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Biomedical subjects

N E Simpson

Publications and source records attributed to N E Simpson.

At least 55 records · Page 3Linked to original sources
PubMed1987

Linkage studies of Friedreich ataxia by means of blood-group and protein markers.

Friedreich ataxia (FA) is an autosomal recessive, neuro-degenerative disorder in which the pathogenetic mechanism remains unidentified despite extensive biochemical studies. Genetic-linkage studies provide an alternative approach to determining the basic defect. Linkage analysis between FA and 36 polymorphic-blood-group and protein markers has been carried out on three separate patient populations--16 families from the inbred Acadian population of Louisiana, 21 French-Canadian families from Quebec, and nine apparently unrelated British families--in an attempt to determine the chromosomal location of the disease mutation. Neither evidence of linkage to any of the markers investigated nor heterogeneity among the populations was found for any of the comparisons. The negative lod scores exclude the locus for FA from greater than 20% of the genome.

Blood Group Antigens↗
PubMed1986

The effect of method of infection on the pathway of juvenile Strongyloides ratti in the host.

Subcutaneous injection of the larvae is the almost universally adopted means of initiating experimental infections of skin-invading roundworms but, so far, the possibility that this procedure introduces artefacts of one kind or another has not been critically studied. Experiments described in this paper were used to compare the effect of (a) injection and (b) skin application, of a small, precisely counted ('exact') dose of larvae. Results with two strains of S. ratti showed that the same proportion of the dose developed to adults in the intestines of rats irrespective of the method. With the same exact dose technique it has been shown that milk-borne infection of the pups of lactating rats is not an artefact produced by injection. Large doses (mean 4000) of larvae of the homogonic strain of S. ratti carrying a radioactive label of 75Se were tracked in their migration to the mammary gland following injection or skin application at two different sites on the right-hand side of nursing mother rats. The broad conclusion of earlier work in this laboratory using injection, that larvae move by a local route and not a systemic one, was supported by the results. The detailed distribution of the label and of unlabelled worms of the heterogonic strain in families was, however, different for the two methods, indicating that subtle variations in pathway can be brought about by the use of injection. If migration involves the lymphatic system, then the interpretation of immunological experiments in terms of lymphatic anatomy must take account of such procedural effects. The extent to which these results contribute to theories of migration in Strongyloides ratti is discussed.

Anesthesia↗
PubMed1986

Regional localization of 18 human X-linked DNA sequences.

A series of human probes with unique sequences has been isolated from a recombinant phage library constructed with DNA obtained from a human-hamster hybrid cell line. This cell line contained the X chromosome as the only human component. For 18 of these probes, a human X-chromosome origin has been confirmed and they have been regionally assigned by a combination of techniques: dosage studies utilizing DNA from human fibroblasts carrying X-chromosome duplications and deletions; the presence or absence of hybridization to digested DNA from hybrid lines carrying fragments of the X chromosome; and in situ hybridization to metaphase chromosomes. The use of dosage as a means to regionally assign probes significantly improves resolution of the X chromosome.

Animals↗
PubMed1986

Localization of X-linked dominant Charcot-Marie-Tooth disease (CMT 2) to Xq13.

A family is described in which Charcot-Marie-Tooth disease is inherited as an X-linked dominant mutation (CMT2). Ten DNA marker loci on the X chromosome were used to map the disease locus by linkage analysis. The DXYS1 sequence at Xq13 was found to be linked to the CMT2 locus at an estimated distance of 6 cM (Zmax = 2.87 at theta max = 0.06). The data also suggested close linkage of the CMT2 locus to PGK1 (Zmax = 1.51 at theta max = 0) which has also been mapped to Xq13. Another DNA locus (DXS3), in the Xq21.3----Xq22 region, did not show close linkage (Zmax = -2.231 at theta max = 0.01). We conclude that the CMT2 locus is probably in or close to band Xq13.

Charcot-Marie-Tooth Disease↗
PubMed1985

The genetic distance between the coagulation factor IX gene and the locus for the fragile X syndrome: clinical implications.

In 3 families with the fragile-X [fra(X)] syndrome, we have identified a minimum of 4 recombinations in 9 meioses between the syndrome locus and the coagulation Factor IX gene. Two Factor IX intragenic restriction fragment length polymorphisms (RFLPs), produced with TaqI and XmnI, were used as markers. In lod score calculations, incomplete penetrance of the fra(X) mutation in males and females was taken into account by the computer program LIPED. The cumulative maximum lod score calculated from these data and from data previously reported was 2.75 at a recombination frequency of 20% (theta = 0.20). This indicates that the genetic distance between the Factor IX gene and the fra(X) locus is too great for Factor IX probes to be used alone for carrier detection in the fra(X) syndrome. Additional polymorphic loci more tightly linked to the fra(X) syndrome locus are required.

