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Biomedical subjects

S Elias

Publications and source records attributed to S Elias.

At least 109 records · Page 6Linked to original sources
PubMed1991

Carrier screening for cystic fibrosis: implications for obstetric and gynecologic practice.

Cystic fibrosis, which is one of the most common autosomal recessive disorders, has a carrier frequency of approximately 1 in 25 among whites in the United States. In this population approximately 75% of the mutations in patients with cystic fibrosis correspond to a 3 base pair deletion that results in the loss of a phenylalanine residue at amino acid position 508 (designated delta F508) from the coding region of the cystic fibrosis gene. Currently, only about half of the couples at risk can be identified as cystic fibrosis carriers. We support conclusions of the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis Gene, which state that carrier testing should be offered to all individuals or couples with a family history of cystic fibrosis. Good science and solid educational and counseling strategies must be in place before screening for cystic fibrosis is routinely offered to those with a negative family history. Pilot programs that investigate research questions in the delivery of population screening for cystic fibrosis carriers are urgently needed.

Advisory Committees↗
PubMed1991

Segregation analysis and genetic counseling when both parents carry balanced chromosomal translocations.

OBJECTIVE: To assess the risk of chromosomally abnormal offspring and discuss counseling approach when both parents carry balanced translocations. DESIGN: Theoretical segregation analysis is performed and use of empiric data is used in genetic counseling. SETTING: Patients are referred to Division of Reproductive Genetics at the University of Tennessee, Memphis. PATIENTS, PARTICIPANTS: The mother, heterozygous for reciprocal translocation 46,XX, rcp(7;13)(p21;q22) and father, heterozygous for Robertsonian translocation 45,XY,rob(13q;14q) were referred for genetic counseling concerning risks of chromosomally abnormal offspring. INTERVENTIONS: Segregation analysis, genetic counseling, and chorionic villus sampling. MAIN OUTCOME MEASURE(S): A cumulative risk was derived to use for counseling purposes. Cytogenetics using GTG-banding was performed on cultured chorionic villus cells. RESULTS: Theoretical risk of this couple having chromosomally abnormal offspring was 40.5%. On the basis of empirical data and risk factors inherent in the specific translocations, the maternal contribution at midtrimester was 3.5%; the paternal contribution was 1% to 2%. The sum of these risks was used in counseling. CONCLUSIONS: The fetus was found to be 46,XY,rcp(7;13)(p21;q22).

Abortion, Habitual↗
PubMed1991

Fetal cells in the maternal circulation: isolation by multiparameter flow cytometry and confirmation by polymerase chain reaction.

During pregnancy, nucleated fetal erythrocytes enter the maternal circulation and can be isolated efficiently from the maternal cells by multiparameter flow cytometry. Male DNA, implying presence of a male fetus, can be identified in flow-sorted maternal blood by polymerase chain reaction with oligonucleotide primers flanking single-copy Y-specific DNA sequences. Among flow-sorted samples, we correctly identified fetal sex in 17/18 (94%) pregnancies of 10-21 weeks gestation. Maternal blood thus provides a potential opportunity for prenatal diagnosis that could preclude the need for invasive procedures in current use.

Base Sequence↗
PubMed1991

Identification of a serum protein polymorphism via two-dimensional electrophoresis. Family and population studies in two genetically isolated groups: North American Hutterites and Australian aborigines.

We report the identification and initial family and population studies of a previously undescribed serum protein polymorphism with two allelic forms. It was discovered in Hutterites, a reproductively isolated religious sect, and is also present in Australian aborigines and a sample of Chicago residents. A two-allele model is consistent with the segregation pattern observed in five kindreds within our initial study group. This polymorphism, provisionally designated SPPM-158, appears as a horizontal (charge-based) doublet in silver-stained ISO-DALT high-resolution two-dimensional electrophoresis gels. It is a low-concentration polypeptide (approximately 1 mg/dL) that has an apparent MWSDS of 43.6 kD and an isoelectric point of approximately 5.5. We infer that it circulates as a multimer or in a high-molecular-weight (greater than 200 kD) complex with other proteins because it is not observed in normal body fluids derived from physiologically ultrafiltered plasma such as amniotic fluid, urine, or cerebrospinal fluid; however, it is present in urine of patients with glomerular proteinuria. The high heterozygosity rates imply utility of this new serum protein marker for both forensic and population studies.

