Neuroendocrine activation after myocardial infarction: causes and consequences.
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Animals↗
Biomedical subjects
K Morgan
Publications and source records attributed to K Morgan.
A rapid and efficient method for DNA extraction from paraffin wax embedded tissue for PCR amplification.
DNA from archival, formaldehyde fixed, paraffin wax embedded human tissue, suitable for amplification by the polymerase chain reaction (PCR), was obtained using a microwave method based on the capture of DNA by magnetic beads. Fragments of the alpha-1-antitrypsin gene (AAT) and the apolipoprotein E gene (APOE) were amplified successfully from human liver and brain tissue, respectively. This procedure provides a more rapid, simple and efficient method for reproducibly obtaining DNA from preserved tissue that has been kept in storage for up to 30 years.
Journal Article↗
Epidemiology of gonococcal and chlamydial infections in Harrow and Brent.
OBJECTIVE: To describe the epidemiology and associated clinical features of gonorrhoea and chlamydial infection and to develop a profile of sexually transmitted diseases (STDs) in an outer London health district. DESIGN: Hospital-based retrospective study. SETTING: Genitourinary medicine clinic, Northwick Park Hospital, Harrow and Brent Health Authority. SUBJECTS: 70 male and female individuals with gonorrhoea and 129 with chlamydial infection, diagnosed consecutively over 28 months in 1992-94. RESULTS: More men than women had gonorrhoea (43 versus 27) but more women than men had chlamydial infection (84 versus 45), p < 0.001. There was a clear tendency for cases with either infection to locate along major road and rail transport routes. Foci of gonococcal infection were concentrated mainly in the densely populated areas, whereas chlamydial cases were more evenly spread. There was no significant effect of gender or type of STD on the odds ratio for residence in Harrow, single marital status or attendance for test of cure. However, the odds ratios for women having sexual intercourse with a regular partner only or previous STD were 5 (95% CI 2.4 to 10.2), p < 0.001 and 0.3 (95% CI 0.18 to 0.69), p = 0.002 times the odds for men, respectively. The odds ratios for patients with gonococcal infection being employed or having sex with a regular partner only were 0.5 (95% CI 0.27 to 0.98), p = 0.04 and 0.30 (95% CI 0.15 to 0.60), p < 0.001 times the odds for patients with chlamydial infection, respectively. Of the women with gonorrhoea and previous pregnancy, 68% gave a history of abortion compared with 44% of those with chlamydial infection (p = 0.03). CONCLUSION: The identification of foci gonococcal and chlamydial infection and apparent location of these infections along the major transport routes in our health district require further study. That chlamydial infection, unlike gonorrhoea, is evenly distributed irrespective of population concentration and deprivation, suggests urgent need for a comprehensive local effort to control both STDs.
Adult↗
Gemfibrozil stimulates apolipoprotein A-I synthesis and secretion by stabilization of mRNA transcripts in human hepatoblastoma cell line (Hep G2).
Gemfibrozil is a widely used drug that elevates plasma HDL and lowers triglycerides and LDL. The mechanism of action of this pharmacological agent on HDL metabolism is not established. Since the liver is the major organ involved in HDL production and removal, we assessed the effect of gemfibrozil on the modulation of apoA-I (a major protein of HDL)-containing particles by a human hepatoblastoma cell line (Hep G2). Incubation of Hep G2 cells with gemfibrozil resulted in the following statistically significant findings: (1) increased accumulation of apoA-I in the medium without affecting uptake of radiolabeled HDL-protein or HDL-apoA-I; (2) accelerated incorporation of [3H]leucine and [35S]methionine into apoA-I; (3) equivalent increases in [3H]leucine incorporation into HDL particles without and with apoA-II (LpA-I and LpA-I+A-II, respectively); (4) equal efflux of fibroblast cholesterol by harvested LpA-I and LpA-I+A-II particles; (5) increased steady state apoA-I mRNA without affecting apoA-I transcription; and (6) increased apoA-I mRNA half-life (2.2-fold). These data indicate that gemfibrozil stabilizes apoA-I mRNA transcripts, resulting in increased translation of functional apoA-I-containing particles capable of effluxing cellular cholesterol, thus defining a major mechanism by which gemfibrozil increases HDL.
Apolipoprotein A-I↗
Psychological markers in the detection of autism in infancy in a large population.