Factor IX↗
PubMed1985

Linkage analysis of a DNA marker localized to 20p12 and multiple endocrine neoplasia type 2A.

A DNA segment D20S5 isolated from a chromosome 19/20 flow-sorted library was shown to identify two restriction fragment length polymorphisms (RFLPs) with MspI and PvuII. The probe was localized by hybridization in situ to 20p12, the putative site of an interstitial deletion in some MEN 2A and 2B patients. Linkage of the D20S5 and MEN 2A loci was excluded at theta less than or equal to .13 using two large MEN 2A kindreds. These data suggest that the MEN 2A locus may not lie within 20p12 as previously suggested.

Chromosome Mapping↗
PubMed1985

Genetic mapping of DNA segments relative to the locus for the fragile-X syndrome at Xq27.3.

We have tested linkage between the locus for the fragile-X [fra(X)] syndrome at Xq27.3 and five polymorphic restriction sites identified by four DNA probes mapping distal to Xq26.1. A maximum distance of approximately 15 centimorgans (cM) between Xq27.3 and the marker loci mapping to this region was predicted based on the physical chromosome length. Close linkage between the disease and marker loci was excluded for probes DXS19 and DXS37 (theta = .05, Z = -2.94 and Z = -4.17, respectively). These marker loci were estimated to be less than five cM apart but approximately 40 cM proximal to the fragile site, indicating that there is a significantly greater frequency of recombination in this region of the X chromosome than expected from the physical length. Linkage results for the other marker loci and the fra(X) syndrome were inconclusive. However, the pX45d probe locus appears very closely linked to the factor IX locus (Z = 1.94 at theta = 0) and is approximately 20 cM proximal to Xq27.3. A relative map of the polymorphic restriction sites, fra(X) syndrome locus, and factor IX locus was constructed by maximizing lod scores over the Xq26.1----q27.3 region.

Animals↗
PubMed1984

Fragile-X syndrome III: dermatoglyphic studies in males.

Dermatoglyphics of 39 males with the fragile-X syndrome were compared with those of 3 groups of control subjects; 497 school boys, 15 males with non-specific mental retardation, and 15 with Down syndrome. Compared with the control males, there was an increased frequency of radial loops, whorls, and arches on the fingers and of third interdigital patterns and abnormal creases on the hands, and a decreased frequency of ulnar loops and fourth interdigital patterns in the patients with the fragile-X syndrome. The mean a-b ridge count was lower than in controls and there were more patients than controls with an a-b ridge count less than 70. All of these differences were significant at p less than 0.01. There was no differences between patients and controls with respect to total ridge count on the fingers and the dermatoglyphics in other areas of the hands or feet. From this small study a preliminary index was developed that attempts to distinguish male patients with the fragile-X syndrome from normal male controls and males with non-fragile-X forms of mental retardation. The patterns on the left and right third fingers, the a-b ridge count, and the palmar creases were used in the index. Sixty-four % of patients with the fragile-X syndrome would be selected out if greater than or equal to + 0.5 was used as the criterion and 90% of these males would be expected to have the fragile-X chromosome.

Adolescent↗
PubMed1983

Suggested assignment of peptidase S (PEPS) to 4p11-4q12 by exclusion using gene dosage, accounting for variability in fibroblasts.

A colorimetric assay using leucyl-beta-napthylamide hydrochloride as substrate and fast garnet GBC as the color reagent was developed for these regional mapping studies of peptidase S (PEPS). PEPS activity was measured in white blood cells from three patients with Wolf-Hirschhorn syndrome (4p-) and 50 controls. The enzyme activity of the three patients, mean 0.097 +/- 0.060 (SD) did not exhibit a significant dosage effect compared to the controls, mean 0.125 +/- 0.060 (SD) mIU/mg protein. Peptidase activity was compared among five fibroblast control lines and eight lines with chromosome 4 aberrations. There was no significant difference found among the 128 samples from aberrant lines, mean of partial monosomies = 0.095 +/- 0.049 (SD) and mean of partial trisomies = 0.084 +/- 0.046 (SD) and the 79 samples from control lines, mean = 0.092 +/- 0.043 (SD) mIU/mg protein. Degree of confluence, site of biopsy, and sex and age of donor did not affect PEPS activity in fibroblasts but generation number did (r = 0.367, P = 0.001). No gene dosage was found in the white blood cells or fibroblast lines studied. The locus for PEPS is therefore mapped to 4p11 leads to 4q13 by exclusion. Combining these data with those previously reported, the suggested assignment for the PEPS locus is the 4p11 leads to 4q12 segment of chromosome 4.

