Biomedical subjects
P Benn
Publications and source records attributed to P Benn.
Medicine, lies and deceptions.
This article offers a qualified defence of the view that there is a moral difference between telling lies to one's patients, and deceiving them without lying. However, I take issue with certain arguments offered by Jennifer Jackson in support of the same conclusion. In particular, I challenge her claim that to deny that there is such a moral difference makes sense only within a utilitarian framework, and I cast doubt on the aptness of some of her examples of non-lying deception. But I argue that lies have a greater tendency to damage trust than does non-lying deception, and suggest that since many doctors do believe there is a moral boundary between the two types of deception, encouraging them to violate that boundary may have adverse general effects on their moral sensibilities.
Efficacy of screening for fetal Down syndrome in the United States from 1974 to 1997.
OBJECTIVE: To estimate the 16-week prevalence of Down syndrome in the United States from 1974 to 1997 and to determine the efficacy of maternal age cutoffs and triple screens for detecting it antenatally. METHODS: Using natality statistics for the United States from 1974 to 1997 of maternal-age-specific live births to women 13-49 years old, we evaluated advanced maternal age (35-49 years at delivery) and the triple serum test (maternal serum alpha-fetoprotein, hCG, and unconjugated estriol) as screening tests for Down syndrome. Efficacy was evaluated using sensitivity, false-positive rate, positive predictive value, and likelihood ratio (likelihood ratio = sensitivity/false-positive rate). RESULTS: In 1974, the estimated second-trimester prevalence of Down syndrome was one in 740, but by 1997 that had increased to one in 504. The proportion of Down syndrome fetuses at 16 weeks' gestation in women 35-49 years old increased from 28.5% in 1974 to 47.3% in 1997. However, live births to women 35-49 years old increased more rapidly from 4.7% in 1974 to 12.6% in 1997. The likelihood ratio for maternal age to identify an affected pregnancy decreased during the study period and was substantially lower than that using the serum test. CONCLUSION: A maternal age cutoff of 35 years in the 1990s resulted in high false-positive rates and was less efficacious based on likelihood ratio and positive predictive value. Serum testing of all pregnant women would reduce the number of amniocenteses and decrease procedure-related losses.
Prenatally diagnosed sacrococcygeal teratoma: a unique expression of trisomy 1q.
Partial duplication of the long arm of chromosome 1 has been observed in fetal intracranial teratomas. We sonographically diagnosed a 19-week fetus with sacrococcygeal teratoma, cerebral ventriculomegaly, and cerebellar hypoplasia. Chromosomal analysis of amniocytes showed an unbalanced translocation between chromosomes 1 and 15, resulting in trisomy 1q21-->1 qter. Duplication or over expression at more than one locus on the long arm of chromosome 1 may be required for the development of an extra-gonadal teratoma.
Common trisomy mosaicism diagnosed in amniocytes involving chromosomes 13, 18, 20 and 21: karyotype-phenotype correlations.
Karyotype-phenotype correlations of common trisomy mosaicism prenatally diagnosed via amniocentesis was reviewed in 305 new cases from a collaboration of North American cytogenetic laboratories. Abnormal outcome was noted in 10/25 (40%) cases of 47,+13/46, 17/31 (54%) cases of 47,+18/46, 10/152 (6.5%) cases of 47,+20/46, and in 49/97 (50%) cases of 47,+21/46 mosaicism. Risk of abnormal outcome in pregnancies with less than 50% trisomic cells and greater than 50% trisomic cells were: 26% (4/15) versus 60% (6/10) for 47,+13/46, 52% (11/21) versus 75% (6/8) for 47,+18/46, 4.5% (6/132) versus 20% (4/20) 47,+20/46, and 45% (27/60) versus 59% (22/37) for 47,+21/46. Phenotypically normal liveborns were observed with mean trisomic cell lines of 9.3% for 47,+13/46, 8.6% for 47,+18/46, 27% for 47, +20/46, and 17% for 47,+21/46. Cytogenetic confirmation rates were 46% (6/13 cases) for 47,+13/46 mosaicism, 66% (8/12 cases) for 47, +18/46, 10% (10/97 cases) for 47,+20/46, and 44% (24/54 cases) for 47,+21/46. There were higher confirmation rates in pregnancies with abnormal versus normal outcome: 50% versus 44% for 47,+13/46 mosaicism, 100% versus 33% for 47,+18/46, 66% versus 7% for 47, +20/46, and 55% versus 40% for 47,+21/46. Repeat amniocentesis is not helpful in predicting clinical outcome. It may be considered when there is insufficient number of cells or cultures to establish a diagnosis. Fetal blood sampling may have a role in mosaic trisomy 13, 18, and 21 as the risk for abnormal outcome increases with positive confirmation: 1/5 (20%) normal cases versus 5/8 (62%) abnormal cases. High resolution ultrasound examination(s) is recommended for clinical correlation and to facilitate genetic counselling.
