The life of Johann Benedict Listing.
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Germany↗
Biomedical subjects
E F Robertson
Publications and source records attributed to E F Robertson.
Redefined duplex ultrasonographic criteria for diagnosis of carotid artery stenosis.
OBJECTIVE: To evaluate duplex ultrasonographic criteria for the determination of 50% or more and 70% or more stenosis of the diameter of the internal carotid artery based on conventional angiography in order to align ultrasonographic diagnostic categories with current clinical management schemes. PATIENTS AND METHODS: Between January 1, 1995, and June 30, 1999, 915 patients underwent both carotid duplex ultrasonography and cerebral angiography within 30 days at Mayo Clinic, Rochester, Minn. Of these patients, 294 were excluded from this study because of occlusion of one or both of the internal carotid arteries or atypical flow characteristics. In the remaining 621 patients (61 % male, 39% female; mean age, 67.7 years [range, 14-88 years]), 1218 vessels were available for correlation. Several Doppler ultrasonographic velocity variables were compared with the angiographic findings by use of receiver operating characteristic curve analysis. The primary end point was verification of optimal ultrasonographic criteria to diagnose 70% or more internal carotid artery stenosis. The secondary end point was establishment of threshold values to detect stenosis of 50% or more. RESULTS: At angiography, 382 patients had internal carotid arteries with 70% or more stenosis. Peak systolic and end diastolic velocities of the internal carotid artery and internal carotid artery:common carotid artery peak systolic velocity ratios were measured. For an internal carotid artery stenosis of 70% or more, a peak systolic velocity of 230 cm/s or more resulted in a sensitivity of 86.4%, a specificity of 90.1%, a positive predictive value of 82.7%, a negative predictive value of 92.3%, and an accuracy of 88.8%. An end diastolic velocity of 70 cm/s or more and an internal carotid artery:common carotid artery ratio of 3.2 or more yielded similar values. For an internal carotid artery stenosis of 50% or more, a peak systolic velocity of 130 cm/s or more resulted in a sensitivity of 92.1 %, a specificity of 89.5%, a positive predictive value of 90.3%, a negative predictive value of 91.3%, and an overall accuracy of 90.8%. An internal carotid artery:common carotid artery ratio of 1.6 or more yielded similar values. CONCLUSION: In our ultrasonography laboratory, a carotid artery stenosis of 70% or more (for which carotid endarterectomy is typically recommended in symptomatic patients) is diagnosed reliably with the following duplex ultrasonographic criteria: a peak systolic velocity of 230 cm/s or more, an end diastolic velocity of 70 cm/s or more, or an internal carotid artery:common carotid artery ratio of 3.2 or more.
Adolescent↗
Exposure to environmental lead and visual-motor integration at age 7 years: the Port Pirie Cohort Study.
Early childhood exposure to environmental lead may result in subtle deficits in neuropsychological development. Most studies, however, have reported global measures of development, and the findings have not been consistent. In this report, we examine the association between blood lead concentration and a specific aspect of neuropsychological development, visual-motor integration. Each child in a cohort of 494 children living in and around the lead smelting town of Port Pirie, South Australia, was followed for its first 7 years of life. Serial blood samples were collected at various ages to estimate the lifetime burden of each individual. At the time of each blood sampling, systematic information was obtained on a wide range of other variables relevant to child development. We evaluated visual-motor integration at age 7 with the Beery Developmental Test of Visual-Motor Integration (mean score: 13.4). There was an inverse relation between blood lead concentration and visual-motor performance. After adjustment for potential confounding factors, both prenatal and postnatal blood lead concentrations exhibited a dose-related inverse association with children's visual-motor performance. For an increase in life-time average blood lead concentration from 10 micrograms per dl (0.48 mumol per liter) to 30 micrograms per dl (1.45 mumol per liter), the estimated deficit in children's visual-motor performance was 1.6 points (95% confidence interval = 0.3-2.9). The results indicate that visual-motor integration may be a more sensitive index than global measures of development, such as intelligence quotient, for the assessment of lead effects on child development.
Child↗
The sensitivity of ultrasound and serum alpha-fetoprotein in population-based antenatal screening for neural tube defects. South Australia 1986-1991.
