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Biomedical subjects

K Morgan

Publications and source records attributed to K Morgan.

At least 127 records · Page 7Linked to original sources
PubMed1997

Microsatellite polymorphism of the alpha 1-antichymotrypsin gene locus associated with sporadic Alzheimer's disease.

A variant of the apolipoprotein E gene, APOE*4, is associated with both sporadic Alzheimer's disease (AD) and a subset of familial AD and this association is stronger with early as opposed to late onset AD. Both APOE*4 and alpha 1-antichymotrypsin (ACT) will accelerate the rate of amyloid filament formation and are major constituents of the plaques associated with AD. We now show that a dinucleotide microsatellite allele in the 5'-flanking sequence of the ACT gene, designated A10, in association with APOE*4 significantly increases the risk of developing sporadic AD, which accounts for the majority of AD cases.

Aged↗
PubMed1997

Regulation of the serine proteinase inhibitor (SERPIN) gene alpha 1-antitrypsin: a paradigm for other SERPINs.

alpha 1-antitrypsin (AAT) is the archetypal member of the serine proteinase inhibitor (SERPIN) gene family. AAT is an acute-phase reactant and the plasma concentration increases three- to four-fold during the inflammatory response. In hepatocytes this increase is mediated primarily by the cytokine interleukin-6 (IL-6) via the transcription factor NF-IL6. The AAT gene contains at least two enhancer elements, one at the 5' end of the gene and the other at the 3' end. Functional studies performed in mammalian hepatoma cells (Hep G2) using constructs containing these AAT enhancer regions linked to a reporter gene have demonstrated that the 5' enhancer is dominant under basal conditions and that, following stimulation with IL-6, both enhancers are essential and the 3' enhancer plays a major role. We have identified a mutation associated with lung disease which occurs in the 3' AAT enhancer; the mutation occurs at a binding site for the ubiquitous transcription factor Oct-1. The functional significance of this mutation is a deficient IL-6 response. Using the AAT gene as a model, we describe the interactions which occur between transcription factors within the 3' enhancer and also those which take place between the 5' and 3' enhancers. These studies shed light on the molecular mechanism of the acute-phase response which could possibly be extended to other members of the SERPIN gene family.

Acute-Phase Reaction↗
PubMed1997

Longitudinal trends in late-life insomnia: implications for prescribing.

OBJECTIVE: To assess trends in insomnia and hypnotic drug use in a representative sample of elderly general practice patients. DESIGN: Longitudinal study with three interview waves--1985, 1989 and 1993. SETTING: Urban and suburban Nottingham. PARTICIPANTS: 1042 patients originally aged 65 and over randomly sampled from general practitioner lists. MAIN OUTCOME MEASURES: Point prevalence estimates, status (case/non-case/died) at 4-year follow-up, episode incidence and survival functions. RESULTS: At baseline (1985) 221 respondents met the survey criteria for insomnia. Of these, 36.1% continued to report severely disrupted sleep in 1989. Within this period 84 new cases of insomnia were identified (an incidence rate of 3.1% per person-year at risk). Controlling for age and sex, insomnia was unrelated to survival among prevalent cases, but significantly related to survival among incident cases (odds ratio = 1.7; 95% confidence interval = 1.1-2.5). Of 166 respondents using prescription hypnotics in 1985, 31.7% continued to report usage in 1989. Similarly, out of 41 new hypnotic drug users identified in 1989, 29.3% continued to report usage in 1993. CONCLUSIONS: Important clinical differences in the natural history of insomnia are evident when incident and prevalent cases are compared. Nevertheless, outcomes at 4-year follow-up suggest that, for the majority of surviving cases identified in a prevalence screen and for a substantial minority of incident cases, late-life insomnia shows a level of chronicity incompatible with hypnotic drug therapy as currently recommended.

Aged↗
PubMed1997

Resistance to salmonellosis in the chicken is linked to NRAMP1 and TNC.

