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Biomedical subjects

K Morgan

Publications and source records attributed to K Morgan.

At least 235 records · Page 13Linked to original sources
PubMed1991

Kinetic abnormalities of the red blood cell sodium-proton exchange in hypertensive patients.

The present study was designed to examine the kinetics of Na(+)-H+ exchange in red blood cells of normotensive and hypertensive subjects and its relation to the previously reported abnormalities in Na(+)-Li+ exchange. The Na(+)-H+ antiporter activation kinetics were studied by varying cell pH and measuring net Na+ influx (mmol/l cell x hr = units) driven by an outward H+ gradient. The Na(+)-Li+ exchange was determined at pH 7.4 as sodium-stimulated Li+ efflux. Untreated hypertensive patients (n = 30) had a higher maximal rate of Na(+)-Li+ exchange (0.43 +/- 0.05 versus 0.26 +/- 0.02 units, p less than 0.0003), a higher maximal rate of Na(+)-H+ exchange (62.3 +/- 6.2 versus 47 +/- 4 units; p less than 0.02), but a similar affinity for cell pH compared with normotensive subjects (n = 46). The cell pH activation of the Na(+)-H+ antiporter exhibited a lower Hill coefficient than that of normotensive subjects (1.61 +/- 0.12 versus 2.56 +/- 0.14; p less than 0.0001). This index of occupancy of internal H+ regulatory sites was found reduced in most of the hypertensive patients (73%) whether their hypertension was untreated or treated. Hypertensive patients with Na(+)-Li+ exchange above 0.35 units (0.68 +/- 0.057 units, n = 16) did not exhibit elevated maximal rates of Na(+)-H+ exchange (57.3 +/- 10 units, NS) in comparison with those with Na(+)-Li+ exchange below 0.35 units (66.4 +/- 7.6 units, n = 26), but both groups exhibited reduced Hill coefficients. Hypertensive patients with enhanced Na(+)-H+ exchange activity (more than 90 units) had normal maximal rates of Na(+)-Li+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Identification of antibody epitopes within the CB-11 peptide of type II collagen. I: Detection of antibody binding sites by epitope scanning.

Using epitope scanning, the precise location of antibody binding sites on the CB-11 peptide of bovine type II collagen have been identified for the first time. Two hundred and seventy two peptides (8 amino acids in length and overlapping by seven amino acids), representing the complete CB-11 sequence, were synthesised on solid phase supports, in duplicate, and were screened with sera from arthritic and non-arthritic, bovine type II collagen-immunised rats. A total of twenty one different antibody binding sites were identified with no epitope being uniquely recognised by sera from arthritic, as compared to non-arthritic, rats although differences in the relative amount of antibody binding were seen. Individual sera identified between two and thirteen epitopes with one epitope being recognised by all sera. Some of the amino acid sequences, of the CB-11 region of bovine type II collagen, recognised by the rat sera are identical to the sequences in human type II collagen and thus these epitopes may be relevant to autoimmunity to type II collagen in patients with rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1991

Identification of antibody epitopes within the CB-11 peptide of type II collagen. II. Computer modelling studies of peptides and the interpretation of epitope scanning results.

Computer modelling techniques were used to investigate the structure of 8-mers from the CB-11 peptide of bovine type II collagen which were recognised by sera from rats which had previously been injected with bovine type II collage. It was discovered that all the hydrophobic peptides recognised by the rat sera were predicted to have collagenous-like secondary structures. The primary structure of the 8-mers which were recognised was also compared against the sequences in the OWL protein sequence database. The combined results of the computer modelling and sequence analysis suggested that the sequence Gly-Pro-Gly-Phe-Pro is a minimal B cell epitope of the CB-11 fragment of bovine type II collagen.

Amino Acid Sequence↗
PubMed1990

Identification of deletion and triple alpha-globin gene haplotypes in the Montreal beta-thalassemia screening program: implications for genetic medicine.

