Search PubMed⌕ Search

Biomedical subjects

E Feingold

Publications and source records attributed to E Feingold.

At least 19 recordsLinked to original sources
PubMed1999

Multicolor fluorescence in situ hybridization analysis of the spermatozoa of a male heterozygous for a reciprocal translocation t(11;22)(q23;q11).

A reciprocal translocation between chromosomes 11 and 22 is a site-specific translocation that has been seen in many families with no common ancestry. This translocation is of particular interest because balanced carriers have a 0.7-3.7% risk of having children with the supernumerary der(22), resulting from a 3:1 segregation. We have used a three color fluorescence in situ hybridization (FISH) with specific DNA probes to determine the chromosome segregation pattern of a male carrier of a translocation t(11;22)(q23;q11). The probes selected included a centromeric marker for chromosome 11, a marker closely linked to the centromere of chromosome 22, and a third probe distal to the translocation breakpoint of chromosome 22. The results showed that 3:1 segregation is preferential in this patient, with 40.1% of spermatozoa belonging to this segregation type. Alternate segregation followed with 27.4% of analyzed spermatozoa; 17.6% resulted from adjacent 1 and 12.5% resulted from adjacent 2 segregation. We detected 0.5% of presumably diploid spermatozoa. Complementary adjacent 1 products were observed at statistically different frequencies (P = 0.02). Complementary adjacent 2 products without recombination in the interstitial segments were also seen at different frequencies (P = 0.002). In 3:1 segregation, the products containing one chromosome were observed more frequently than those with three chromosomes (P = 0.0001). The 24,+der(22) gamete was seen more frequently than all of the other gametes combined which had 24 chromosomes resulting from 3:1 segregation. The results of this study demonstrate that in this t(11;22) carrier, 3:1 segregation is preferential but not exclusive.

Adult↗
PubMed1998

Testing for contributions of mitochondrial DNA mutations to complex diseases.

Several complex disorders are suspected of being associated with mitochondrial DNA (mtDNA) mutations. We studied the statistical properties of a test based on proband-relative pairs to identify potential mtDNA mutation involvement in a complex disorder. The test compares the recurrence risk of relatives of probands along the mitochondrial lineage with that of relatives along the nonmitochondrial lineage. If mtDNA mutations are involved, the recurrence risk will be higher among relatives in the mitochondrial lineage. The form of the test is independent of the assumed models of inheritance and interaction of the nuclear autosomal mutations with mtDNA mutations. The power of the test, however, differs among the different models and by the type of proband-relative pairs used in the test. We considered heterogeneity models with and without phenocopies, a three-state heteroplasmic mtDNA transmission model, and a multiplicative epistasis model. Under the heterogeneity model, the power of the test increases as the relationship between the proband and the relative becomes more distant. Under the multiplicative epistasis model, the power of the test decreases as the relationship between the proband and the relative becomes more distant.

DNA, Mitochondrial↗
PubMed1998

Meiotic products of two reciprocal translocations studied by multicolor fluorescence in situ hybridization.

The sperm products of two male carriers of reciprocal translocations were studied by fluorescence in situ hybridization (FISH) using a combination of three probes for each translocation. One patient carried a t(2;18)(p21;q11.2), the other a t(8;9)(q24.2;q32). The probes selected included a centromeric marker for each chromosome involved in the translocation plus a third probe distal to the translocation breakpoint of one of the translocation chromosomes. This assay identifies alternate, adjacent 1, adjacent 2, and 3:1 types of meiotic products. It allows the identification of recombination events and also estimation of the frequency of diploidy. For the t(2;18), the frequency of normal and balanced sperm and of adjacent 1, adjacent 2, and 3:1 products was 43.6%, 29. 8%, 10.5%, and 12.8%, respectively. Similar segregation patterns had been reported for this donor by direct sperm karyotyping of sperm cells. For the t(8;9), the frequency of normal and balanced sperm and of adjacent 1, adjacent 2, and 3:1 products was 44.4%, 41%, 3.1%, and 9.4%, respectively. The frequency of complementary adjacent 1 products was statistically different in both the t(2;18) (P < 0. 0001) and the t(8;9) (P < 0.0001) carrier. When the number of adjacent 2 products with one translocation chromosome (regardless of normal or derivative) was compared to the number of adjacent 2 products with the second translocation chromosome (again, regardless of normal or derivative), no statistical difference was noted for either the t(2;18) (P = 0.32) or the t(8;9) (P = 0.69). Recombination events within the interstitial segment of chromosome 2 were statistically higher than those seen in chromosome 18 (P < 0. 0001), whereas in chromosomes 8 and 9, recombination in the interstitial segments was similar (P = 0.64). The rate of diploidy was similar in both the t(2;18) (0.5%) and the t(8;9) (0.6%). Thus, FISH provides chromosome information on the sperm products produced by translocation carriers, although it cannot provide an assessment of the full chromosome complement of the spermatozoon.

