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Biomedical subjects

K Morgan

Publications and source records attributed to K Morgan.

At least 181 records · Page 10Linked to original sources
PubMed1994

Evidence for origin, by recurrent mutation, of the phenylalanine hydroxylase R408W mutation on two haplotypes in European and Quebec populations.

The R408W mutation in the phenylalanine hydroxylase gene (PAH) of phenylketonuria patients occurs on haplotypes 2.3 and 1.8 in Europeans. The mutation involves a CpG dinucleotide; nonetheless, a single recombination event might also explain the two haplotype associations. By analysis of an STR in the PAH gene 5' to the 408 codon and of the VNTR system in the 3' UTR, we identified unique features of the haplotype 1.8 chromosome harbouring the R408W mutation which are not accounted for by recombination. We conclude that recurrent mutation is the origin of R408W on different PAH haplotypes in Europeans.

Alleles↗
PubMed1994

The gene for hereditary breast-ovarian cancer, BRCA1, maps distal to EDH17B2 in chromosome region 17q12-q21.

A gene for hereditary breast and ovarian cancer, BRCA1, has been mapped to chromosome 17q12-q21. This gene is responsible for cancer susceptibility in the majority of families with multiple cases of ovarian cancer and early-onset breast cancer. We report linkage results of a family with 10 cases of breast cancer and a single case of ovarian cancer. A recombinant event in this family places BRCA1 distal (telomeric) to the locus EDH17B2, which codes for the enzyme estradiol 17 beta-dehydrogenase II. This recombinant is based on the appearance of breast cancer in a 45 year old woman. Under our genetic model, we estimate the probability that this woman carries a BRCA1 mutation to be 94%. These data further reduce the region of assignment of BRCA1 on chromosome 17q12-q21 and should expedite positional cloning of this important gene.

Adult↗
PubMed1994

The prevalence of serum IgG antibodies to type II collagen in American patients with rheumatoid arthritis.

Serum IgG antibody levels to native and denatured bovine type II collagen were elevated in 31.5 and 21.5% sera respectively from 200 American patients with RA. The prevalence of serum antibodies to native type II collagen is significantly higher than previously found in large studies of the prevalence of this autoantibody in Britain and Japan when using the same methodology.

Adult↗
PubMed1994

Identification of antibody epitopes in the CB-11 peptide of bovine type II collagen recognized by sera from arthritis-susceptible and -resistant rhesus monkeys.

Sera from eight rhesus monkeys that had been immunized with native bovine type II collagen were tested for antibodies to cyanogen bromide peptides (CB peptides) of type II collagen by Western blotting. The monkeys produced IgG antibodies to a number of different CB peptides, with five out of eight animals producing antibodies to the CB-11 peptide (four arthritic, one non-arthritic). Antibody epitopes on the CB-11 peptide of bovine type II collagen recognized by these sera were investigated by epitope mapping. Peptides (8-mers overlapping by seven amino acids) representing the CB-11 region were synthesised and the sera screened for binding to these peptides to determine areas of high IgG antibody binding to this region of type II collagen. The profiles obtained were not identical, though there were some epitopes that were commonly recognized. Antibodies to one epitope, also present in human type II collagen, were found only in the sera of two animals with the severest arthritis. The technique of epitope mapping has successfully identified a number of epitopes within the CB-11 peptide of type II collagen recognized by antibodies from bovine type II collagen-immunized monkeys. Studies on the relevance of responses to the identified epitopes can now be undertaken.

Amino Acid Sequence↗
PubMed1994

Hypnotic drugs, psychomotor performance and ageing.

This review examines studies, reported since 1976, in which the residual effects of hypnotic drugs on psychomotor performance have been evaluated in older people. The 33 studies involved a total of 934 subjects (aged 60-96 y), evaluated 21 different products, utilized 26 test procedures, and reported 169 drug versus placebo (or drug versus drug) comparisons, of which 42 were associated with significant residual impairment. While performance decrements were more associated with longer half-life drugs, repeated dosing, and frailty, these characteristics were often unreliable in predicting outcome. Significant improvements in performance were rare, and usually consistent with practice effects. While this literature provides a useful basis for clinical caution, it is not characterized by experimental rigour, and provides little or no empirical basis for predicting those real-life skills most likely to be affected. Issues of subject selection, experimental design, testing strategies, and data analysis need to be addressed if the risks and benefits of hypnotic drug use in later life are to be more clearly understood.

Journal Article↗
PubMed1994

Regulation of the alpha 1-antitrypsin gene and a disease-associated mutation in a related enhancer sequence.