Abnormalities, Multiple↗
PubMed1983

HLA haplotype segregation in families of type 1 diabetics.

The hypothesis of linkage between HLA and a disease susceptibility (DS) locus (or loci) for type 1 diabetes was tested. HLA segregation was random among 57 non-diabetic sibs but not among 39 diabetic sibs, suggesting that susceptibility to type 1 diabetes may be due to an HLA-linked gene(s). The data did not fit a genetic model involving either a single recessive or dominant gene. The excess of HLA-identical diabetic sibs and the reduced number who were HLA-discordant compared to expected numbers indicated that factors from both paternal and maternal haplotypes were necessary for DS. In 1 of the 3 families with a diabetic parent and more than one diabetic sib, the diabetic sibs inherited different haplotypes from the affected parent, suggesting that either of these haplotypes conferred DS. HLAB 8, B 18 and B 40 were increased in frequency among 97 unrelated type 1 diabetics compared with 238 controls, especially among those with onset age less than 10 years. This early onset group may represent a subtype of type 1 diabetes.

Adolescent↗
PubMed1983

Prenatal diagnosis of neural tube defects using the cholinesterases.

The usefulness of a cholinesterase assay and electrophoresis in the prenatal diagnosis of neural tube defects was investigated in amniotic fluids from 1,512 women. The assay used a alpha-naphthyl acetate as substrate and measured the combined activity of the enzymes acetylcholinesterase (AChE, E.C. 3.1.1.7) and cholinesterase (ChE, E.C. 3.1.1.8); the activity of both enzymes was raised in amniotic fluid from women carrying open NTDs. The alpha-naphthyl acetate assay distinguished fetuses with neural tube defects from normal fetuses more effectively than assays using acetylthiocholine as substate. A perfect score could be obtained on the sample tested when both enzyme assay and electrophoresis were done on those samples with activity greater than or equal to 4 mU. There was no correlation between gestational age between 13-21 weeks and activity of AChE + ChE (r = 0.03). The electrophoretic band of AChE activity proved to be a valuable diagnostic adjunct to both AFP or the AChE + ChE assay. A similar band or AChE activity was seen in adult brain and intestine but not in kidney, heart, liver, or lung, or in sera from women carrying normal or NTD fetuses.

Amniotic Fluid↗
PubMed1982

Measurement of cholinesterases in amniotic fluid using alpha naphthyl acetate as substrate: a possible initial test for prenatal diagnosis of open neural tube defects.

A quantitative method for cholinesterases in amniotic fluid using the non-specific substrate alpha naphthyl acetate and the cholinesterase-specific inhibitor, eserine, is described. This assay was used to test 671 samples of amniotic fluid. The diagnoses for fetal ONTDs, based on the levels of AChE + ChE, were compared with those made for the same samples by the AFP method. Correct diagnoses were made by both methods with amniotic fluid from 35 women carrying fetuses with ONTDs and 631 carrying normal fetuses. There were five false-positive test results for normal fetuses by both methods when the cut-off points were 5 standard deviations above the mean for AFP and above the upper limit of the normal range (7.5 milliunits) for cholinesterase (AChE + ChE). None of the false-positive samples from either method had the acetylcholinesterase band of activity characteristic of ONTDs after gel electrophoresis. In addition to the above 671 samples, 37 pregnancies with serious fetal abnormalities other than ONTDs were tested. Two were identified by both the AFP and AChE + ChE methods, two more by AFP assay and one other by the AChE + ChE assay.

Acetylcholinesterase↗
PubMed1982

The incidence of type 1 (insulin-dependent) diabetes in Toronto.

An incidence of 9.0 out of 100,000 children under 19 years of age with Type 1 (insulin-dependent) diabetes was detected in Toronto during a 2 year prospective study. An increased number of cases occurred in the winter months of one of the years but not of the other during the study. The annual incidence was the same in each year. There were slightly more boys than girls but this was not significant. The diabetic children were significantly younger than their non-affected siblings. The incidence of Type 1 diabetes in Toronto is similar to other North American studies.

Adolescent↗