Adult↗
PubMed1997

Genome scanning for segments shared identical by descent among distant relatives in isolated populations.

In this paper, we address some of the statistical issues concerning false-positive rates that arise when the whole genome, or a portion thereof, is scanned in distantly related individuals, to search for a disease locus. We derive a method for correcting false-positive probabilities for the large number of comparisons that are performed when scanning a large portion of the genome. We consider both the idealized situation of a dense set of fully informative markers and the more realistic data-collection strategy of an initial scan at low resolution to identify promising areas, which then are typed with markers at high resolution. We also examine the accuracy of false-positive rates approximated using a conservative estimate of the separation distance between affected individuals in the current generation and the common ancestral couple. Calculation of false-positive rates when inbreeding is present in the pedigree also is considered.

Alleles↗
PubMed1997

Estimating meiotic exchange patterns from recombination data: an application to humans.

We present analytical methods to estimate the recombinational history of chromosomes in a human population. Our analysis, similar to those utilized in Drosophila, can be used to construct meiotic maps based upon crossover frequencies observed in family data. We apply this method of exchange estimation to a population of paternally and maternally inherited chromosomes 21. The patterns of chromosomal exchange estimated by this type of analysis are comparable to those obtained by the more technically difficult method of cytologically counting chiasmata among human male meiotic events (sperm). This type of analysis can be applied to both male and female meiosis, circumventing many technical problems inherent to cytological counting. Moreover, the distribution of exchange locations along a chromosome for each exchange type (i.e., single, double, or triple exchanges) can be examined individually, an advantage compared to examination of genetic maps that only provide a summary of these distributions. We discuss how this analysis can be used to examine various assumptions concerning meiotic exchange in humans and investigate properties of the analysis that contribute to the accuracy of the results.

Female↗
PubMed1997

Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

Chromosomes, Human, Pair 21↗
PubMed1997

Stability of motor-unit force thresholds in the decerebrate cat.

To further test the hypothesis that some fixed property of motoneurons determines their recruitment order, we quantified the variation in force threshold (FT) for motoneurons recruited in muscle stretch reflexes in the decerebrate cat. Motor axons supplying the medial gastrocnemius (MG) muscle were penetrated with micropipettes and physiological properties of the motoneuron and its muscle fibers, i.e., the motor unit, were measured. FT, defined as the amount of MG force produced when the isolated motor unit was recruited, was measured from 20 to 93 consecutive stretch trials for 29 motor units. Trials were selected for limited variation in base force and rate of rise of force, which have been shown to covary with FT, and in peak stretch force, which gives some index of motor-pool excitability. Under these restricted conditions, large variation in FT would have been inconsistent with the hypothesis. Analysis of the variation in FT employed the coefficient of variation (CV), because of the tendency for FT variance and mean to increase together. We found that CV was distributed with a median value of 10% and with only 2 of 29 units exceeding 36%. Some of this variation was associated with measurement error and with intertrial fluctuations in base, peak, and the rate of change of muscle force. CV was not significantly correlated with motor-unit axonal conduction velocity, contraction time, or force. In three cases FT was measured simultaneously from two motor units in the same stretch trials. Changes in recruitment order were rarely observed (5 of 121 stretch trials), even when FT ranges for units in a pair overlapped. We suggest that the large variation in recruitment threshold observed in some earlier studies resulted not from wide variation in the recruitment ranking of motoneurons within one muscle, but rather from variation in the relative activity of different pools of motoneurons. Our findings are consistent with the hypothesis that recruitment order is determined by some fixed property of alpha-motoneurons and/or by some unvarying combination of presynaptic inputs that fluctuate in parallel.

Animals↗
PubMed1997

Strategies for mapping heterogeneous recessive traits by allele-sharing methods.