Attenuated familial adenomatous polyposis in a man with an interstitial deletion of chromosome arm 5q.
Familial adenomatous polyposis (FAP) is an inherited colon cancer syndrome caused by mutations in the APC gene on chromosome region 5q21. Patients typically present with several hundred to several thousand polyps throughout the colon. Benign and malignant extracolonic manifestations are often present. Attenuated FAP (AFAP) is a recognized variant of FAP in which patients present with fewer than 100 polyps and appear to have a delayed onset of the clinical manifestations of FAP. Mutations in specific regions of the APC gene are associated with AFAP. A full deletion of the APC gene region has previously been thought to be associated with typical FAP. We now report on a 39-year-old man with a cytogenetically visible interstitial 5q deletion. Fluorescent in situ hybridization analysis with two cosmid probes specific for the 5' and 3' ends of the gene indicated that the entire APC locus is deleted. The number of polyps (50-60) seen in this patient was consistent with AFAP, as was the absence of multiple congenital hypertrophy of the retinal pigment epithelium (CHRPE). This is the first reported case of AFAP associated with a germline deletion of the entire APC gene.
Trisomy 16 and trisomy 16 Mosaicism: a review.
A review of all prenatal and postnatal diagnoses of trisomy 16 and trisomy 16 mosaicism was carried out in the context of the current understanding of confined placental mosaicism and uniparental disomy (UPD). The prenatal detection of trisomy 16 cells is associated with a high probability of fetal death, preterm delivery, intrauterine growth retardation, and fetal anomalies. Birth defects were typical of those seen in nonmosaic partial duplications of chromosome 16. Surprisingly, anomalies were sometimes limited to a single organ and included some relatively common isolated defects such as a ventricular septal defect, hypospadias, imperforate anus, inguinal hernia, and clubfoot. The risk for abnormality appeared to be higher in those pregnancies in which trisomy 16 cells were identified in amniotic fluid compared to the detection in chorionic villi samples. Contrary to nonmosaic trisomy 16 with an excess of males, mosaic trisomy 16 shows an excess of female karyotypes. Following the prenatal detection of trisomy 16 cells, aneuploid cells are almost never found in fetal or neonatal lymphocytes. Studies on fibroblasts also often fail to confirm the presence of the abnormal cell line even in cases in which multiple anomalies are present. It is likely that trisomy 16 cells are sometimes present in the early developing embryo even though subsequent cytogenetic studies on fetal or neonatal tissues may not detect any aneuploid cells. UPD can be excluded as a mechanism for those anomalies that are common to mosaic trisomy 16 and nonmosaic partial duplications. The term "occult mosaicism" is suggested to describe the situation in which the presence of an abnormal cell line is suspected on the basis of clinical data but unproven by laboratory analysis.
Economic evaluation of prenatal screening for Down syndrome in the U.S.A.
Maternal serum screening for Down syndrome involves biochemical tests such as alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG) and unconjugated oestriol (uE3), either alone or in combination, that have variable detection and false-positive rates. Choosing a screening protocol requires a trade-off between a desired detection rate and an acceptable false-positive rate. Selecting a screening protocol that maximizes the net benefit to society provides one approach. We have developed a general formula for calculating the per case net social benefit of a screening test and have applied it to United States data. The maximum net benefit associated with each of the various screening options currently available is estimated and the model is further applied to determine the conditions under which the addition of a new marker to an existing protocol can be justified. For each test, or combination of tests, optimal net benefits occur at different detection and false-positive rates. Net benefits are strongly and positively dependent on maternal age; high net benefits are associated with older patients and low, or even negative, net benefits with younger patients. Also, net benefits are affected by the term risk cut-off rate. For triple testing, the 1:351 Down syndrome term risk cut-off appears to provide a higher net benefit than that obtained with 1:250 or 1:300. The optimization of societal net benefit provides a powerful approach to evaluating screening strategies, but the policies used must also consider individuals' freedom in decision making at each step of the prenatal diagnosis pathway.