BACKGROUND: Investigation to see if there are key psychological risk indicators for autism in a random population study of children at 18 months of age; and to assess how well these discriminate children who receive a diagnosis of autism from other forms of developmental delay. METHOD: Sixteen thousand children in the southeast of England were screened for autism by their health visitor or GP, during their routine 18-month-old developmental check-up, using the CHAT (Checklist for Autism in Toddlers). From a previous high-risk study we predicted that children at 18 months of age who failed three items ('protodeclarative pointing', 'gaze-monitoring', and 'pretend play') would be at risk for receiving a diagnosis of autism. From other evidence, we further predicted that those 18-month-olds who failed one or two of the key items (either pretend play, or protodeclarative pointing and pretend play) would be at risk for developmental delay without autism. RESULTS: Twelve children out of the total population of 16,000 consistently failed the three key items. Of these, 10 (83.3%) received a diagnosis of autism. Thus, the false positive rate was 16.6% (2 out of 12 cases), and even these 2 cases were not normal. When the 10 children with autism were reassessed at 3.5 years of age, their diagnosis remained the same. Thus the false positive rate among the cases diagnosed with autism was zero. In contrast, of 22 children who consistently failed either protodeclarative pointing and/or pretend play, none received a diagnosis of autism, but 15 (68.2%) received a diagnosis of language delay. CONCLUSIONS: Consistent failure of the three key items from the CHAT at 18 months of age carries an 83.3% risk of autism; and this pattern of risk indicator is specific to autism when compared to other forms of developmental delay.
Autistic Disorder↗
Molecular analysis of X-linked nephrogenic diabetes insipidus.
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Amino Acid Sequence↗
Heritability of X chromosome--inactivation phenotype in a large family.
One of the two X chromosomes in each somatic cell of normal human females becomes inactivated very early in embryonic development. Although the inactivation of an X chromosome in any particular somatic cell of the embryonic lineage is thought to be a stochastic and epigenetic event, a strong genetic influence on this process has been described in the mouse. We have attempted to uncover evidence for genetic control of X-chromosome inactivation in the human by examining X chromosome-inactivation patterns in 255 females from 36 three-generation pedigrees, to determine whether this quantitative character exhibits evidence of heritability. We have found one family in which all seven daughters of one male and the mother of this male have highly skewed patterns of X-chromosome inactivation, suggesting strongly that this quantitative character is controlled by one or more X-linked genes in some families.
Alleles↗
Greater frequency of K-ras Val-12 mutation in colorectal cancer as detected with sensitive methods.
Assays for tumor mutations need to be sufficiently sensitive that a mutation can be readily detected in a high background of wild-type sequence. We have evaluated competitive allele-specific oligonucleotide (cASO) hybridization, the amplification refractory mutation system (ARMS), and a combination of cASO with mutant-enriched polymerase chain reaction (ME-PCR) for their respective sensitivities in detecting the K-ras Val-12 mutation. cASO hybridization detected 1 mutant allele in 100 wild-type alleles and identified 6 of 74 (8%) colorectal tumors as having the Val-12 mutation. ARMS detected 1 mutant in 1000 and 12 of 74 (16%) tumor samples, and the ME-PCR with cASO hybridization detected 1 in 5000 and 20 of 74 (27%) tumor samples. The mutation was not detected in normal bowel mucosa from selected Val-12 tumor-positive patients. ME-PCR combined with cASO resulted in a threefold higher detection rate than has previously been reported and suggests that other studies may have underestimated the frequency of K-ras mutations.
Base Sequence↗
Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype.
We report the results of our investigations of a large, inbred, aboriginal Canadian kindred with nine muscular dystrophy patients. The ancestry of all but two of the carrier parents could be traced to a founder couple, seven generations back. Seven patients presented with proximal myopathy consistent with limb girdle-type muscular dystrophy (LGMD), whereas two patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy (distal autosomal recessive muscular dystrophy) (MM). Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MM is consistent with autosomal recessive inheritance, and the putative locus is significantly linked (LOD scores >3.0) to six marker loci that span the region of the LGMD2B locus on chromosome 2p. Our initial hypothesis that the affected patients would all be homozygous by descent for microsatellite markers surrounding the disease locus was rejected. Rather, two different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating that there are two mutant alleles of independent origin in this kindred. There was no association, however, between the two different haplotypes and clinical variability; they do not distinguish between the LGMD and MM phenotypes. Thus, we conclude that LGMD and MM in our population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must contribute to the clinical phenotype.
Adolescent↗
Generation of a transcription map at the HSD17B locus centromeric to BRCA1 at 17q21.