We obtained blood samples in a screening program designed to detect beta-thalassemia heterozygotes in Montreal; additional samples were obtained from referred persons. We analyzed DNA for variant numbers of alpha-globin genes, notably the alpha-thalassemia2 (-alpha/), alpha-thalassemia1, (- -/), and triplicated alpha-globin gene (alpha alpha alpha/) haplotypes using restriction enzymes and probes for alpha-globin and zeta-globin gene sequences. We estimated the numbers of Montreal residents of Italian and Greek ethnic origin with -alpha/alpha alpha genotype. Thus, 4.3% of Italians and 1.5% of Greeks, or about 7,500 persons, are estimated to be alpha-thalassemia2, trait (silent carriers), largely (80%) in the -alpha 3.7/type I form. The triplicated alpha-globin gene haplotype was also found. The risk of a severe (alpha-thalassemia1) phenotype associated with inheritance of - -/alpha alpha or -alpha/-alpha genotypes was low and was found predominantly in this study, in persons of Asian ethnic origin. The sample of Asians was too small to estimate carrier frequencies; however, based on results from the beta-thalassemia screening program, we estimated that about 4% of Asians (about 1,300 persons) in Montreal are alpha-thalassemia carriers. We identified persons heterozygous for both beta-thalassemia and alpha-thalassemia mutations. In these double heterozygotes, the effect of the triplicated alpha-globin gene was to make the erythrocyte parameters used for screening (MCV and %HbA2) more deviant from normal whereas deletion of 2 alpha-globin genes tended to normalize the erythrocyte values. These findings have implications for the screening program and reproductive counseling.

Adolescent↗
PubMed1990

Dental agenesis in the Dariusleut Hutterite Brethren: comparisons to selected Caucasoid population surveys.

We report the results of a study of the prevalence of nonsyndromic dental agenesis among a sample of 208 individuals (105 females, 103 males) between the ages of 15 and 29 years from a North American religious and genetic isolate, the Dariusleut Hutterites of Western Canada. Direct examination of dental casts, oral examination reports, dental treatment records, and a limited number of dental radiographs reveals congenital absence and/or obvious morphometric reduction of at least one tooth (excluding third molars) in 98 subjects (55 females, 43 males), yielding a prevalence estimate of approximately 47%. This estimate is nearly four times those reported for nonisolate Caucasoid populations of European descent and substantially higher than the elevated prevalences observed in several other isolated populations. Although the prevalence of dental agenesis in the Dariusleut is indeed high, neither the incidence of bilateral agenesis (exhibited at least once in 58% of affected dentitions), number of affected teeth per person (mean, 2.4), morphologic tooth classes affected, or combinations of tooth classes affected ostensibly distinguish them from other populations with similar geographic origins. We conclude that the dental agenesis observed in this North American genetic isolate does not represent a private polymorphism or rare developmental variant. Consequently, the results of further study in these Dariusleut Brethren will be directly relevant to critically testing as yet unresolved hypotheses for the mode of gene action and the relative contributions of hereditary and environmental factors to the reduction of tooth numbers in human dentitions.

Adolescent↗
PubMed1990

Interactions of external and internal H+ and Na+ with Na+/Na+ and Na+/H+ exchange of rabbit red cells: evidence for a common pathway.

We have studied the kinetic properties of rabbit red cell (RRBC) Na+/Na+ and Na+/H+ exchanges (EXC) in order to define whether or not both transport functions are conducted by the same molecule. The strategy has been to determine the interactions of Na+ and H+ at the internal (i) and external (o) sites for both exchanges modes. RRBC containing varying Nai and Hi were prepared by nystatin and DIDS treatment of acid-loaded cells. Na+/Na+ EXC was measured as Nao-stimulated Na+ efflux and Na+/H+ EXC as Nao-stimulated H+ efflux and delta pHo-stimulated Na+ influx into acid-loaded cells. The activation of Na+/Na+ EXC by Nao at pHi 7.4 did not follow simple hyperbolic kinetics. Testing of different kinetic models to obtain the best fit for the experimental data indicated the presence of high (Km 2.2 mM) and low affinity (Km 108 mM) sites for a single- or two-carrier system. The activation of Na+/H+ EXC by Nao (pHi 6.6, Nai less than 1 mM) also showed high (Km 11 mM) and low (Km 248 mM) affinity sites. External H+ competitively inhibited Na+/Na+ EXC at the low affinity Nao site (KH 52 nM) while internally H+ were competitive inhibitors (pK 6.7) at low Nai and allosteric activators (pK 7.0) at high Nai. Na+/H+ EXC was also inhibited by acid pHo and allosterically activated by Hi (pK 6.4). We also established the presence of a Nai regulatory site which activates Na+/H+ and Na+/Na+ EXC modifying the affinity for Nao of both pathways. At low Nai, Na+/Na+ EXC was inhibited by acid pHi and Na+/H+ stimulated but at high Nai, Na+/Na+ EXC was stimulated and Na+/H+ inhibited being the sum of both pathways kept constant. Both exchange modes were activated by two classes of Nao sites, cis-inhibited by external Ho, allosterically modified by the binding of H+ to a Hi regulatory site and regulated by Nai. These findings are consistent with Na+/Na+ EXC being a mode of operation of the Na+/H+ exchanger. Na+/H+ EXC was partially inhibited (80-100%) by dimethyl-amiloride (DMA) but basal or pHi-stimulated Na+/Na+ EXC (pHi 6.5, Nai 80 mM) was completely insensitive indicating that Na+/Na+ EXC is an amiloride-insensitive component of Na+/H+ EXC. However, Na+ and H+ efflux into Na-free media were stimulated by cell acidification and also partially (10 to 40%) inhibited by DMA; this also indicates that the Na+/H+ EXC might operate in reverse or uncoupled modes in the absence of Na+/Na+ EXC.(ABSTRACT TRUNCATED AT 400 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1990