Australia↗
PubMed1990

Post-translational addition of an arginine moiety to acidic NH2 termini of proteins is required for their recognition by ubiquitin-protein ligase.

Recent studies have shown that selection of proteins for degradation by the ubiquitin system occurs most probably by binding to specific sites of the ubiquitin-protein ligase, E3. A free alpha-NH2 residue of the substrate is one important determinant recognized by the ligase. Selective binding sites have been described for basic and bulky-hydrophobic NH2 termini (Reiss, Y., Kaim, D., and Hershko, A. (1988) J. Biol. Chem. 263, 2693-2698) and for alanine, serine, and threonine at the NH2-terminal position (Gonda, D. K., Bachmair, A., Wünning, I., Tobias, J. W., Lane, W. S., and Varshavsky, A. (1989) J. Biol. Chem. 264, 16700-16712). Proteins with acidic NH2-terminal residues are degraded by the ubiquitin system only following conversion of the acidic residue to a basic residue by the addition of an arginine moiety (Ferber, S., and Ciechanover, A. (1987) Nature 326, 808-811). Although the enzymes involved in this post-translational modification have been characterized, the underlying mechanism has been obscure. By using a chemical cross-linking technique, we demonstrate that proteins with acidic NH2 termini do not bind to E3 without prior modification of this residue by the addition of arginine. In contrast, proteins with a basic NH2-terminal residue bind to the ligase without any modification. The recognition of acidic NH2-terminal substrates by E3 is dependent upon the addition of all the components of the modifying machinery, arginyl-tRNA-protein transferase, arginyl-tRNA synthetase, tRNA, and arginine. The ligase-bound modified proteins are converted to ubiquitin conjugates in a "pulse-chase" experiment, indicating that the binding is functional and that the enzyme-substrate complex is an obligatory intermediate in the conjugation process. Chemical modification of the carboxyl groups, which results in their neutralization, generates substrates that bind to E3 without modification. This finding suggests that the amino-terminal binding site of E3 is negatively charged, and only positively charged amino-terminal residues may bind to it. Negatively charged (acidic) NH2-terminal residues will bind only following neutralization or reversal of the charge.

Acyltransferases↗
PubMed1990

Legal and ethical implications of fetal diagnosis and gene therapy.

With rapidly expanding capabilities in prenatal diagnosis and treatment resulting from new technologies, the medical profession is increasingly being confronted with legal uncertainties and ethical dilemmas. In this paper, we review current acceptable standards of care in the area of medical practice as related to genetic counseling and prenatal diagnosis. We emphasize that any attempts at therapeutic genetic intervention be carried out only 1) when there is reasonable scientific evidence that it will cure or prevent a disabling disease, and b) with the informed, voluntary, competent, and understanding consent of the individuals involved.

Ethics, Medical↗
PubMed1990

Applicability of 19-DEJ-1 monoclonal antibody for the prenatal diagnosis or exclusion of junctional epidermolysis bullosa.

Recently a monoclonal antibody (19-DEJ-1) was produced with binding specificity for the mid-lamina lucida of the skin dermo-epidermal junction, in very close association with overlying hemidesmosomes. Since skin cleavage occurs within the lamina lucida in the inherited blistering disorder, junctional epidermolysis bullosa (EB), and is associated with aberrations in the morphology and/or number of hemidesmosomes in such tissue, we have sought to determine whether this monoclonal antibody could be used for prenatal diagnosis. Fetoscopy-directed skin biopsies were obtained from two fetuses at risk for junctional EB and post-mortem samples from two other fetuses with the Herlitz type of junctional EB, the latter after prenatal diagnosis by electron microscopy and termination of each pregnancy. Specimens were examined in part by light and electron microscopy for evidence of skin cleavage or other alterations in morphology, and in part by indirect immunofluorescence for altered basement membrane antigenicity. Three of four fetuses were shown to have intra-lamina lucida blister formation indicative of, and hemidesmosome hypoplasia proving, junctional EB. Each was also shown to lack expression of GB3 and 19-DEJ-1 antigens, consistent with findings noted postnatally in junctional EB; diagnosis was confirmed in each at the time of therapeutic abortion. A fourth fetus had no abnormalities detected; lack of disease involvement was confirmed at the time of delivery, and subsequently over 8 months of careful serial evaluation. We conclude that 19-DEJ-1 monoclonal antibody is an accurate and sensitive immunohistochemical probe for junctional EB, and may be employed in the prenatal diagnostic evaluation of fetuses at risk for this disorder.

