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M J Mahoney

Publications and source records attributed to M J Mahoney.

At least 37 records · Page 2Linked to original sources
PubMed1999

Urinary screening tests for fetal Down syndrome: II. Hyperglycosylated hCG.

Hyperglycosylated hCG is a form of hCG with more complex oligosaccharide side chains. A specific immunoassay was developed to measure hyperglycosylated hCG. Levels were measured in urine samples from 1157 women between 11 to 22 weeks of gestation, undergoing genetic analysis because of advanced maternal age. Values were normalized to urine creatinine concentration and plotted against gestational age, median values were determined and multiples of the control median (MoM) calculated. The median MoM and log standard deviation (log SD) of the 1134 control samples was 1.0 and 0.47, and of the 23 Down syndrome cases was 7.8 and 0.48, respectively. This indicated a 7.8-fold increase in hyperglycosylated hCG levels in Down syndrome cases. In the accompanying article, a stability problem was found with beta-core fragment measurements in frozen urine samples. In anticipation of similar problems, nine urine samples were tested for hyperglycosylated hCG fresh and after storage in the freezer. No clear difference was found in hyperglycosylated hCG values. In addition, no trend was found in hyperglycosylated hCG MoM values or in Down syndrome detection rates in urine samples stored for one, two or three years in the freezer. Samples were split into five equal groups according to creatinine concentration. A trend was observed, hyperglycosylated hCG MoM values decreasing with advancing creatinine concentration (1.77, 1.08, 1.01, 0.73 and 0.60 at 0.25, 0.50, 0.79, 1.11 and 1.73 mg/ml, respectively). An error was noted. This was corrected with a regression equation. After correction, the median MoM and log SD of the control samples was 1.0 and 0.44, and of Down syndrome samples was 7.3 and 0.42, respectively. Correction of this error, while reducing the elevation of Down syndrome cases, tightened the spread of samples. Samples were ranked and centiles determined. 18 of 23 Down syndrome cases (78 per cent) exceeded the 95th centile of the control population. ROC analysis indicated 79 per cent detection at 5 per cent false-positive rate. Urine samples were collected during two periods of gestation, an early period (11th to 14th completed week) and the period when chemical screening is normally performed (15th to 21st week). ROC analysis indicated 80 per cent and 78 per cent detection rates, respectively, at 5 per cent false-positive rate, in the two gestational periods. Hyperglycosylated hCG values were modelled with beta-core fragment values, total oestriol values and maternal age. ROC analysis indicated 97 per cent detection rate at 5 per cent false-positive rate. This detection rate and this level of Down syndrome and control patient discrimination surpasses that of any other serum, urine or ultrasound screening protocol. Hyperglycosylated hCG should be considered as a new screening test for aneuploid pregnancies, with the potential of detecting almost all cases of Down syndrome. Evaluation is needed by other centres in order to bring hyperglycosylated hCG into clinical practice.

Chorionic Gonadotropin↗
PubMed1999

Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen) immunoassay: A new basis for gestational Down syndrome screening.

BACKGROUND: Serum human chorionic gonadotropin (hCG) and hCG free beta-subunit tests are used in combination with unconjugated estriol and alpha-fetoprotein in the triple screen test, and with the addition of inhibin-A in the quadruple marker test for detecting Down syndrome in the second trimester of pregnancy. These tests have a limited detection rate for Down syndrome: approximately 40% for hCG or free beta-subunit alone, approximately 60% for the triple screen test, and approximately 70% for the quadruple marker test, all at 5%, or a relatively high, false-positive rate. New tests are needed with higher detection and lower false rates. Hyperglycosylated hCG (also known as invasive trophoblast antigen or ITA) is a new test. It specifically detects a unique oligosaccharide variant of hCG associated with Down syndrome pregnancies. We evaluated this new Down syndrome-directed test in prenatal diagnosis. METHODS: Hyperglycosylated hCG was measured in urine samples from women undergoing amniocentesis for advanced maternal age concerns at 14-22 weeks of gestation, 1448 with normal karyotype and 39 with Down syndrome fetuses. RESULTS: The median hyperglycosylated hCG value was 9.5-fold higher in Down syndrome cases (9.5 multiples of the normal karyotype median). The single test detected 80% of Down syndrome cases at a 5% false-positive rate. Urine hyperglycosylated hCG was combined with urine beta-core fragment (urine breakdown product of serum hCG free beta-subunit), serum alpha-fetoprotein, and maternal age-related risk. This urine-serum combination detected 96% of Down syndrome cases at a 5% false-positive rate, 94% of cases at a 3% false-positive rate, and 71% of cases at a 1% false-positive rate. These detection rates exceed those of any previously reported combination of biochemical markers. CONCLUSIONS: Hyperglycosylated hCG is a new base marker for Down syndrome screening in the second trimester of pregnancy. The measurement of hyperglycosylated hCG can fundamentally improve the performance of Down syndrome screening protocols.