OBJECTIVE: To determine the sensitivity of antenatal screening methods for neural tube defects in population-based screening in South Australia in 1986-1991, and whether ultrasound can replace serum alpha-fetoprotein screening in terms of achieving an equivalent level of sensitivity. DESIGN AND SETTING: Ascertainment of all births and terminations of pregnancy with neural tube defects from multiple sources for 1986-1991 in South Australia. Serum and amniotic fluid alpha-fetoprotein results were obtained from the only laboratory performing the tests as a Statewide antenatal screening programme, and information on ultrasound screening from case notifications, hospital case records and medical practitioners who cared for the women. SUBJECTS: All 243 births and terminations of pregnancy with neural tube defects in South Australia in 1986-1991. MAIN OUTCOME MEASURES: The sensitivity of individual screening methods and of all methods used, particularly for spina bifida. RESULTS: For pregnancies with neural tube defects screened by any method (serum alpha-fetoprotein, ultrasound or amniocentesis), 86% sensitivity was achieved. Ultrasound screening for anencephaly achieved 100% sensitivity even in low risk pregnancies, compared with 92% for serum alpha-fetoprotein. For spina bifida, the sensitivity of ultrasound screening increased with the level of risk in pregnancy: it was 60% in low risk pregnancies, which was equivalent to that of serum alpha-fetoprotein screening (64%); 89% in high risk pregnancies and 100% for women referred for confirmation of a suspected spina bifida by another ultrasonographer (chi 1(2) for trend = 23.49, P < 0.0001). Ultrasound screening in high risk pregnancies for spina bifida achieved higher sensitivity in teaching hospitals compared with other ultrasound services in the State (97% vs 65%), but sensitivity was equivalent for low risk pregnancies. It is estimated that, had the serum screening programme not been in place, the level of sensitivity achieved for spina bifida by ultrasound and amniocentesis would have been 62% compared with the actual situation of 76% with the programme in existence, a difference of nearly 15% (95% CI 2.5 to 26.7) (chi 1(2) = 5.45, P = 0.02). CONCLUSIONS: Antenatal screening for neural tube defects in South Australia achieved a higher level of sensitivity with the maternal serum alpha-fetoprotein programme in place. We conclude that the serum screening programme should continue in South Australia pending a significant improvement in the sensitivity of routine ultrasound screening for spina bifida.
Anencephaly↗
Neural tube defects and maternal serum zinc and copper concentrations in mid-pregnancy: a case-control study.
OBJECTIVE: To assess the relationship between mid-pregnancy maternal serum zinc and copper concentrations and neural tube defects. DESIGN: A prospective case-control study during 1978-1988 within a statewide hospital-based neural tube defect screening program measuring maternal serum alpha-fetoprotein levels at mid-pregnancy. SUBJECTS: Cases were 69 women with fetuses with confirmed neural tube defects. Controls were 592 women with fetuses without neural tube defects who were individually matched to cases for hospital, calendar date of screening, age and parity; there was a variable control-to-case ratio. RESULTS: For both unmatched and adjusted matched analyses, mean maternal serum zinc concentration was higher in cases than controls (P = 0.02 and P = 0.03, respectively). There were no case-control differences for serum copper concentrations. Conditional logistic regression analysis showed a (statistically non-significant) 50% increase in risk of neural tube defects in women whose serum zinc concentration was more than two standard deviations above the population mean. CONCLUSION: Within the normal range of maternal serum zinc and copper concentrations there is no variation in risk of neural tube defects. However, women with very high serum zinc levels may have an increased risk of neural tube defects. This could reflect deficient maternal-to-fetal transfer of zinc in some of those individuals. Any such phenomenon would be manifest in observational, but not experimental, studies.
Adult↗
Tooth lead levels and IQ in school-age children: the Port Pirie Cohort Study.
The relation between lead concentration in deciduous central upper incisor teeth and intellectual functioning was examined in 262 children who were followed from birth to age 7 years in the lead smelter town of Port Pirie, South Australia, and its environs. Intellectual functioning of the children was assessed over the 3-year period from 1986 to 1989 with the revised Wechsler Intelligence Scale for Children (WISC-R) while each child was in his or her eighth year. There was an inverse relation between tooth lead concentration and intellectual development; the intelligence quotient declined by 2.6 points (90% confidence interval (CI) 0.13-4.9) for each natural-log unit increase in tooth lead concentration, expressed in parts per million. Some WISC-R subscales were more strongly associated with lead exposure than others. In particular, tooth lead was significantly negatively associated with scores for the "Block Design" test (partial regression coefficient -1.25 points per unit of natural-log tooth lead; 90% CI -0.61 to -1.89). No statistically significant interaction between a child's sex and tooth lead concentration was found for any of the WISC-R scales. These findings are in agreement with previously published results from this cohort for which serial blood lead concentrations were used to estimate lifetime lead burden.