Antibodies, Monoclonal↗
PubMed1990

Failure to document fetal cells in maternal circulation using the Selypes-Lorencz "air-culture" cytogenetic technique.

Isolating and analyzing fetal cells circulating in the maternal circulation would allow a relatively noninvasive method (i.e., venipuncture) for prenatal cytogenetic diagnosis. Several groups have claimed evidence for the presence of fetal cells in maternal circulation, and in one communication, Selypes and Lorencz (1988) reported the presence of relatively large numbers of fetal mitotic cells in phytohemagglutinin-stimulated blood cultures derived from pregnant women. We employed the laboratory method of Selypes and Lorencz in evaluating maternal blood from 29 patients (9.7 to 19.5 weeks gestation) in which the fetal complement differed from that of the mother (e.g., 46,XY, aneuploidy). Unfortunately, we were unable to confirm the results of Selypes and Lorencz.

Cell Separation↗
PubMed1990

Fetomaternal transfusion depends on amount of chorionic villi aspirated but not on method of chorionic villus sampling.

Transcervical and transabdominal chorionic villus sampling are believed, on the basis of indirect evidence, to result in fetomaternal transfusion. We sought to measure this phenomenon by devising a simple method that would allow us to identify variables that influence fetomaternal transfusion. We investigated patients undergoing transcervical-chorionic villus sampling (n = 15) and transabdominal-chorionic villus sampling (n = 15), restricting the sample to subjects who required only a single catheter passage or needle insertion to obtain villi. Maternal serum alpha-fetoprotein was measured before and after the procedure along with alpha-fetoprotein concentration of the transport medium into which the villi had been aspirated. We first confirmed that the change in maternal serum alpha-fetoprotein levels after chorionic villus sampling, an indirect measure of fetomaternal transfusion, was indeed correlated with the alpha-fetoprotein concentration of transport medium into which the villi were aspirated (p = 0.0350). Fetomaternal transfusion next proved to be correlated with the amount of villi obtained (p = 0.0279). However, when adjusted for the amount of villi obtained, no significant difference was observed between transcervical and transabdominal-chorionic villus sampling with respect to the change in maternal serum alpha-fetoprotein levels after chorionic villus sampling (p = 0.8512). These data suggest that the magnitude of fetomaternal transfusion depends on the amount of villi obtained but not on the chorionic villus sampling method used.

Adult↗
PubMed1990

Direct analysis of uncultured cytotrophoblastic cells from second- and third-trimester placentas: an accurate and rapid method for detection of fetal chromosome abnormalities.

Transabdominal chorionic villus sampling can be readily used for detection of fetal chromosome abnormalities in the second and third trimesters of pregnancy. Although culture of chorionic villi offers little advantage over cultured amniotic fluid cells with respect to time required to obtain results, cytogenetic analysis of chorionic villi by direct analysis of uncultured cytotrophoblastic cells offers clear advantages because of the very short time required to obtain results. To determine whether direct analysis of uncultured cytotrophoblastic cells from second- and third-trimester placentas can routinely provide rapid and accurate assessment of fetal status, we evaluated chorionic villus specimens obtained from 57 placentas; 49 placentas were sampled in the second trimester whereas eight were sampled in the third trimester. Direct preparations yielded karyotypes in 56 (98.2%) preparations; all results of direct analyses were available within 72 hours and, when requested, within 12 hours. All results were confirmed by chromosome analysis of cultured mesenchymal core cells or cultured fetal tissue. We conclude that direct analysis of cytotrophoblastic cells from second- and third-trimester placentas is a very rapid and accurate method for determining fetal chromosome status that is comparable with, if not superior to, percutaneous umbilical blood sampling.

Adult↗
PubMed1990

Diagnosis of trisomy 18 using spontaneously dividing cells from fetal umbilical cord blood: a novel approach for rapid late second and third trimester prenatal diagnosis.