Aging chromosome telomeres: parallel studies with terminal repeat and telomere associated DNA probes.
Human chromosome telomeres consist of tandemly repeated (TTAGGG)n sequences with variant and more complex telomere-associated DNA sequences proximal to the terminal repeats. Terminal restriction fragment (TRF) sizes have been evaluated by Southern blot analysis using a terminal repeat probe, (TTAGGG)3 that will simultaneously detect all telomeres and with a telomere-associated DNA probe, TelBamll, that identifies a specific sub-group of chromosome ends. For DNA extracted from in vitro aging fibroblasts, a progressive reduction in the size of the TRFs could be demonstrated using both probes. For both fibroblasts and adult lymphocyte DNA, there were differences in the size of the fragments detected with the two probes. Studies were carried out to determine whether this difference might, in part, be attributable to variability in terminal repeat lengths as well as heterogeneity in the location of terminal restriction enzyme recognition sites. Using the (TTAGGG)3 probe to identify all telomeres, the terminal repeat lengths from lymphocytes of two adults appeared to be highly variable with sizes upto 20 kb. For the sub-group of telomeres identified by TelBamll the terminal repeat lengths were estimated to be 2-4 kb and appeared to show relatively little size diversity. If it assumed that the molecular weights of the DNA fragments identified in these studies do accurately reflect individual telomere structures, then it can be concluded that some specific telomere repeat arrays are substantially shorter than others. Variation in terminal repeat length may be related to the extent that telomeres participate in chromosome rearrangement.
Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15.
Prader-Willi syndrome (PWS) is a complex multiple anomaly syndrome that has been shown to result from deficient expression of paternal chromosome 15(q11-q13). In most cases, it is caused either by deletion of this region in the paternally inherited chromosome 15 or by maternal uniparental disomy (UPD) of chromosome 15. In order to determine whether there are phenotypic differences between patients whose PWS is caused by these two different mechanisms, 54 affected individuals (37 with deletion, 17 with UPD) were personally examined and studied using molecular techniques. The previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the two groups, those with UPD were less likely to have a "typical" facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average. Possible mechanisms by which these differences could occur and the implications of these differences for diagnosis are described.
Trisomy 16 mosaicism in amniotic fluid cell cultures.
Trisomy 16 mosaicism was found in amniotic fluid cells in a patient undergoing amniocentesis because of elevated second-trimester maternal serum alpha-fetoprotein (MSAFP) (2.80 MOM), a markedly elevated human chorionic gonadotropin level (hCG) (12.02 MOM), and a Down syndrome risk of 1:55. Ultrasound evaluation of the fetus indicated the presence of an atrial septal defect and clinodactyly. Cytogenetic analyses of various fetal tissues using fluorescence in situ hybridization (FISH) failed to detect substantial numbers of trisomy 16 cells; however, trisomy 16 mosaicism was identified in placental tissue. Molecular genetic analysis at five different loci [four analysed by polymerase chain reaction (PCR) and one by Southern blot analysis] failed to show any evidence for uniparental disomy. Although trisomy 16 cells could not be clearly demonstrated in the fetus, the presence of a clinically significant proportion of aneuploid cells early in development could not be excluded and it therefore cannot be assumed that a 'confined placental mosaicism' existed. The markedly elevated hCG and elevated MSAFP levels are consistent with abnormal placental function in trisomy 16 mosaicism. Serial ultrasound evaluation (to detect any late-onset growth retardation) and fetal echocardiography may be indicated for patients with extraordinarily high levels of hCG, especially if MSAFP is also elevated.
Developing a role for genetics within a cancer program.
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Trisomy 16 fetus surviving into the second trimester.
A 27-year-old gravida 4, para 3 was found to have anhydramnios at 14 weeks' gestation following a size/date discrepancy noted at her routine prenatal visit. A detailed ultrasound revealed multiple fetal anomalies including congenital heart defect, chest hypoplasia, and bilateral dysplastic kidneys. Karyotype revealed trisomy 16 in 15/15 cells from a tissue specimen obtained from the fetal cord insertion site following elective pregnancy termination.
Variable clinical expression of mosaic trisomy 16 in the newborn infant.