Adult↗
PubMed1998

Renal tubular dysgenesis, absent nipples, and multiple malformations in three brothers: a new, lethal syndrome.

We report on three brothers with renal tubular dysgenesis and absent nipples, each also had other malformations including pre-auricular pits and a preauricular tag, branchial clefts, choanal atresia, pulmonary lobation anomaly, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, absent thymus, parathyroid gland, accessory spleen, imperforate anus, clinodactyly, and broad digits and small nails. All three infants died neonatally. This pattern of clinical malformations appears to be a previously unreported syndrome.

Abnormalities, Multiple↗
PubMed1998

An alternative for women initially declining genetic amniocentesis: individual Down syndrome odds on the basis of maternal age and multiple ultrasonographic markers.

OBJECTIVE: Our purpose was to develop a method of calculating the individual odds of Down syndrome on the basis of a combination of maternal age and multiple ultrasonographic parameters that can be used to counsel women at high risk who initially decline amniocentesis. STUDY DESIGN: Maternal age and ultrasonographic biometry data were collected prospectively on 3254 normal and 30 Down syndrome singleton fetuses between 15 and 24 weeks' gestation. Humerus length data were expressed as multiples of the normal median. Log transformation of the humerus length data permitted their expression in gaussian frequency distributions and the calculation of likelihood ratios for Down syndrome on the basis of humerus length. We also developed likelihood ratios on the basis of the degree of nuchal skinfold thickening and the presence or absence of hyperechoic fetal bowel and hypoplastic fifth digit. RESULTS: The ultrasonographic parameters and maternal age did not significantly correlate with each other and were significant independent predictors of Down syndrome. We therefore calculated the individual odds of Down syndrome by using the product of the age-related risk and the likelihood ratios associated with nuchal thickening, humerus length shortening, and the presence or absence of hyperechoic fetal bowel or fifth digit hypoplasia, respectively. At a Down syndrome risk level of >1:50, a 60.0% detection rate with 4.5% false-positive rate was observed with a screen-positive rate of 5.5%, positive predictive value of 1:10, and odds ratio (95% confidence interval) of 28.4 (12.8 to 64.0). CONCLUSION: This is the first report of individual odds calculation based on multiple midtrimester biometry parameters and maternal age. The screening efficiency is similar to that reported with triple-analyte serum screening. These data are useful for counseling women who are at increased Down syndrome risk and initially decline amniocentesis.

Adult↗
PubMed1998

Subtle ultrasonographic anomalies: do they improve the Down syndrome detection rate?