Child↗
Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience.
OBJECTIVE: To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. DESIGN: Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in samples with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus or family history of cystic fibrosis. SETTING: South Australian Neonatal Screening Programme, Adelaide. SUBJECTS: All 88,752 neonates born in South Australia between December 1989 and December 1993. INTERVENTIONS: Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test; infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing. MAIN OUTCOME MEASURES: Identification of all children with cystic fibrosis in the screened population. RESULTS: Of 1004 (1.13%) neonates with immunoreactive trypsinogen > or = 99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes; 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks; six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were $A1.50 per neonate screened. CONCLUSION: This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.
Cystic Fibrosis↗
Lorenzo's oil: a reassessment.
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Adolescent↗
Mutation analysis of 28 Gaucher disease patients: the Australasian experience.
Gaucher disease is the most common lysosomal storage disease. It is an autosomal recessive disorder that results from a deficiency of beta-glucocerebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacute neuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the non-neuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. We consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families.
Adolescent↗
Pitfalls in the prenatal diagnosis of peroxisomal beta-oxidation defects by chorionic villus sampling.
Variability in the level of expression of very long chain fatty acids (VLCFAs) is documented in cultured chorionic villus (CV) cells derived from two fetuses, one at risk for an unusual peroxisomal fatty acid beta-oxidation defect, and the other at risk for the X-linked form of adrenoleucodystrophy (ALD). Cells from early subcultures of chorionic cells from both cases gave normal values for VLCFA ratios. The results for the fetus at risk for the beta-oxidation defect were interpreted to indicate that the fetus was not affected; however, at birth, the infant was clinically and biochemically affected. In the case of the fetus at risk for X-linked ALD, although VLCFAs were normal in subculture 1, the levels of these fatty acids increased dramatically in subculture 3, suggesting an abnormal fetus. Termination of the pregnancy and subsequent biochemical and morphological follow-up confirmed that the fetus was indeed affected by ALD.
Adrenal Cortex↗
Plasma cis-dec-4-enoic acid measured by isotope dilution mass spectrometry; an improved assay to diagnose medium-chain acyl-CoA dehydrogenase deficiency.
An isotope dilution mass spectrometric assay for plasma cis-dec-4-enoic acid is described. It is quicker, more reliable and more accurate than previous methods. It confirmed previous findings that cis-dec-4-enoic acid is a reliable indicator for medium-chain acyl-CoA dehydrogenase deficiency (MCAD). The plasma cis-dec-4-enoic acid levels of both asymptomatic and symptomatic MCAD patients (3.5-71 mumol/L) are demonstrably higher than those of normal children (0.2-1.7 mumol/L), MCAD heterozygotes (0.1-1.5 mumol/L), those with other fatty acid oxidation defects (0.2-2.2 mumol/L) or those receiving high doses of valproic acid (0.2-0.4 mumol/L).
Acyl-CoA Dehydrogenase↗
Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.
OBJECTIVE: To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN: All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. SETTING: Southern Australia. SUBJECTS: All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. MAIN OUTCOME MEASURES: Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. RESULTS: Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). CONCLUSIONS: While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.
Confidence Intervals↗
An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.
Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA; EC 3.1.6.8). The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) amplified in seven discrete reactions. Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products. The patient was found to be homozygous for a C-->T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M). Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M. All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages. The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans; therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity. This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation.
Amino Acid Sequence↗
Childhood porphyrias: implications and treatments.
In describing the clinical, biochemical, and family findings in five children with porphyria, we examine initial treatments and, where appropriate, the effectiveness of long-term therapy. We note that porphyria diagnosis, particularly in childhood, relies heavily on specialist laboratory investigations. Because disease expression in some porphyrias requires exposure to precipitating factors, it may be prevented or delayed by their avoidance.
Adolescent↗
Environmental exposure to lead and children's intelligence at the age of seven years. The Port Pirie Cohort Study.