Ten years ago a search was initiated for DNA variation in the alpha-1-antitrypsin gene (alpha 1-AT) to determine whether there were mutations more commonly associated with patients who had chronic obstructive airways disease (COAD) than with healthy individuals. Using the conventional approach of Southern blotting and searching for restriction fragment length polymorphisms, we identified a potentially useful polymorphism that resulted in the loss of a recognition site for the restriction enzyme, Taq I. The polymorphism occurred in about 17% of patients with COAD and about 5% of the general population (p = 0.0016). The normal sequence in the 3' flanking region of the alpha 1-antitrypsin gene had to be characterized, as it was not known. On the basis of homology, a number of closely clustered sequence motifs demonstrating the characteristics of an enhancer were identified that would potentially increase the transcription and expression of alpha 1-antitrypsin. The normal Taq I sequence occurred in a motif that demonstrated homology to a DNA sequence for octamer transcription factors. The mutation was characterized by in vitro amplification of the region and direct sequencing as a G to A transition (Taq I site TCGA < TCAA). Specific binding of nuclear proteins by gel-shift analysis and DNase I footprinting and increased in vivo transcriptional activity were demonstrated by transfection of mammalian cells containing DNA fragments corresponding to the region of interest. In contrast, the mutant sequence demonstrated loss of binding to nuclear proteins and reduced transcriptional activity. The latter finding was not confined to tissues known to express alpha 1-antitrypsin.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Longitudinal trends in prescribing for elderly patients: two surveys four years apart.

BACKGROUND: Elderly people are prescribed more drugs than younger people. The consequences of excessive or unwise prescribing, such as drug interactions, are well known. AIM: A longitudinal study was undertaken to examine levels and patterns of prescribed drug use among a group of elderly people. METHOD: Use of prescribed drugs by a sample of elderly people in Nottingham aged 65 years and over was assessed on two occasions four years apart, in 1985 and 1989. RESULTS: Complete drug data were available for 1003 respondents in 1985 and 662 respondents in 1989 (with attrition due mainly to mortality). Drug use increased significantly with age. Women took significantly more drugs than men. Approximately half of respondents were taking at least two drugs. The overall number of drugs per person being taken in 1989 was significantly greater than in 1985. This difference remained significant when age and mortality were controlled, suggesting that changes in drug use over time within this sample may reflect genuine changes in prescribing practice (rather than simply the effects of ageing). The most commonly prescribed drug classes on each occasion were drugs for the cardiovascular system, central nervous system, musculoskeletal system, gastrointestinal tract and respiratory system. The subgroups of drugs most commonly reported at each interview were diuretics, hypnotics and anxiolytics, analgesics and non-steroidal anti-inflammatory drugs. Drugs within the category 'hypnotics and anxiolytics' showed clear and differential trends over time, with the use of anxiolytics falling, while the use of hypnotics increased. Among those respondents admitted to residential care during the course of the study higher levels of psychotropic drug use, and an increase in antipsychotic medication, were observed. CONCLUSION: It is important that the drug regimens of elderly people are frequently reviewed to ensure that only the minimum number of effective drugs, in the simplest regimen, are prescribed.

Age Factors↗
PubMed1994

Volume of distribution and fractional clearance of urea in amputees on continuous ambulatory peritoneal dialysis.

OBJECTIVES: To demonstrate the effects of amputation on the estimates of urea volume of distribution (V) and KT/V urea in continuous ambulatory peritoneal dialysis (CAPD) patients and to present a method for correcting the errors created by the uncorrected anthropometric formulas estimating V. DESIGN: (1) A mathematical analysis of the error and the correction proposed was performed. (2) Urea kinetic modeling with uncorrected and corrected estimates utilizing both the Watson and the Hume anthropometric formulas was performed in amputees on CAPD. SETTING: Subjects were recruited from four dialysis units in one city: one Veterans Affairs unit, one university-affiliated unit, and two community units. PATIENTS: Fourteen amputees on CAPD:12 with unilateral leg amputation and 2 with bilateral leg amputation, at the same length of the leg, were studied. INTERVENTIONS: Urea kinetic studies were performed in 24-hour drained dialysate and urine specimens. MAIN OUTCOME MEASURES: Uncorrected and corrected estimates of V and KT/V urea were compared to each other and to the predictions of the mathematical model. Body weights corresponding to uncorrected and corrected V estimates were compared to the actual body weights. RESULTS: (1) The mathematical model predicts that uncorrected estimates by the anthropometric formulas will falsely characterize unilateral amputees as leaner than they are and bilateral amputees as more obese than they are. (2) In unilateral amputees studied with the Watson formulas, uncorrected V was 0.546 +/- 0.023 L/kg and corrected V was 0.520 +/- 0.023 L/kg (p < 0.001). Corresponding weekly KT/V urea values were 1.97 +/- 0.14 and 2.07 +/- 0.14, respectively (p < 0.001). Similar results were obtained with the Hume formulas. In bilateral leg amputees studied with the Watson formulas, uncorrected V was 0.479 +/- 0.022 L/kg and corrected V was 0.514 +/- 0.023 L/kg. Corresponding KT/V estimates were 2.11 +/- 0.45 and 1.96 +/- 0.14, respectively. The differences were even greater with the Hume formulas. Estimates of body weight calculated from corrected V values were equal to actual weight measurements, whereas those calculated from uncorrected V values were lower than actual body weight measurements in unilateral amputees, and much higher than actual body weight measurements in bilateral amputees. CONCLUSION: Uncorrected anthropometric estimates falsely characterize unilateral amputees as leaner than they actually are and bilateral amputees, amputated at the same leg length, as more obese than they actually are. Uncorrected KT/V estimates are, therefore, falsely low in unilateral amputees, and falsely high in bilateral amputees. The proposed correction of the anthropometric formulas provides estimates agreeing closely with dietary estimates of body composition. Further studies are needed to define the accuracy of the corrected formulas.