A detailed transcription map of the 320-kb region containing the HSD17B locus on chromosome 17 was generated. Thirty unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of mammary gland, ovary, placenta, and the Caco-2 cell line, were aligned into 10 transcription units by physical mapping and hybridization to RNAs of a series of tissues. The cDNAs were then further characterized by sequencing and used to screen mammary gland cDNA libraries. Fragments corresponding to the broadly expressed gamma-tubulin and Ki antigen genes were identified. A full-length cDNA clone encoding a 117-amino-acid protein homologous to the rat ribosomal protein L34 was isolated. Portions of genes with restricted patterns of expression were also obtained, including the previously characterized HSD17B1. One new gene, for which a full-length cDNA was isolated, was found to have an interesting tissue-specific pattern of expression with abundant mRNA in both the colon and the testis and in the mammary carcinoma cell line BT-474. This contrasted with the barely detectable level observed in several tissues including normal mammary gland. Of the five additional transcription units identified, one showed no similarity, two showed identity to human expressed sequences, and two displayed similarity to genes of animal species by amino acid alignment. These latter cDNA clones include potential homologues of a rat nuclear tyrosine phosphatase and of a factor of Drosophila that is known to be involved in the negative regulation of transcription of segment identity genes.
Amino Acid Sequence↗
Large-scale cloning of human chromosome 2-specific yeast artificial chromosomes (YACs) using an interspersed repetitive sequences (IRS)-PCR approach.
We report here an efficient approach to the establishment of extended YAC contigs on human chromosome 2 by using an interspersed repetitive sequences (IRS)-PCR-based screening strategy for YAC DNA pools. Genomic DNA was extracted from 1152 YAC pools comprised of 55,296 YACs mostly derived from the CEPH Mark I library. Alu-element-mediated PCR was performed for each pool, and amplification products were spotted on hybridization membranes (IRS filters). IRS probes for the screening of the IRS filters were obtained by Alu-element-mediated PCR. Of 708 distinct probes obtained from chromosome 2-specific somatic cell hybrids, 85% were successfully used for library screening. Similarly, 80% of 80 YAC walking probes were successfully used for library screening. Each probe detected an average of 6.6 YACs, which is in good agreement with the 7- to 7.5-fold genome coverage provided by the library. In a preliminary analysis, we have identified 188 YAC groups that are the basis for building contigs for chromosome 2. The coverage of the telomeric half of chromosome 2q was considered to be good since 31 of 34 microsatellites and 22 of 23 expressed sequence tags that were chosen from chromosome region 2q13-q37 were contained in a chromosome 2 YAC sublibrary generated by our experiments. We have identified a minimum of 1610 distinct chromosome 2-specific YACs, which will be a valuable asset for the physical mapping of the second largest human chromosome.
Animals↗
Anaemia in lambs.
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Anemia, Iron-Deficiency↗
Purchaser-provider: the international dimension.
Purchaser-provider systems in health care are being implemented in several countries and are under consideration in many more. These new arrangements are described for the United Kingdom, Finland, New Zealand, and Australia, and in each case responsibility for funding, purchasing, providing, and ownership is identified. The four systems, along with managed care organisations in the United States, are also compared with regard to several important features. There is a fundamental similarity between these purchaser-provider arrangements but several key differences are well worth systematic study. This is a major challenge for academic bodies in Britain and other countries, and the opportunity to learn from each other should not be missed.
Australia↗
Transmission-ratio distortion of X chromosomes among male offspring of females with skewed X-inactivation.
We have begun a search for heritable variation in X-chromosome inactivation pattern in normal females to determine whether there is a genetic effect on the imprinting of X-chromosome inactivation in humans. We have performed a quantitative analysis of X-chromosome inactivation in lymphocytes from mothers in normal, three-generation families. Eight mothers and 12 grandmothers exhibited evidence of highly skewed patterns of X-chromosome inactivation. We observed that the male offspring of females with skewed X-inactivation patterns were three times more likely to inherit alleles at loci that were located on the inactive X chromosome (Xi) than the active X chromosome (Xa). The region of the X chromosome for which this phenomenon was observed extends from Xp11 to -Xq22. We have also examined X-chromosome inactivation patterns in 21 unaffected mothers of male bilateral sporadic retinoblastoma patients. Six of these mothers had skewed patterns of X-chromosome inactivation. In contrast to the tendency for male offspring of skewed mothers from nondisease families to inherit alleles from the inactive X chromosome, five of the six affected males inherited the androgen receptor alleles from the active X chromosome of their mother.