Na+/H+ exchange is increased in sickle cell anemia and young normal red cells.

Red cell volume regulation is important in sickle cell anemia because the rate and extent of HbS polymerization are strongly dependent on initial hemoglobin concentration. We have demonstrated that volume-sensitive K:Cl cotransport is highly active in SS whole blood and is capable of increasing MCHC. We now report that Na+/H+ exchange (Na/H EXC), which is capable of decreasing the MCHC of erythrocytes with pHi less than 7.2, is also very active in the blood of patients homozygous for HbS. The activity of Na/H EXC (maximum rate) was determined by measuring net Na+ influx (mmol/liter cell.hr = FU) driven by an outward H+ gradient in oxygenated, acid-loaded (pHi6.0), DIDS-treated SS cells. The Na/H EXC activity was 33 +/- 3 FU (mean +/- SE) (n = 19) in AA whites, 37 +/- 8 FU (n = 8) in AA blacks, and 85 +/- 15 FU (n = 14) in SS patients (P less than 0.005). Separation of SS cells into four density-defined fractions by density gradient revealed mean values of Na/H EXC four to five times higher in reticulocytes (SS1), discocytes (SS2) and dense discocytes (SS3), than in the fraction containing irreversibly sickled cells and dense discocytes (SS4). In contrast to K:Cl cotransport, which dramatically decreases after reticulocyte maturation, Na/H EXC persists well after reticulocyte maturation. In density-defined, normal AA red cells, Na/H EXC decreased monotonically as cell density increased. In SS and AA red cells, the magnitude of stimulation of Na/H EXC by cell shrinkage varied from individual to individual.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Sickle Cell↗
PubMed1990

Mapping of Col3a1 and Col6a3 to proximal murine chromosome 1 identifies conserved linkage of structural protein genes between murine chromosome 1 and human chromosome 2q.

We have investigated the degree of synteny between the long arm (q) of human chromosome 2 and the proximal portion of mouse chromosome 1. To define the limits of synteny, we have determined whether mouse homologs of seven human genes mapping to chromosome 2q cosegregated with anchor loci on mouse chromosome 1. The loci investigated were NEB/Neb, ELN/Eln, COL3A1/Col3a1, CRYG/Len-2, FN1/Fn-1, VIL/Vil, and COL6A3/Col6a3. Ren-1,2 and Acrg were included as two proximal mouse chromosome 1 anchor loci. The segregation of restriction fragment length polymorphisms at these loci was analyzed in the progeny of Mus spretus x C57BL/6J hybrids backcrossed to the C57BL/6J inbred strain. We found that five of the structural protein loci and the two anchor loci form a linkage group on proximal murine chromosome 1. The proposed gene order of this group of linked markers is centromere - Col3a1 - Len-2-Fn-1-Vil-Acrg-Col6a3-Ren1,2. Neb and Eln are linked neither to each other nor to any other marker on proximal mouse chromosome 1. Therefore, the mouse loci Col3a1 and Col6a3 are identified as flanking markers of the linkage group of structural protein loci. The estimated genetic map distances are Col3a1-13.3 cM-Len-2-3.4 cM-Fn-1-3.8 cM-Vil-9.6 cM-Acrg-2.1 cM-Col6a3-18.3 cM-Ren1,2. The available map information for human chromosome 2q markers and mouse chromosome 1 markers presented here tentatively identifies Col3a1 and Col6a3 as the border markers that define the limits of the syntenic chromosome segment. The order of mouse genes on chromosome 1 and their human homologs on chromosome 2q also appears to be conserved, suggesting that mapping of murine genes on the conserved segment may be useful to predict gene order in man.

Animals↗
PubMed1990

Diversity of antibodies to type II collagen in patients with rheumatoid arthritis: detection by binding to alpha-chains and to cyanogen bromide peptides.