Aged↗
PubMed1994

Co-expression of renin-angiotensin system component genes in human atrial tissue.

OBJECTIVES: To detect co-expression of genes coding for components of the renin-angiotensin system and investigate the potential for variation in the level of angiotensin converting enzyme (ACE) gene expression in the right atrial appendage of patients undergoing heart surgery. DESIGN: The right atrial appendage was collected at the time of surgery from 30 randomly chosen patients and was rapidly frozen in liquid nitrogen prior to extraction of messenger (m)RNA. Surgical samples of heart valve (n = 6) and papillary muscle (n = 3) were also examined. METHODS: Aliquots of purified mRNA were reverse-transcribed for analysis of gene expression by a polymerase chain reaction amplification assay. Primers specific for angiotensinogen, renin, ACE, cardiac chymase, atrial natriuretic peptide, glyceraldehyde-3-phosphate dehydrogenase, adenosine deaminase and the transferrin receptor were used for a qualitative analysis of co-expression of these genes within the same sample. In a subgroup of eight patients, a quantitative comparison of the relative levels of ACE gene expression was performed using a competitive polymerase chain reaction. RESULTS: Angiotensinogen and ACE expression were detected in all atrial, valve and ventricular samples examined, at levels similar to those of 'housekeeping' genes such as the transferrin receptor. Atrial renin and chymase expression were more difficult to detect, being demonstrable in only 70 and 63% of the samples, respectively. Higher levels of chymase were detected in ventricular samples than in atrial tissues. A quantitative analysis of ACE expression in eight atrial samples provided evidence of interindividual variation in the relative level of atrial ACE expression. CONCLUSIONS: The essential components of the renin-angiotensin system are co-expressed at a low level in the right atrial appendage and are detectable in other regions of the human heart. Renin and chymase genes are expressed at a lower level than the angiotensinogen and ACE genes and exhibit regional differences in expression. Interindividual variation in the relative level of ACE expression can be detected by a competitive polymerase chain reaction.

Angiotensinogen↗
PubMed1994

Association between Ag1-CA alleles and severity of autosomal recessive proximal spinal muscular atrophy.

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has been mapped to an 850-kb interval on 5q11.2-q13.3, between the centromeric D5S823 and telomeric D5S557 markers. We report a new complex marker, Ag1-CA, that lies in this interval, whose primers produce one, two, or rarely three amplification-fragment-length variants (AFLVs) per allele. Class I chromosomes are those which amplify a single AFLV allele, and class II chromosomes are those which amplify an allele with two or three AFLVs. Ag1-CA shows highly significant allelic association with type I SMA in both the French Canadian (Hôpital Sainte-Justine [HSJ]) and American (Ohio State University [OSU]) populations (P < .0001). Significant association between the Ag1-CA genotype and disease severity was also observed. Type I patients were predominantly homozygous for class I chromosomes (P = .0003 OSU; P = .0012 HSJ), whereas the majority of type II patients were heterozygous for class I and II chromosomes (P = .0014 OSU; P = .001 HSJ). There was no significant difference in Ag1-CA genotype frequencies between type III patients (P = .5 OSU; P = .25 HSJ) and the paired normal chromosomes from both carrier parents. Our results indicate that Ag1-CA is the most closely linked marker to SMA and defines the critical candidate-gene region. Finally, we have proposed a model that should be taken into consideration when screening candidate SMA genes.