Natural resistance to infection with Salmonella typhimurium in mice is controlled by two major loci, Bcg and Lps, located on mouse chromosomes 1 and 4, respectively. Both Bcg and Lps exert pleiotropic effects and contribute to cytostatic/cytocidal activities of the macrophage. Bcg encodes for a membrane phosphoglycoprotein designated Nrampl (natural resistance-associated macrophage protein 1), which belongs to an ancient family of membrane proteins, Lps has not been cloned yet, but its location on mouse chromosome 4 has been refined for positional cloning. As in mice, chicken inbred lines differ in their susceptibility to infection with Salmonella typhimurium. We have tested the candidacy of the chicken homologs of Nrampl and Tnc (a locus closely linked to Lps), in the differential resistance of chicken inbred lines to infection with S. typhimurium. We have first analyzed six inbred chicken lines of Salmonella-resistant or Salmonella-susceptible phenotypes for the presence of nucleotide sequence variations within the coding portion of NRAMP1. We have identified 11 sequence variations within NRAMP1 in the chicken inbred lines tested: 10 of these represented either silent mutations or conservative changes. However, one G-->A substitution at nucleotide 696 resulted in the nonconservative replacement of Arg223 to Gln223 within the predicted TM5-6 region. This allelic variant was specific to the susceptible line C and not observed in any of the resistant strains. To investigate the effect of NRAMP1 and TNC on resistance to infection with S. typhimurium, 425 (W1 x C)F1 x C chicken progeny were examined during a period of 15 days postinfection. Together, NRAMP1 and TNC explain 33% of the early differential resistance to infection with S. typhimurium of parental lines C and W1. Our data established that resistance to infection with S. typhimurium in chickens is inherited as a complex trait and that comparative mapping has proven to be useful to identify Salmonella-resistance genes in the chicken.

Amino Acid Sequence↗
PubMed1997

Evolutionary conservation and predicted structure of the Drosophila extra sex combs repressor protein.

The Drosophila extra sex combs (esc) protein, a member of the Polycomb group (PcG), is a transcriptional repressor of homeotic genes. Genetic studies have shown that esc protein is required in early embryos at about the time that other PcG proteins become engaged in homeotic gene repression. The esc protein consists primarily of multiple copies of the WD repeat, a motif that has been implicated in protein-protein interaction. To further investigate the domain organization of esc protein, we have isolated and characterized esc homologs from divergent insect species. We report that esc protein is highly conserved in housefly (72% identical to Drosophila esc), butterfly (55% identical), and grasshopper (56% identical). We show that the butterfly homolog provides esc function in Drosophila, indicating that the sequence similarities reflect functional conservation. Homology modeling using the crystal structure of another WD repeat protein, the G-protein beta-subunit, predicts that esc protein adopts a beta-propeller structure. The sequence comparisons and modeling suggest that there are seven WD repeats in esc protein which together form a seven-bladed beta-propeller. We locate the conserved regions in esc protein with respect to this predicted structure. Site-directed mutagenesis of specific loops, predicted to extend from the propeller surface, identifies conserved parts of esc protein required for function in vivo. We suggest that these regions might mediate physical interaction with esc partner proteins.

Amino Acid Sequence↗
PubMed1997

A domain shared by the Polycomb group proteins Scm and ph mediates heterotypic and homotypic interactions.