Cytogenetic methodology recently developed by us allows spontaneously dividing cells in fetal cord blood to be used for rapid (24 hours) chromosome analysis. We utilized this methodology to diagnose trisomy 18 and facilitate clinical management in a 32-week pregnancy characterized by multiple fetal anomalies and intrauterine growth retardation.

Abnormalities, Multiple↗
PubMed1990

Anaphase lag as the most likely mechanism for monosomy X in direct cytotrophoblasts but not in mesenchymal core cells from the same villi.

A 36 year old white female was referred for chorionic villus sampling for advanced maternal age. Direct (cytotrophoblast) preparations of chorionic villi were 45,X, but cultured mesenchymal core cells from the same villi were 46,XX. Study of embryonic and extraembryonic tissues showed the aneuploidy to be limited to cytotrophoblasts from specific placental sites. In aggregate, the cytogenetic findings can best be explained by anaphase lag during development of the cytotrophoblast, suggesting that this cytological mechanism and not non-disjunction is responsible for the common occurrence of monosomy X in villi.

Adult↗
PubMed1990

First trimester prenatal treatment and molecular genetic diagnosis of congenital adrenal hyperplasia (21-hydroxylase deficiency).

Prenatal treatment of pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was carried out in conjunction with chorionic villus sampling (CVS) in the first trimester for analysis of restriction fragment length polymorphisms. Fourteen families of a total of 49 families at risk for this disease elected to undergo both prenatal treatment and diagnosis via CVS. Dexamethasone administration to the pregnant woman was initiated at a mean gestational age of 7 weeks (range, 4-10 weeks) before testing to determine whether the fetus was affected with 21-hydroxylase deficiency, and CVS was performed at a gestational age of 8-10 weeks. Two affected female fetuses were identified by molecular genetic techniques among this group; neonatal physical examination demonstrated amelioration of the degree of genital ambiguity compared with both nonprenatally treated older sisters with 21-hydroxylase deficiency. The duration of unnecessary prenatal dexamethasone treatment for unaffected or male fetuses was substantially reduced in the CVS group compared with that in a cohort of 8 prenatally treated pregnancies in which amniocentesis was performed in the early second trimester. There were no major morbidities observed in the treated pregnancies. Postnatal confirmation of CVS diagnosis was obtained in all cases in which DNA from an affected sibling was available for comparative analysis with the DNA from chorionic villus tissue. We conclude based on these data that the benefit/risk ratio is favorable for prenatal administration of dexamethasone in pregnancies at risk for 21-hydroxylase deficiency. Treatment should be initiated during the first trimester in conjunction with diagnosis by CVS/molecular genetic techniques. Long term postnatal surveillance is recommended for all offspring of dexamethasone-treated pregnancies.

Adrenal Hyperplasia, Congenital↗
PubMed1990

Degradation of proteins by the ubiquitin-mediated proteolytic pathway.

Degradation of a protein by the ubiquitin system involves two distinct processes. In the first step, ubiquitin is covalently linked in an ATP-dependent mode to the protein substrate. The protein moiety of the conjugate is then degraded by a specific protease into free amino acids, resulting in the release of free and reutilizable ubiquitin. This process also requires energy. In this review we will briefly summarize our current knowledge of the role of the ubiquitin system in protein turnover and discuss in detail the mechanism involved in selection of substrates for conjugation and in degradation of ubiquitin-conjugated proteins.

Adenosine Triphosphate↗
PubMed1990

Dilation and evacuation for second-trimester genetic pregnancy termination.

Dilation and evacuation (D&E) is the most common procedure for second-trimester pregnancy termination currently used by United States obstetrician-gynecologists. Although this method carries morbidity and mortality rates significantly lower than methods requiring labor induction, the procedure most commonly used for second-trimester genetic terminations seems to be labor induction (eg, vaginal prostaglandin suppositories). Many geneticists appear reluctant to recommend D&E over induction methods of pregnancy termination because they perceive that fetal abnormalities cannot be consistently confirmed by evaluation of the products of conception obtained by D&E. We report here 60 consecutive patients who underwent D&E (14-22 weeks' gestation) after detection of fetal abnormalities. The prenatal diagnoses were confirmed in all cases. Our experience thus indicates that D&E is reliable in confirming most prenatal diagnoses and should be the procedure of choice when second-trimester pregnancy termination is chosen because of fetal abnormalities.

Abortion, Eugenic↗