OBJECTIVE: Our purpose was to determine whether the identification of subtle anomalies further improves Down syndrome detection over standard ultrasonographic biometry and the detection of gross morphologic defects. STUDY DESIGN: The screening efficiency of clinodactyly, dilated renal pelvis (> or =4 mm), echogenic bowel, mild ventriculomegaly (> or =10 to 15 mm), and two-vessel cord was determined prospectively in midtrimester fetuses at amniocentesis. The screening efficiency of increased nuchal thickness and shortened long-bone length (standard biometry) and gross morphologic defects was determined for comparison. Multiple backward stepwise regression analysis was used to determine which subtle anomalies significantly correlated with Down syndrome detection rate and whether they increased Down syndrome detection over that with standard biometry and morphologic defects. RESULTS: Although all subtle anomalies except two-vessel cord correlated with the presence of Down syndrome on univariate analysis, only echogenic bowel (Wald chi2 = 15.0211, p = 0.0001) and clinodactyly (Wald chi2 = 9.4273, p = 0.002) persisted in regression analysis of the subtle anomaly group. When either of the above-described anomalies was present, the detection rate for Down syndrome was 28.6%, p < 0.00001. For the combination of standard biometry (either increased nuchal thickness or short humerus) or gross anatomic defect, Down syndrome detection rate was 53.3% (p < 0.00000001). This increased to 63.2% (p < 0.00000001) when subtle anatomic defects (either echogenic bowel or clinodactyly) were included in the definition of an abnormal sonogram. CONCLUSION: Subtle anomalies, of which echogenic bowel and clinodactyly are the most significant, further increase Down syndrome screening efficiency over standard biometry or the finding of gross anatomic defect. Our data appear to support the addition of subtle anomaly findings to ultrasonographic screening for Down syndrome.

Abnormalities, Multiple↗
PubMed1998

A new screening protocol combining urine beta-core fragment and ultrasonography for Down syndrome detection.

OBJECTIVE: Our purpose was to ascertain the screening efficiency of a new midtrimester Down syndrome detection protocol that combines maternal urine testing and ultrasonographic examination. STUDY DESIGN: In a prospective study, beta-core fragment, the stable end product of human chorionic gonadotropin metabolism, was measured in maternal urine. The results were standardized for urine creatinine levels. The study was performed in women undergoing midtrimester genetic amniocentesis (15 to 24 weeks' gestation). Urine beta-core fragment values were expressed as multiples of the normal median for gestational age. The screening performance of a combination of ultrasonographic parameters and urine beta-core values for Down syndrome detection was determined. RESULTS: A total of 511 singleton pregnancies in women undergoing amniocentesis were studied, 18 of the women (3.5%) had a Down syndrome fetus. A urine beta-core fragment level > or = 97th percentile had a sensitivity of 61.1% and a false-positive rate of 3.2%. An abnormal prenatal screen was defined as a urine beta-core level > or = 97th percentile, increased nuchal thickness (> or = 5 mm), or the presence of gross structural defects. Corresponding values for the screening efficiency of an abnormal prenatal screen were sensitivity of 77.8% and a false-positive rate of 4.1%. With an abnormal prenatal screen the odds ratio is 82.8 (95% confidence interval 22.6 to 364.9) for having a Down syndrome fetus. CONCLUSION: The presence of an abnormal maternal urine beta-core level, a gross ultrasonographic anomaly, or increased nuchal thickness had a high detection rate and a low false-positive rate for Down syndrome. This novel screening algorithm is useful for further delineating the risk status in patients at high risk who are reluctant to undergo or decline genetic amniocentesis.

Adult↗
PubMed1998

Prenatal confirmation of true fetal trisomy 22 mosaicism by fetal skin biopsy following normal fetal blood sampling.

Trisomy 22 mosaicism diagnosed at 20 weeks' gestation by amniocentesis in a 35-year-old woman was not confirmed by fetal blood sampling. Subsequent fetal skin biopsy revealed trisomy 22 in 7 of the 15 fibroblasts analysed. We conclude that, depending on the chromosome involved, fetal skin biopsy should be considered in the diagnostic work-up when mosaicism is found in amniotic fluid.

Abortion, Induced↗
PubMed1998

Hyperglycosylated hCG, a potential alternative to hCG in Down syndrome screening.

Hyperglycosylated hCG (H-hCG) is a minor variant of hCG with abnormal oligosaccharide side chains. It is the principal gonadotropin detected in the serum and urine of patients with gestational choriocarcinoma. A monoclonal antibody was produced against this antigen and an immunoassay developed. Levels of hCG and H-hCG were determined in 142 urine samples from normal pregnancies from 10 to 21 weeks of gestation. Levels were normalized to urine creatinine concentration, and were each plotted against gestational age. Bi-weekly median values were calculated, the best-fitting regression lines were determined, and multiples of the normal median (MoM) were computed. 10 Down syndrome pregnancy samples were tested from 11 to 21 weeks of gestation. The median hCG and H-hCG levels in the Down syndrome cases were 1.9 MoM and 5.7 MoM of unaffected cases, respectively. Four of 10 hCG measurements and 9 of 10 H-hCG determinations exceeded the 95th centile of unaffected cases. H-hCG identified 90 per cent of Down syndrome cases with a 5 per cent false-positive rate. This is more than twice the number of cases detected by an hCG assay. H-hCG may be an effective replacement for hCG in antenatal Down syndrome screening. This is a preliminary report consisting of only 152 samples. Further studies are needed now to verify the Down syndrome screening utility of this potentially valuable new marker.