The Sex comb on midleg (Scm) and polyhomeotic (ph) proteins are members of the Polycomb group (PcG) of transcriptional repressors. PcG proteins maintain differential patterns of homeotic gene expression during development in Drosophila flies. The Scm and ph proteins share a homology domain with 38% identity over a length of 65 amino acids, termed the SPM domain, that is located at their respective C termini. Using the yeast two-hybrid system and in vitro protein-binding assays, we show that the SPM domain mediates direct interaction between Scm and ph. Binding studies with isolated SPM domains from Scm and ph show that the domain is sufficient for these protein interactions. These studies also show that the Scm-ph and Scm-Scm domain interactions are much stronger than the ph-ph domain interaction, indicating that the isolated domain has intrinsic binding specificity determinants. Analysis of site-directed point mutations identifies residues that are important for SPM domain function. These binding properties, predicted alpha-helical secondary structure, and conservation of hydrophobic residues prompt comparisons of the SPM domain to the helix-loop-helix and leucine zipper domains used for homotypic and heterotypic protein interactions in other transcriptional regulators. In addition to in vitro studies, we show colocalization of the Scm and ph proteins at polytene chromosome sites in vivo. We discuss the possible roles of the SPM domain in the assembly or function of molecular complexes of PcG proteins.

Amino Acid Sequence↗
PubMed1997

Customary physical activity and survival in later life: a study in Nottingham, UK.

OBJECTIVE: To assess the value of broadly based customary physical activity scores, derived from a questionnaire inventory, in predicting 10 year mortality among elderly people. DESIGN: A 10 year survival analysis of participants in the first wave of the Nottingham longitudinal study of activity and ageing who, in face to face interviews in 1985, provided detailed information on customary physical activity, health, and lifestyle. SETTING: Urban and suburban Nottingham PARTICIPANTS: A total of 1042 people aged 65 years and over randomly sampled from general practitioner records. MAIN RESULTS: On the basis of factor scores derived from the interview questionnaire, activity levels were graded as "high", "intermediate", or "low". In Cox regression models controlling for age, health status, and cigarette smoking at the time of the activity assessment, these gradings were significantly related to 10 year survival. Relative to the "high" activity groups, the risk of dying was significantly increased in both the "intermediate" (hazard ratio (HR) 1.53; 95% CI 1.12, 2.09) and "low" (HR 2.07; 95% CI 1.53, 2.79) groups for women, and in the "low" group (HR 1.59; 95% CI 1.12, 2.25) for men (p < 0.01 throughout). CONCLUSION: Since the survival model controlled for age, health status, and cigarette smoking, it is unlikely that the activity gradings used here are simple proxies for physical health. It is concluded, therefore, that within the elderly population, recall based survey assessments covering a wide range of customary or habitual physical activities, can provide indices showing both cross sectional utility and predictive validity.

Activities of Daily Living↗
PubMed1997

Physical illness and disability among elderly people in England and Wales: the Medical Research Council Cognitive Function and Ageing Study. The Analysis Group.

STUDY OBJECTIVE: This study was conducted as part of the MRC cognitive function and ageing study. It aimed to estimate the lifetime prevalence of self reported physical illnesses and other health related events, and the prevalence of limiting disability in people over 65 in six areas of England and Wales. DESIGN: Screening phase of a two stage prevalence study. SETTING: Geographically delimited areas in four urban and two rural areas including institutions. PARTICIPANTS: Random population samples of people in their 65th year and above on the sample definition date, interviewed between 1989 and 1994. In Newcastle, Nottingham, and Oxford (urban) and in Cambridgeshire and Gwynedd(rural), the sample was stratified to provide equal numbers in the 65-74 and 75 years and over age groups. In Liverpool (urban), equal numbers in the five year age groups were taken. MAIN RESULTS: Age standardised prevalences were calculated for each geographical area, sex, and age group (65-74, 75+). Many conditions were more prevalent in the older age group including stroke, Parkinson's disease, arthritis, diabetes, and shingles but hypertension was more common in the younger age group. Conditions that were more prevalent in men included angina, heart attack, stroke, head injury, and peptic ulcers while hypertension, shingles, pernicious anaemia, and thyroid disease were more common in women. There was a complex pattern of area differences for individual conditions. Cambridgeshire had generally low prevalences for many diseases, including vascular problems, Gwynedd and Newcastle had less healthy elderly populations, and Nottingham and Newcastle had the highest percentages of housebound. CONCLUSIONS: This study provides the most robust available estimates for life-time prevalence of a variety of health conditions on a regional and national basis. It shows the greatly increased prevalence of disability in the very old population, particularly women.