Antibodies to denatured type II collagen were detected in the sera of a group of patients with rheumatoid arthritis by ELISA and by immunoblotting. The antibodies were further examined by immunoblotting against cyanogen-bromide derived peptides of type II collagen. The majority of sera reacted against only one or two peptides and antibodies to the CB-10 and CB-11 peptides were those most commonly found. However, some sera reacted with up to eight peptides, indicating that patients had antibodies to differing combinations of epitopes on type II collagen. Examination of sequential serum samples from an individual patient showed that there were changes in the class of antibody produced to type II collagen and that antibodies to different peptides were preferentially produced at different times in the course of the disease. Thus there was a selective response to different peptides of type II collagen not only between patients but also at different times in the course of disease in the same patient.

Antibodies↗
PubMed1990

Hypnotics in the elderly. What cause for concern?

At any age hypnotic drug use can give rise to 3 major problems: unwanted effects on daytime mood and behaviour associated with drug consumption; rebound effects associated with drug withdrawal; and dependency associated with long term drug use. For 2 reasons elderly hypnotic users are both more vulnerable and more exposed to each of these problems. Firstly, age-related changes in pharmacodynamic and pharmacokinetic processes amplify the behavioural impact of many hypnotics; and secondly, age-related changes in the structure and quality of sleep tend to increase the demand for, and the long term use of, sedative hypnotic compounds in old age. The existence of physical illness, cognitive impairment, or daytime behaviour already compromised by normal aging processes further increases the likelihood of hypnotic drugs detrimentally affecting well-being in later life. These important causes for concern emphasise the need for 2 separate clinical responses: the need for greater circumspection in the choice and use of hypnotic drugs among elderly patients, and the need for a more broadly based clinical approach to the management of sleep problems in old age.

Aged↗
PubMed1990

Proliferative fascitis in childhood: a case report.

A case of proliferative fascitis in the forearm of a 7-year-old child is presented. The lesion is composed of spindle cells and large bizarre ganglionlike cells in a collagenous matrix with some myxoid areas. The cells contain intracytoplasmic inclusions of collagen. The cytoplasm stains for vimentin, and the cells have ultrastructural features of myofibroblasts. This is the second case reported of proliferative fasciitis occurring in a child, and the importance of distinguishing this lesion from childhood neoplasms with a similar appearance is discussed.

Child↗
PubMed1990

Beta-thalassemia genes in French-Canadians: haplotype and mutation analysis of Portneuf chromosomes.

beta-Thalassemia minor occurs at approximately 1% frequency in French-Canadians--in families residing in Portneuf County (population approximately 40,000) of Quebec province. We found eight different RFLP haplotypes at the beta-globin gene cluster in 37 normal persons and in 12 beta-thalassemia heterozygotes from six families. beta-Thalassemia genes in these families associated with two haplotypes only: Mediterranean I and Mediterranean II. There were two different beta-thalassemia mutations segregating in the Portneuf population: an RNA processing mutation (beta(+)IVS-1,nt110) on haplotype I (five families) and a point mutation leading to chain termination (beta(0) nonsense codon 39) on haplotype II (one family). The distribution of 5' haplotypes on normal beta A Portneuf chromosomes compared with other European populations was most similar to that in British subjects (data for French subjects have not yet been reported). Genealogical reconstructions traced the ancestry of carrier couples to settlers emigrating from several different regions of France to New France in the 17th century. These findings indicate genetic diversity of a greater degree among French-Canadians than recognized heretofore.

DNA Mutational Analysis↗
PubMed1990

Mapping autosomal recessive vitamin D dependency type I to chromosome 12q14 by linkage analysis.

Linkage analysis in French-Canadian families with vitamin D dependency type I (VDD1) demonstrated that the gene responsible for the disease is linked to polymorphic RFLP markers in the 12q14 region. We studied 76 subjects in 14 sibships which included 17 affected individuals and 17 obligate heterozygotes. Significant results for linkage were obtained with the D12S17 locus at the male recombination fraction (theta m) .018 (Z[theta m theta f] = 3.20) and with D126 at (theta m = .025 (Z[theta m theta f] = 3.07). Multipoint linkage analysis and studies of haplotypes and recombinants strongly suggest the localization of the VDD1 locus between the collagen type II alpha 1 (COL2A1) locus and clustered loci D12S14, D12S17, and D12S6, which segregate as a three-marker haplotype. Linkage disequilibrium between VDD1 and this three-marker haplotype supports the notion of a founder effect in the studied population. The current status of the localization of the disease allows for carrier detection in the families at risk.

Chromosome Banding↗