Antibodies, Monoclonal↗
PubMed1997

Screening for Down syndrome using urine hCG free beta-subunit in the second trimester of pregnancy.

Human chorionic gonadotropin (hCG) free beta-subunit levels were determined in 709 control and 13 Down syndrome urine samples from the second trimester of pregnancy. Results were normalized to urine creatinine concentration and converted to multiples of the unaffected pregnancy medium (MOM). The concentration of free beta-subunit in Down syndrome cases was 3.9 MOM. Seven of 13 Down syndrome pregnancies (54 per cent) had free beta-subunit levels at or above the 95th centile of unaffected pregnancies. Urine free beta-subunit may potentially be useful as a screening test for Down syndrome.

Adult↗
PubMed1997

First-trimester growth restriction and fetal aneuploidy: the effect of type of aneuploidy and gestational age.

OBJECTIVE: Our purpose was to determine the effect of type of aneuploidy and gestational age on first-trimester fetal growth. STUDY DESIGN: Crown-rump length measurement was obtained in pregnancies undergoing chorionic villus sampling in three large prenatal diagnosis centers. One hundred forty-four aneuploid fetuses, from 9 to 13 weeks' gestation, were compared with 440 matched control fetuses for evidence of crown-rump length shortening. Shortening was defined by the observed/expected crown-rump length. Expected values of crown-rump length based on last menstrual period were obtained from regression equations generated from a separate normal group. Threshold values for aneuploidy screening were determined on the basis of receiver-operator characteristic curves. RESULTS: There was significant crown-rump length shortening in trisomy 18 compared with normal fetuses, with observed/expected values < or = 0.80 (odds ratio 13.78, 95% confidence interval 5.64 to 33.88, p < 0.000001); for trisomy 13 the observed/expected crown-rump length was < or = 0.90 (odds ratio 3.64, 95% confidence interval 1.08 to 12.96, p < 0.03). There was no significant shortening of crown-rump length in Down syndrome, with observed/expected values < or = 0.92 (odds ratio 0.86, 95% confidence interval 0.50 to 1.47, p = 0.6). With shortened crown-rump length (observed/expected value < 0.86) the risk of any aneuploidy is increased (odds ratio 2.52, 95% confidence interval 1.6 to 3.96, p < 0.0001). When the first-trimester crown-rump length was shortened by > or = 14 mm, the aneuploidy risk was high (odds ratio 9.04, 95% confidence interval 3.26 to 28.67, p < 0.00001). CONCLUSION: In the first trimester fetuses with trisomy 18 and 13 appear to be growth restricted, in contrast to fetuses with trisomy 21. In at-risk pregnancies crown-length that is shorter than expected significantly increase the odds that aneuploidy is present.

Aneuploidy↗
PubMed1996

Prenatal detection of two different monosomic cell lines by chorionic villus sampling.

We present a prenatal case of mosaicism with at least two monosomy cell lines: one with monosomy 21 (45,XY,-21) and one missing the Y (45,X) and a possible third 46,XY in chorionic villus cell culture. Cytogenetic studies were initiated following the ultrasound detection at 11 weeks of a large cystic hygroma and in utero growth retardation. Spontaneous fetal demise occurred at 12 weeks and the pregnancy was terminated. To our knowledge, this is the first report of two different monosomic cell lines found in chorionic villus cells.

Adult↗
PubMed1996

Ultrasonographically adjusted midtrimester risk of trisomy 21 and significant chromosomal defects in advanced maternal age.