Age Distribution↗
PubMed1997

Risk factors for late-life insomnia in a representative general practice sample.

BACKGROUND: Insomnia is widely reported and widely treated in general practice, yet relatively little research has focused on the natural history of the condition in primary care settings. As a result, there is at present little information to enable clinicians to assess insomnia risk, or anticipate outcomes in older general practice populations. AIM: To estimate, using 8-year longitudinal data, the risk of insomnia onset associated with selected health and lifestyle factors. METHOD: Survivors from a nationally representative sample (n = 1042) of elderly people originally interviewed in 1985 were reassessed in 1989 (n = 690) and 1993 (n = 410). At the first follow up in 1989, 84 new cases of insomnia were identified (a weighted incidence rate per person per year at a risk of 3.1%; 95% CI = 2.7-3.5). In logistic regression analyses controlling for age and sex, the risk of insomnia onset was then assessed in relation to the selected factors. RESULTS: Three factors assessed in 1985 were significantly and independently related to incident insomnia: psychometric ratings consistent with depressed mood odds ratio (OR) = 4.41; 95% CI = 3.32-5.43); health index scores indicating lower physical health status (OR = 1.19; 95% CI = 1.06-1.31 per unit change in scale score); and moderate and low levels of physical activity (OR = 1.91 and 2.14; 95% CI = 1.91-3.62 and 2.14-3.64 respectively). However, although depressed mood represented a major risk factor, the most likely source of risk was physical rather than mental ill-health. CONCLUSIONS: Psychiatric, somatic and lifestyle factors significantly and independently increase the risk of insomnia in older general practice patients. In predicting incident sleep disturbance, these factors exceed in importance the age and sex of patients.

Aged↗
PubMed1997

Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study.

OBJECTIVE: To define chronic hepatitis C virus (HCV) infection among patients with persistently normal aminotransferase levels (PNAL). DESIGN: Retrospective chart review of all patients encountered during 1-yr with positive hepatitis C antibody (anti-C100-3 ELISA), no alternative cause for their liver disease and PNAL for 6 or more consecutive months prebiopsy. Blinded review of liver histology. SETTING: Outpatient hepatology clinics of two academic centers. PATIENTS: Fifty patients with PNAL among 303 with hepatitis C. MEASUREMENTS: Epidemiologic profiles, reasons for seroscreening and confirmatory analyses were tabulated. Histology was reviewed and grading of inflammatory activity and stage of fibrosis was determined by protocol. RESULTS: Among 50 patients with PNAL, 35 (70%) were female, 34 (68%) had parenterally acquired HCV, 44 (88%) abstained (> 2 yr) from ethanol, all were HIV-negative and none pharmacologically immunosuppressed. HCV infection was uniformly confirmed by RIBA II or HCV-RNA assay. The mean level of HCV-RNA by quantitative PCR was 3.79 x 10(5) copies/ml (range, 500 to 1.8 x 10(6) copies/ ml) and by B-DNA, 53 x 10(5) copies/ml (range, 3.5-230 x 10(5) copies/ml). Traditional histoevaluation yielded chronic hepatitis ("active", n = 15; "persistent", n = 25), cirrhosis (n = 7), and normal histology (n = 3). Blinded protocol review of histology (inflammatory grade/fibrotic stage) revealed 0/0 (n = 4), 1/0 (n = 6), 2/0 (n = 17), 2/1 (n = 3), 2/4 (n = 1), 3/0 (n = 2), 3/1 (n = 6), 3/2 (n = 2), and 3/3 (n = 9). CONCLUSIONS: In chronic HCV infection, active inflammation, fibrosis, and variable circulating HCV-RNA levels may coexist with PNAL, particularly among female nondrinkers. Asymptomatic carriers with normal histology comprise 6 to 8% of chronic hepatitis C with PNAL. Management guidelines for this group of patients need to be developed.

