustrates the potential use of DNA-based analysis for early prenatal diagnosis of OI, and the complexities of genetic counselling.

Adult↗
PubMed2000

Sperm chromosome analysis and outcome of IVF in patients with non-mosaic Klinefelter's syndrome.

OBJECTIVE: The aim of the study was to determine the potential risk for fetal chromosomal anomalies in non-mosaic Klinefelter's syndrome patients undergoing IVF and intracytoplasmic sperm injection. DESIGN: Individually collected spermatozoa were isolated from wet testicular tissue preparations and fixed on glass slides using micromanipulation. Their nuclei were analyzed for chromosomes X, Y, and 18 by fluorescent in situ hybridization. SETTING: Assisted reproductive technology program. PATIENT(S): Consenting patients with non-mosaic Klinefelter's syndrome undergoing testicular biopsy and IVF (fresh specimens) or following such treatment (cryopreserved specimens). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rates of numerical chromosome abnormalities for chromosomes X, Y, and 18 among spare testicular sperm and the pregnancy outcome following treatment. RESULT(S): Testicular sperm were found in 8 of 20 patients. Four couples became pregnant following embryo replacement. Sperm chromosomes were analyzed in five patients. One hundred and five sperm of 112 analyzed (93.7%) were normal with X to Y ratio of 50:55 (NS) respectively. Among the 112 sperm tested, seven (6.3%) demonstrated chromosomal abnormalities, of which five were related to the sex chromosomes and two to chromosome 18. One set of triplets, one set of twins, and two singletons (four males and three females) with normal karyotypes were born. CONCLUSION(S): Most of the testicular sperm retrieved from Klinefelter's syndrome patients demonstrates a normal pattern of sex chromosome segregation. Therefore, the risk of transmitting numerical sex chromosome abnormalities is relatively low and probably comparable with the rates found in other severe male factor infertility patient groups.

Chromosome Aberrations↗
PubMed1999

Use of interphase fluorescence in situ hybridization in third trimester fetuses with anomalies and growth retardation.

In the last few years, attention has been focused on the use of interphase fluorescence in situ hybridization (FISH) for prenatal diagnosis with chromosome-specific DNA probes in the second trimester. This technique is accurate, rapid, and detects the most common aneuploidies. We present a preliminary study using FISH technique on uncultured amniotic cells derived from 30 fetuses with ultrasonographic evidence of intrauterine growth retardation (IUGR) in the third trimester. Fifteen fetuses were males and 15 were females. Seven fetuses (23.3%) had abnormal chromosomal constitution: five (18.6%) had trisomy 21, one (2.35%) had trisomy 18, and one (2.35%) showed a mosaic trisomy 18. No abnormalities were detected in the other 23 fetuses. Amniocentesis combined with FISH appears to be a safe, rapid, and accurate alternative to blood sampling in the third trimester, reducing the clinical and emotional stress of the time required to complete chromosome analysis by routine cytogenetics.

Abnormalities, Multiple↗
PubMed1999

Pulmonary agenesis, microphthalmia, and diaphragmatic defect (PMD): new syndrome or association?

We present the prenatal diagnosis of a 22-week-gestation fetus with unilateral pulmonary agenesis, diaphragmatic hernia, microphthalmia, pulmonary vessel agenesis, and intrauterine growth retardation. The "association" of pulmonary agenesis, diaphragmatic defect, and microphthalmia was described previously in two patients but the resemblance was not noted by the authors. While each case differs slightly in some of the associated anomalies, it is evident that the mainstay of diagnosis is similar to the case presented here and that this represents a new syndrome or association.

Abnormalities, Multiple↗