Base Sequence↗
Evolution of a repeat sequence in the parathyroid hormone-related peptide gene in primates.
A polymorphism of the variable number of tandem repeat (VNTR) type is located 97 bp downstream of exon VI of the parathyroid hormone-related peptide (PTHrP) gene in humans. The repeat unit has the general sequence G(TA)nC, where n equals 4-11. In order to characterize the evolutionary history of this VNTR, we initially tested for its presence in 13 different species representing four main groups of living primates. The sequence is present in the human, great apes, and Old World monkeys, but not in New World monkeys; and this region failed to PCR amplify in the Loris group. Thus, the evolution of the sequence as part of the PTHrP gene started at least 25-35 millions years ago, after divergence of the Old World and New World monkeys, but before divergence of Old World monkeys and great apes and humans. The structural changes occurring during evolution are characterized by a relatively high degree of sequence divergence. In general, the tandem repeat region tends to be longer and more complex in higher primates with the repeat unit motifs all being based on a TA-dinucleotide repeat sequence. Intra-species variability of the locus was demonstrated only in humans and gorilla. The divergence of the TA-dinucleotide repeat sequence and the variable mutation rates observed in different primate species are in contrast to the relative conservation of the flanking sequences during primate evolution. This suggests that the nature of the TA-dinucleotide repeat sequence, rather than its flanking sequences, is responsible for generating variability.(ABSTRACT TRUNCATED AT 250 WORDS)
Alleles↗
Natural resistance to infection with Legionella pneumophila: chromosomal localization of the Lgn1 susceptibility gene.
Legionella pneumophila is a strict intracellular pathogen that replicates in the professional phagocytes of the human and guinea pig host. Although murine macrophages from most inbred strains are non-permissive to intracellular replication of L. pneumophila, inflammatory macrophages from the mouse strain A/J are completely permissive to intracellular replication of this bacterium. This genetic difference is controlled by the expression of a single autosomal gene designated Lgn1, with non-permissiveness behaving as completely dominant over permissiveness. We have used a total of 25 AXB/BXA recombinant inbred mouse strains and 182 (A/J x C57BL/6J) x A/J segregating backcross progeny (A/J, permissive; C57BL/6J, non-permissive) to map the Lgn1 gene. Animals were individually typed for tolerance to intracellular replication by in vitro infection of their inflammatory macrophages with L. pneumophila. All animals segregated into two nonoverlapping groups. Examination of the strain distribution pattern of the AXB/BXA strains for Lgn1 initially identified linkage to Chromosome (Chr) 13 markers. Genotyping of the 25 AXB/BXA strains and the 182 backcross progeny for 11 Chr 13 markers established that Lgn1 mapped to Chr 13, with the gene order and intergene distance D13Mit231-(5.5 +/- 1.5)-D13Mit193-(2.2 +/- 0.9)-D13Mit194- (1.1 +/- 0.6)-D13Mit128-(2.6 +/- 1.0)-Lgn1-(2.2 +/- 0.9)-D13Mit70-(3.9 +/- 1.3)- D13Mit73-(7.2 +/- 1.7)-D13Mit53-(0.7 +/- 0.5)-D13Mit32-(0.7 +/- 0.5)-D13Mit77- (0.7 +/- 0.5)-D13Mit78. This portion of Chr 13 is homologous to the distal portion of human Chr 5, 5q11-5q13, suggesting a possible location of a human LGN1 homolog. Understanding the molecular basis of the high permissiveness of A/J macrophage to L. pneumophila may shed light on the survival strategy of this bacterium in highly permissive human phagocytes. This may be achieved by positional cloning of Lgn1, and the identification of the Lgn1 subchromosomal region reported here is a first step towards that goal.
Animals↗
The sensitivity of competitive hybridisation for the detection of mutant p53 alleles in a background of wild type.
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Alleles↗
The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy which presents typically after the age of 50 with progressive eyelid drooping and an increasing difficulty in swallowing. Though OPMD has a world-wide incidence, it is more common in the French Canadian population. We have identified a homogeneous group of families and studied 166 polymorphic markers as part of a genome search before establishing linkage to chromosome 14. We determined that the OPMD locus maps to a less than 5 cM region of chromosome 14q11.2-q13. The maximum two-point lod score in three French Canadian families of 14.73 (theta = 0.03) was obtained for an intronic cardiac beta myosin heavy chain gene (MYH7) marker. The regional localization for the OPMD locus raises the intriguing possibility that either the cardiac alpha or beta myosin heavy chain genes may play a role in this disease.
Base Sequence↗