Adult↗
PubMed1996

Friedreich ataxia in Acadian families from eastern Canada: clinical diversity with conserved haplotypes.

The gene for Friedreich ataxia (FRDA), an autosomal-recessive neurodegenerative disease, remains elusive. The current candidate region of about 150 kb lies between loci FR2 and F8101 near the D9S15/D9S5 linkage group at 9q13-21.1. Linkage homogeneity between classical FRDA and a milder, slowly progressive Acadian variant (FRDA-Acad) has been demonstrated. An extended D9S15-D9S5 haplotype (C6) predominates in FRDA-Acad chromosomes from Louisiana. We studied 10 Acadian families from New Brunswick, Canada. In eight families, affected individuals conformed to the clinical description of FRDA-Acad; in one, 2 sibs presented with spastic ataxia (SPA-Acad). In the last family, 2 sibs had FRDA-Acad, and one had SPA-Acad. We found that SPA-Acad is linked to the FRDA gene region. The C6 haplotype and a second major haplotype (B7) were identified. The same ataxia-linked haplotypes segregated with both FRDA-Acad and SPA-Acad in two unrelated families. The parental origins of these haplotypes were different. Our observation of different phenotypes associated with the same combination of haplotypes may point to the influence of the parent of origin on gene expression, indicate the effect of modifier genes, or reflect the presence of different mutations on the same haplotypes. Our findings underline the need to investigate families with autosomal-recessive ataxias for linkage to the FRDA region, despite lack of key diagnostic manifestations such as cardiomyopathy or absent deep-tendon reflexes.

Canada↗
PubMed1996

The human mammary-derived growth inhibitor (MDGI) gene: genomic structure and mutation analysis in human breast tumors.

The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor gene for human breast cancer. It has been shown to reduce the tumorigenicity of breast cancer cell lines in nude mice, and loss of expression of this gene has been shown in primary breast tumors. Furthermore, the human MDGI gene has been mapped to human chromosome 1p32-p35, a common region of deletion in sporadic breast tumors. We have determined the genomic structure of the human MDGI gene from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers approximately 8 kb of genomic DNA and is divided into four exons. In an attempt to identify possible inactivating mutations in the MDGI gene in human breast cancer, we have sequenced all four exons and their surrounding splice junctions in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion containing the MDGI gene. No mutations were found in this analysis. A polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in this study, which resulted in the conversion of a lysine to an arginine residue at codon 53. This variant was present in the constitutional DNA of a further 3/26 women with sporadic breast cancer and 2/90 control individuals (P = 0.20). Despite experimental evidence that MDGI has tumor suppressor activity, our data suggest that mutations in the coding region are uncommon in human breast tumorigenesis.

Base Sequence↗
PubMed1996

Regional changes in angiotensin II receptor density after experimental myocardial infarction.

The plasma and cardiac renin-angiotensin systems may be activated after myocardial infarction. The myocardium may therefore be exposed to increased concentrations of angiotension II, which may contribute to myocardial injury. The purpose of this study was to identify the potential sites of action of angiotensin II in the infarcted heart. Myocardial infarction was induced in rats by left coronary artery ligation, and the hearts were removed for study after 18 h, 7 days, or 8 months. The regional ventricular angiotensin II receptor density was assessed by [125I](Sar1,Ile8)angiotensin II binding and quantitative autoradiography. The [125I](Sar1,Ile8)angiotensin II binding was unchanged at 18 h, but was increased at 7 days in the infarcted region of the left ventricle (73.2 +/- 3.2 amol/mm2, mean +/- S.E.M.) compared with the non-infarcted region (1.6 +/- 0.2 amol/mm2, P < 0.0001) and with the left ventricular myocardium of sham-operated control animals (1.3 +/- 0.1 amol/mm2, P < 0.0001). The increased [125I](Sar1,Ile8)angiotensin II binding density was still present, but diminished, at 8 months after coronary ligation (49.0 +/- 5.7 amol/mm2, P < 0.0001 v control, P = 0.0058 v 7-day infarcts). The increased binding of [125I](Sar1,Ile8)angiotensin II was antagonised by losartan, an AT1 receptor antagonist, but not by an AT2 receptor antagonist. Microautoradiography of [125I](Sar1,Ile8) angiotensin II, and assessment of collagen deposition using picrosirius staining and immunostaining demonstrated that the regional increase in AT1 receptor density in the infarcted region of myocardium was associated with fibroblast infiltration and collagen deposition. The infarct scar and the cardiac fibroblasts within it express high levels of angiotension II receptors and therefore represent potential targets for the actions of angiotensin II after myocardial infarction.