We investigate strategies for detecting linkage of recessive and partially recessive traits, using sibling pairs and inbred individuals. We assume that a genomewide search is being conducted and that locus heterogeneity of the trait is likely. For sibling pairs, we evaluate the efficiency of different statistics under the assumption that one does not know the true degree of recessiveness of the trait. We recommend a sibling-pair statistic that is a linear compromise between two previously suggested statistics. We also compare the power of sibling pairs to that of more distant relatives, such as cousins. For inbred individuals, we evaluate the power of offspring of different types of matings and compare them to sibling pairs. Over a broad range of trait etiologies, sibling pairs are more powerful than inbred individuals, but for traits caused by very rare alleles, particularly in the case of heterogeneity, inbred individuals can be much more powerful. The models we develop can also be used to examine specific situations other than those we look at. We present this analysis in the idealized context of a dense set of highly polymorphic markers. In general, incorporation of real-world complexities makes inbred individuals, particularly offspring of distant relatives, look slightly less useful than our results imply.

Chromosome Mapping↗
PubMed1996

Prospective study of a PACS: information flow and clinical action in a medical intensive care unit.

PURPOSE: To prospectively compare efficiency and outcome of a standard film-only system with those of a digital picture archiving and communication system (PACS). MATERIALS AND METHODS: The film-only system, which used either analog film or computed radiography (CR) hard copy, was compared with a PACS, which used CR images displayed on a multiviewer in the radiology department and a workstation in the medical intensive care unit. A random sample of nonroutine, bedside chest radiographs was studied. RESULTS: Within 20 minutes of completion of radiography, 246 of 328 (75%) of the images were available at the workstations; it took 1.8 hours for 238 of 317 (75%) of the images to be displayed on the multiviewer. When the workstation was used, the staff did not access the image information earlier, but clinical actions were initiated more promptly in response to imaging findings. Consultation with radiologists decreased from 507 of 561 (90%) images with hard copies to 70 of 249 (28%) with the workstation. CONCLUSION: Use of a PACS improves the delivery of chest images, facilitates the initiation of clinical actions, and decreases input by radiologists.

Computer Systems↗
PubMed1996

Factors affecting the electronic communication of radiological information to an intensive-care unit.

In order to examine communication of radiological information under circumstances where rapid exchange of information was essential, we studied communication of non-routine portable chest radiographs to an intensive-care unit (ICU). Images and reports were available through the usual communication channels and through a PACS workstation in the ICU. Data were obtained to determine how quickly and by what means ICU physicians first viewed images and received radiologists' reports of chest radiographs. Peak information demand occurred within 4 h of the examination. The most rapid means of communication was for the physician to visit the radiology department. Image viewing and report receipt were tightly coupled, usually for images which were first viewed as hard copy. PACS performance suffered from unreliable film digitization and delayed report transcription. Integration of computed radiography and digital dictation into a PACS could markedly reduce the delays in ICU physicians' access to radiological information.

Efficiency, Organizational↗
PubMed1996

Statistical models for trisomic phenotypes.

Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known.

Abortion, Spontaneous↗
PubMed1996

Sex ratio in normal and disomic sperm: evidence that the extra chromosome 21 preferentially segregates with the Y chromosome.

In humans, deviations from a 1:1 male:female ratio have been identified in both chromosomally normal and trisomic live births: among normal newborns there is a slight excess of males, among trisomy 18 live borns a large excess of females, and among trisomy 21 live borns an excess of males. These differences could arise from differential production of or fertilization by Y- or X-bearing sperm or from selection against male or female conceptions. To examine the proportion of Y- and X-bearing sperm in normal sperm and in sperm disomic for chromosomes 18 or 21, we used three-color FISH (to the X and Y and either chromosome 18 or chromosome 21) to analyze >300,000 sperm from 24 men. In apparently normal sperm, the sex ratio was nearly 1:1 (148,074 Y-bearing to 148,657 X-bearing sperm), and the value was not affected by the age of the donor. Certain of the donors, however, had significant excesses of Y- or X-bearing sperm. In disomy 18 sperm, there were virtually identical numbers of Y- and X-bearing sperm; thus, the excess of females in trisomy 18 presumably is due to selection against male trisomic conceptions. In contrast, we observed 69 Y-bearing and 44 X-bearing sperm disomic for chromosome 21. This is consistent with previous molecular studies, which have identified an excess of males among paternally derived cases of trisomy 21, and suggests that some of the excess of males among Down syndrome individuals is attributable to a nondisjunctional mechanism in which the extra chromosome 21 preferentially segregates with the Y chromosome.