OBJECTIVE: Our purpose was to determine whether normal midtrimester ultrasonography results reduces the risk of fetal Down syndrome and any clinically significant chromosomal defects in pregnancies with advanced maternal age and to develop risk tables on the basis of age and ultrasonographic results. STUDY DESIGN: Biometry data were obtained in 4079 women between 15 and 24 weeks undergoing amniocentesis for maternal age. Expected values of humerus, femur, both combined, and abdominal circumference based on biparietal diameter were generated from a normal group. Observed/expected values of each parameter and nuchal thickness > or = 6 mm was used to screen for Down syndrome and any clinically significant chromosome defects. Receiver-operator characteristic curves were used to determine threshold screening values for each parameter. By use of stepwise logistic regression the optimal measurements for detection of chromosome anomalies were established. An abnormal ultrasonography result was defined as either abnormal biometry choroid plexus cysts or a structural defect. RESULTS: The finding of shortened humerus (observed/expected < 0.90), abnormal nuchal thickness, or an anatomic defect had the highest sensitivity for Down syndrome detection, 70.6%, p < 0.0001, whereas a short humerus, small abdominal circumference, (observed/expected < 0.92), or an anatomic defect had a sensitivity of 46.7%, p < 0.0001, for any significant chromosome defect. With a normal ultrasonography the risk of Down syndrome in a 39-year-old woman falls from 1:100 to < 1:292. CONCLUSION: A normal ultrasonography substantially reduces the risk of Down syndrome and any chromosome abnormality. This information is useful in counseling women who decline amniocentesis on the basis of maternal age.

Biometry↗
PubMed1996

Risk of Down syndrome and any clinically significant chromosome defect in pregnancies with abnormal triple-screen and normal targeted ultrasonographic results.

OBJECTIVE: Our purpose was to study prospectively the use of ultrasonographic biometry to refine the risk estimates for both Down syndrome and any clinically significant chromosome defect in women with abnormal biochemical triple-screen results. STUDY DESIGN: Ultrasonographic biometry and anatomic survey were performed on study and control cases. Expected values for humerus, femur, combined humerus plus femur lengths, and abdominal circumference were generated on the basis of biparietal diameter obtained from a normal group. Threshold observed/expected values of each measurement for screening for Down syndrome and clinically significant chromosome defects were determined with receiver-operator characteristic curves. By stepwise logistic regression analysis the optimal screening parameters, including nuchal thickness, for detection of Down syndrome and clinically significant chromosome defect were determined. Risk tables for chromosome anomalies were developed on the basis of ultrasonography and triple-screen values. RESULTS: Of 1034 cases at risk for Down syndrome (risk > or = 1/270) or trisomy 18 on the basis of triple-screen results, there were 11 cases of Down syndrome, 1 of trisomy 18, and 17 clinically significant chromosome defects. Abnormal nuchal thickness or observed/expected humerus length < 0.92 was the most sensitive parameter for Down syndrome detection. Abnormal nuchal thickness or observed/expected combined femur and humerus length < 0.90 was the most sensitive for significant chromosome defects. With abnormal biometry or anatomy the Down syndrome risk was 8 of 127 versus 1 of 753 in normals, odds ratio 50.4 (95% confidence interval 6.4 to 90.2), p < 0.00001, and the risk of significant defects was 11 of 90 versus 6 of 830 in normals, odds ratio 19.3 (95% confidence interval 6.4 to 60.5), p < 0.00001. In a pregnancy with a 1 in 270 triple-screen risk for Down syndrome, normal biometric and anatomic results reduce the risk to 1 in 2100. CONCLUSION: Normal ultrasonographic anatomy and biometry significantly reduces the risk of both Down syndrome and any significant chromosome defects in pregnancies with abnormal triple-screen results.

Biochemistry↗
PubMed1996

Controlled release of proteins to tissue transplants for the treatment of neurodegenerative disorders.