Trisomy 16 is common in embryos and fetuses aborted early during development. Mosaicism for trisomy 16 is sometimes encountered during prenatal diagnosis, particularly with chorionic villi biopsy specimens, and, until recently, was thought to be confined to the placenta. However, recently, several liveborn infants with trisomy 16 mosaicism have been described. We report on an additional liveborn infant with trisomy 16 mosaicism and compare the clinical findings with those of the previously reported cases in an attempt to delineate a mosaic trisomy 16 syndrome. Cytogenetic analysis from our patient showed that there was a different proportion of abnormal cells in different tissues and that the anomaly was undetectable in blood lymphocyte cultures. This observation was consistent with some of the previous reports. DNA analysis of parents and child was carried out using a polymorphic dinucleotide marker that maps to the long arm of chromosome 16. This analysis showed that the extra chromosome 16 in the infant was maternal in origin and suggested that the nondisjunction was probably a first meiotic division error. Our results suggest that an investigation of multiple tissues is required before concluding that mosaicism is confined to the placenta. We conclude that a finding of trisomy 16 mosaicism at prenatal diagnosis should be regarded with extreme caution. This diagnosis may be associated with a highly variable phenotype that may occasionally be compatible with extrauterine life.
Steroid hormone receptor immunohistochemistry and amplification of c-myc protooncogene. Relationship to disease-free survival in breast cancer.
BACKGROUND: It is important to develop parameters that aid in prognosticating which patients with breast cancer are more likely to have a rapid disease course and therefore might benefit from early aggressive therapies. METHODS: Specimens from two groups of women, deliberately selected because their clinical courses differed greatly, were studied to detect amplification of the protooncogenes c-myc, int-2, and C-erbB-2/neu by slot-blot assay, the estrogen receptor (ER), and the progesterone receptor (PR) by both biochemical and immunohistochemical procedures (ERICA and PRICA). One group of 50 patients had a prolonged disease-free interval after initial surgery (mean, 6.4 years); the other group of 52 women had had rapid disease recurrence (mean, 1.4 years) or progression (5 patients died of disease within 1 year of diagnosis). The patients were selected from 1700 consecutively accessioned cases if they fit the study criteria and sufficient tissue was available for oncogene hybridization studies. RESULTS: The two groups differed statistically by stage, number of involved axillary lymph nodes, ERICA and PRICA results (P = 0.001), and amplification of c-myc (P = 0.003). The percentage of patients with rapid disease recurrence and progression increased from 0-93% when risk factors changed from best case (ERICA and PRICA results, positive; c-myc, not amplified; and axillary nodes, not involved) to worst case (ERICA and PRICA findings, negative; c-myc, amplified; and axillary nodes, involved). CONCLUSIONS: Women with these worst-case parameters were more likely to have a recurrence sooner and rapidly progressive disease. They might benefit from early aggressive therapeutic measures.
A rapid (but wrong) prenatal diagnosis.
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Cytogenetic studies of bone marrow fibroblasts cultured from patients with myelofibrosis and myeloid metaplasia.
Cytogenetic studies of bone marrow fibroblasts and blood cells from peripheral blood or bone marrow were performed in 19 patients with myelofibrosis with myeloid metaplasia (group 1), nine patients with other myeloproliferative syndromes without myelofibrosis (group 2), and 12 patients with anaemia secondary to iron deficiency or chronic inflammatory disease (group 3). Clonal cell populations with abnormal karyotypes were seen in the bone marrow or blood in five of 14 (36%) group 1 patients, one of nine (11%) group 2 patients and none (0%) of the group 3 patients. Abnormal karyotypes of bone marrow fibroblasts were found in three of 16 (19%) of patients of group 1, and in two of nine (22%) and two of 12 (17%) patients each of groups 2 and 3, respectively. Since abnormal karyotypes can be found in bone marrow fibroblasts cultured from normal subjects, and since the abnormalities seen in the bone marrow fibroblasts differed from those found in bone marrow or blood cells, it is suggested that abnormal karyotypes found in bone marrow fibroblasts cultured from patients with primary myelofibrosis do not necessarily reflect neoplasia. The results of this study are compatible with the widely accepted hypothesis that in patients presenting with 'primary' myelofibrosis, the fibrosis is a secondary reactive process.
Does the breakpoint within the major breakpoint cluster region (M-bcr) influence the duration of the chronic phase in chronic myeloid leukemia? An analytical comparison of current literature.
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