Chromosomes, Human, Pair 18↗
PubMed1996

Familial transmission of the FMR1 CGG repeat.

To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes for 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X chromosome to the full mutation was seen in 13.4% of offspring from premutation mothers with 56-59 repeats, 20.6% of those with 60-69 repeats, 57.8% of those with 70-79 repeats, 72.9% of those with 80-89 repeats, and 97.3% of those with 90-199 repeats. For premutation fathers, the majority (62%) of their daughters had a larger repeat number, while a few had either a smaller (22%) or the same (16%) repeat number, compared with their fathers' sizes. However, daughters with a smaller repeat number were observed only if their fathers had > or = 80 repeats. Fifteen (39.5%) of 38 such daughters carried a smaller repeat than did their fathers. We observed that a similar repeat number was inherited more often than expected by chance, among the members of a sibship segregating fragile X. This familial clustering, observed in the offspring of both males and females with a premutation, implies there may be an additional factor, independent of parental repeat size, that influences CGG-repeat instability. Instability in gray-zone allele transmissions was observed in 25% of alleles with 50-60 CGGs but in <8% of those with 40-49 CGGs. Examination of gray-zone allele organization revealed that long tracts of pure CGGs (>34) are not always unstably transmitted. These results raise new questions regarding the familial factors that may determine transmission expansions.

Alleles↗
PubMed1995

Non-disjunction in human sperm: evidence for an effect of increasing paternal age.

In humans, the relationship between advancing maternal age and the incidence of trisomy has been long established, but the possible effect of increasing age of the father remains controversial. Using a fluorescence in situ hybridization (FISH) approach to directly examine individual sperm for aneuploidy of the sex chromosomes and chromosome 18, we have analyzed approximately 400,000 sperm from 24 men aged 18-60 years. There was no obvious relationship between increasing age and disomy 18, but the incidence of XY,YY and XX disomy all were significantly elevated among older men. This suggests that older men, like older women, have an increased likelihood of producing aneuploid offspring by comparison with their younger counterparts.

Adolescent↗
PubMed1995

Methods for genetic linkage analysis using trisomies.

Certain genetic disorders are rare in the general population, but more common in individuals with specific trisomies. Examples of this include leukemia and duodenal atresia in trisomy 21. This paper presents a linkage analysis method for using trisomic individuals to map genes for such traits. It is based on a very general gene-specific dosage model that posits that the trait is caused by specific effects of different alleles at one or a few loci and that duplicate copies of "susceptibility" alleles inherited from the nondisjoining parent give increased likelihood of having the trait. Our mapping method is similar to identity-by-descent-based mapping methods using affected relative pairs and also to methods for mapping recessive traits using inbred individuals by looking for markers with greater than expected homozygosity by descent. In the trisomy case, one would take trisomic individuals and look for markers with greater than expected homozygosity in the chromosomes inherited from the nondisjoining parent. We present statistical methods for performing such a linkage analysis, including a test for linkage to a marker, a method for estimating the distance from the marker to the trait gene, a confidence interval for that distance, and methods for computing power and sample sizes. We also resolve some practical issues involved in implementing the methods, including how to use partially informative markers and how to test candidate genes.

Chromosome Mapping↗
PubMed1994

Walk-through surveys for child labor.

Child labor is increasing in both developing and developed countries. Walk-through surveys were used to identify children, aged 8-15 years, working in six sites in Tel Aviv and Jerusalem, the largest cities in Israel. Of the 45 children who were interviewed, 20 were Jewish Israeli born, 19 were recent Jewish immigrants from the former Soviet Union, and six were Arabs from Judea, Samaria, and Gaza. The majority of children were either too young for employment, according to the Israeli Child Labor Laws, and/or receiving less than the legal minimum wage. Many were performing physical labor that might be expected to interfere with normal growth and development. Many of the children had visible signs of impaired physical health. Some were subjected to physical and/or verbal abuse. Walk-through surveys are recommended as a tool for routine use for surveillance of hazardous working conditions, case-finding, and evaluating the efficacy of preventive measures. The World Health Organization recommendations are emphasized to eliminate hazardous working conditions and to provide on-the-job health and social services to working children.

Adolescent↗