BACKGROUND: Exposure to lead in early childhood is thought to result in delayed neuropsychological development. As yet there is little longitudinal evidence to establish whether these effects persist into later childhood. METHODS: We measured IQ scores in 494 seven-year-old children from the lead-smelting community of Port Pirie, Australia, in whom developmental deficits associated with elevated blood lead concentrations had already been reported at the ages of two and four years. Exposure to lead was estimated from the lead concentrations in maternal blood samples drawn antenatally and at delivery and from blood samples drawn from the children at birth (umbilical-cord blood), at the ages of 6 and 15 months and 2 years, and annually thereafter. Data relating to known covariates of child development were collected systematically for each child throughout the first seven years of life. RESULTS: We found inverse relations between IQ at the age of seven years and both antenatal and postnatal blood lead concentrations. After adjustment by multiple regression for sex, parents' level of education, maternal age at delivery, parents' smoking status, socioeconomic status, quality of the home environment, maternal IQ, birth weight, birth order, feeding method (breast, bottle, or both), duration of breast-feeding, and whether the child's natural parents were living together, the relation with lead exposure was still evident for postnatal blood samples, particularly within the age range of 15 months to 4 years. For an increase in blood lead concentration from 10 micrograms per deciliter (0.48 mumol per liter) to 30 micrograms per deciliter (1.45 mumol per liter), expressed as the average of the concentrations at 15 months and 2, 3, and 4 years, the estimated reduction in the IQ of the children was in the range of 4.4 points (95 percent confidence interval, 2.2 to 6.6) to 5.3 points (95 percent confidence interval, 2.8 to 7.8). This reduction represents an approximate deficit in IQ of 4 to 5 percent. CONCLUSIONS: Low-level exposure to lead during early childhood is inversely associated with neuropsychological development through the first seven years of life.
Australia↗
An N-acetylgalactosamine-4-sulfatase mutation (delta G238) results in a severe Maroteaux-Lamy phenotype.
Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is an autosomally inherited lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (EC 3.1.6.1; 4-sulfatase). In order to determine the gene defect in a clinically severe MPS VI patient, polymerase chain reaction (PCR) products were generated from the patient's fibroblast mRNA and also from a 4-sulfatase cDNA clone and subjected to the chemical cleavage technique to detect mismatched bases, which were then identified by direct DNA sequencing of the PCR products. The patient was homozygous for an early frameshift mutation caused by the deletion of a G at position 238 (delta G238), which produces a truncated 4-sulfatase with an altered amino acid sequence from amino acid 80 to a premature stop codon at codon 113 relative to the normal 4-sulfatase reading frame of 533 amino acids. Since the mutation occurs only 40 amino acids past the signal peptidase cleavage site, it is most likely that this will result in a protein with no 4-sulfatase activity. This is consistent with the severe clinical presentation and the absence of 4-sulfatase enzyme activity or mutant 4-sulfatase protein in the patient. The patient was also found to be homozygous for two polymorphisms, i.e., a G to A transition at nucleotide 1072 resulting in a valine358 to methionine substitution (V358M) and a salient A to G transition in the third base of the proline397 codon at nucleotide 1191.
Amino Acid Sequence↗
Improved performance in a prenatal screening programme for Down's syndrome incorporating serum-free hCG subunit analyses.
A prenatal screening programme for Down's syndrome potentially detecting 76 per cent of affected pregnancies in the South Australian general population at an amniocentesis rate of 3.9 per cent was designed following analysis of mid-trimester serum samples from 57 women who carried an affected fetus. This equates to one affected pregnancy being detected for 41 chromosomal analyses performed. For the experimental series, 75.4 per cent of affected pregnancies were detected, while 4.1 per cent of control specimens produced estimated risk odds consistent with further action. A maternal risk odds of birth of a Down's syndrome fetus of 1:420 was taken as the decision value, which is the prevalence of Down's syndrome births to 35-year-old mothers in South Australia. This screening performance was achieved by investigating combinations of serum analytes not previously reported and by refining the calculation of maternal risk odds to include selective weighting of indicator analytes. Combination of the measurements of free alpha-subunits and beta-subunits of chorionic gonadotrophin, alpha-fetoprotein, unconjugated oestriol, and placental lactogen was found to be most effective in indicating Down's syndrome fetuses. In all combinations of analytes tested, replacing the measurements of free alpha-subunits and free beta-subunits of chorionic gonadotrophin with the measurement of intact chorionic gonadotropin produced a less effective screen.
Adult↗
Maternal serum screening for neural tube defects and Down's syndrome.
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Down Syndrome↗