Alzheimer's disease involves substantial cholinergic cell deficits; other neurodegenerative diseases involve similar losses of certain cell populations. Optimal therapies may involve tissue replacement coupled with the controlled delivery of appropriate growth factors, such as nerve growth factor, to the graft site. In this review article we describe the kinetics of protein release from three modes of controlled protein delivery to transplants: delivery from a polymer matrix, delivery form polymeric microspheres, and delivery from genetically engineered cells. The efficacy and feasibility of each of these delivery strategies for potential treatment of patients diagnosed with neurodegenerative disorders is discussed.

Alzheimer Disease↗
PubMed1995

Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results.

OBJECTIVE: Our purpose was to determine whether nuchal thickness measurement can identify the euploid fetuses in midtrimester pregnancies at increased risk for Down syndrome on the basis of maternal age and serum screening. STUDY DESIGN: Nuchal thickness was obtained prospectively in 651 consecutive fetuses at 14 to 21 weeks' gestation and at > or = 1:270 risk for Down syndrome on the basis of unconjugated estriol, alpha-fetoprotein, and human chorionic gonadotropin levels. The risk of Down syndrome with a normal nuchal thickness was determined. A receiver-operator characteristic curve was used to determine a serum-based risk threshold below which the risk for Down syndrome was low. The prevalence of Down syndrome in fetuses with both a normal nuchal thickness and a below-serum-risk threshold was compared with prevalence in either those above threshold risk or with an abnormal nuchal thickness. RESULTS: There were eight cases of trisomy 21 and one case each of 46,XX/47,XXX, 46,XY/47,XY, +7, and 46,XX, 11q-. The sensitivity of an abnormal nuchal thickness (> or = 6 mm) for detecting Down syndrome was four in eight (50%) (95%) confidence interval 15.3% to 84.6%). The risk of Down syndrome was significantly increased with an abnormal compared with a normal nuchal thickness, four in 13 (30.8%) versus four in 638 (0.6%), p < 0.0001. A risk threshold was defined at > or = 1:100 on the basis of the receiver-operator characteristic plot. Of 390 cases with a normal nuchal thickness and a serum risk estimate < 1:100, there were no cases of Down syndrome (0/390 vs 8/253, p = 0.002). CONCLUSION: Normal nuchal thickness significantly reduces the risk of Down syndrome and may help reduce the number of amniocenteses done for abnormal triple screen results.

Adult↗
PubMed1995

Cognition and causation in human experience.

Arguments that thoughts cannot have the power to cause or influence behavior are briefly addressed. Despite being couched in traditional behavioristic terminology, some of these arguments actually invoke the very dualism that they criticize. Likewise problematic are portrayals of scientific activity as being necessarily grounded in an ontology of physical extension and an epistemology that grants the visual system (and hence observability) sole and supreme authority. Contemporary cognitivists challenge classical mind-body dualism and refer to thoughts and other "mental" phenomena as activities of the living system. Three conclusions are drawn: (1) humans think, (2) human thinking influences human behavior, and vice-versa, and (3) dialogues on this topic would be well served by a refinement of the questions under consideration.

Arousal↗
PubMed1995

First-trimester endocervical irrigation: feasibility of obtaining trophoblast cells for prenatal diagnosis.

We sought to determine the feasibility of obtaining trophoblast cells for first-trimester prenatal diagnosis using endocervical irrigation. We studied 20 pregnant patients between 7-10.5 weeks' gestation who presented for elective pregnancy termination. Under ultrasound guidance, a specially designed plastic catheter was advanced to the level of the internal cervical os. Gentle flushing and aspiration was performed with 3 mL of normal saline. The material obtained was fixed and stained. A placental pathologist identified trophoblast cells using light microscopy. In another five cases, we attempted to culture the endocervical washings. Trophoblast cells were identified by microscopy after staining the cultured material with an anti-alpha-hCG-antibody bound stain. In ten of 20 cases (50%), trophoblast material was retrieved on irrigation. Of the five additional cases on which culture was attempted, trophoblast was successfully cultured in one, the results were equivocal in two, and culture was unsuccessful in the other two. Trophoblast cells for prenatal diagnosis can be obtained in a significant percentage of cases by first-trimester endocervical irrigation. The advantages of irrigation include technical simplicity, brief duration (less than 3 minutes), and suitability to first-trimester diagnosis. Further testing is necessary to determine the risks.

Cells, Cultured↗