Alleles↗
PubMed1994

Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration.

Corticobasal degeneration (CBD) is a neurodegenerative disorder associated with extensive cytoskeletal abnormalities. These include tau-positive neuropil threads and grains, ballooned or swollen neurons, neurofibrillary tangles, and glial inclusions. Given the presence of tau-positive structures in CBD, we investigated whether abnormalities in tau proteins associated with CBD were similar to those in Alzheimer's disease (AD). Fractions of abnormal tau proteins were isolated as Sarkosyl-insoluble pellets. By electron microscopic examination, the fraction from CBD contained twisted filaments that differed from paired helical filaments of AD. In CBD, filaments were shorter in length, rarely longer than 400 nm, 10 to 20% wider in the maximum and minimum widths (26 to 28 nm and 13 to 14 nm, respectively), and the periodic twist (169 to 202 nm) was twice as long as that in AD. Immunogold labeling with a panel of tau-reactive antibodies (Alz 50, Tau 14, AH-1, E-11, PHF-1, and Tau 46) showed no apparent differences in the pattern of tau immunoreactivity between filaments of CBD and AD. Western blots revealed that polypeptides of abnormal tau were present in both fractions; however, only two polypeptides (68 and 64 kd) were present in CBD as compared with three (68, 64, and 60 kd) in AD. Both of these polypeptides were reactive with additional antibodies (E-9, Tau-1 after dephosphorylation, AT8, and NP8). Only one polypeptide (68 kd) bound an antibody to adult-specific tau sequence encoded by exon 2, but neither was reactive with antibodies to adult-specific sequences encoded by exons 3 and 10. The results suggest that abnormalities in the number and heterogeneity of isoforms of tau may be one of the factors contributing to ultrastructural differences in pathological filaments of CBD and AD.

Aged↗
PubMed1993

Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a disorder that has an elevated frequency in Saguenay-Lac-St-Jean (SLSJ) and Charlevoix, two geographically isolated regions in the past of northeastern Quebec. The incidence at birth and the carrier rate in SLSJ were estimated at 1/1,932 liveborn infants and 1/22 inhabitants, respectively, for the period 1941-1985. The mean inbreeding coefficient was twice higher and the mean kinship coefficient 3 times higher among the ARSACS families than among control families. In the SLSJ region, the birth places of the ARSACS individuals and their parents did not show a clustered distribution. The genealogical reconstruction suggests that the high incidence of ARSACS in SLSJ and Charlevoix is likely to be the result of a founder effect. Because the disease is apparently unknown elsewhere in the world and a high proportion of French Canadians presently living in eastern Quebec have ancestors coming from Perche, a small region in France, it also suggests that a unique mutation accounts for most, if not all, of the ARSACS cases known in these regions.

Consanguinity↗
PubMed1993

Molecular characterization of an intragenic minisatellite (VNTR) polymorphism in the human parathyroid hormone-related peptide gene in chromosome region 12p12.1-p11.2.

The human parathyroid hormone-related peptide (hPTHrP) gene in chromosome region 12p12.1-p11.2 plays an important role in mammalian development and specifically in skeletogenesis. We have characterized a VNTR polymorphism in the hPTHrP gene that is located in an intron 100-bp downstream of exon VI that encodes a 3' untranslated region. By PCR analysis eight different alleles were identified in a group of 112 unrelated individuals. All eight alleles were sequenced and the repeat unit was identified as the general sequence [G(TA)nC]N, where n = 4 to 11 and N = 3 to 17. This polymorphic sequence-tagged site will be useful for mapping chromosome 12p and will aid in testing for linkage of genetic diseases to the hPTHrP gene.

Alleles↗
PubMed1993

The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer.

The gene for insulin-like growth factor-binding protein 4 (IGFBP4) codes for a serum protein that binds to the family of insulin-like growth factors and modulates their activity. It has been mapped by in situ hybridization to chromosome region 17q12-q21.1. We have developed a CA-repeat polymorphism from a cosmid clone containing IGFBP4. By linkage analysis, IGFBP4 maps to the chromosome 17q interval THRA1-D17S579. This interval also contains the gene for hereditary breast-ovarian cancer, BRCA1. Genetic recombination between IGFBP4 and BRCA1 places IGFBP4 centromeric to the cancer susceptibility gene and effectively excludes it as a candidate gene for BRCA1. IGFBP4 is, however, one of the closest known centromeric markers for BRCA1; the estimated recombination fraction is 0.015. IGFBP4 and D17S579 together define a 2.8-cM interval that contains BRCA1.

Base Sequence↗