Animals↗
PubMed1996

Dementia and 'borderline dementia' in Britain: 8-year incidence and post-screening outcomes.

Survivors from a nationally representative sample of elderly people originally screened in 1985 were reassessed in 1989 and again in 1993. On each occasion respondents were rated as cognitively impaired, borderline impaired or unimpaired (using a brief information/orientation scale), with the validity of these ratings assessed in subsequent clinical interviews. Where follow-up screening was not possible, information was derived from death certificates and hospital case-notes. Over 8 years (1985-93) the overall incidence rate per person-year at risk was 1.58%, giving age-specific rates of 0.72, 1.32, 1.63, 3.46, 2.55 and 1.41% for the age groups 65-69, 70-74, 75-79, 80-84, 85-89 and > or = 90 respectively. Of 43 individuals classified at screening as borderline impaired in 1985 and 1989, 19 were diagnosed as demented at clinical interviews conducted within 16 weeks of screening. Four-year follow-ups among the remaining 24 showed that 15 had died, while 6 showed a worsened cognitive status. Controlling for both age and sex, aggregated 4-year mortality was significantly higher among those defined at screening in 1985 and 1989 as either impaired or borderline, when compared with the unimpaired.

Aged↗
PubMed1996

Transmission-ratio distortion through F1 females at chromosome 11 loci linked to Om in the mouse DDK syndrome.

We determined the genotypes of > 200 offspring that are survivors of matings between female reciprocal F1 hybrids (between the DDK and C57BL/6J inbred mouse strains) and C57BL/6J males at markers linked to the Ovum mutant (Om) locus on chromosome 11. In contrast to the expectations of our previous genetic model to explain the "DDK syndrome, " the genotypes of these offspring do not reflect preferential survival of individuals that receive C57BL/6J alleles from the F1 females in the region of chromosome 11 to which the Om locus has been mapped. In fact, we observe significant transmission-ratio distortion in favor of DDK alleles in this region. These results are also in contrast to the expectations of Wakasugi's genetic model for the inheritance of Om, in which he proposed equal transmission of DDK and non-DDK alleles from F1 females. We propose that the results of these experiments may be explained by reduced expression of the maternal DDK Om allele or expression of the maternal DDK Om allele in only a portion of the ova of F1 females.

Animals↗
PubMed1996

Inhibition of the renin-angiotensin-aldosterone system in heart failure: new insights from basic clinical research.

It is sobering to recall that, despite much basic research and many small and large clinical trials, we still do not know how angiotensin-converting enzyme inhibitors work. This is true both in terms of their fundamental mode of action at a cellular level as well as in the patient in the clinical setting. New pharmaceutical compounds such as renin inhibitors, angiotensin II receptor antagonists and aldosterone antagonists are bringing new insights not only into the importance of different components of the renin-angiotensin-aldosterone system in heart failure but also into the mode of action of angiotensin-converting enzyme inhibitors. This manuscript also provides a brief update on the organization of the renin-angiotensin-aldosterone system and other angiotensin-II-forming pathways with special relevance to heart failure. Data on the potential relevance of genetic polymorphisms of the renin-angiotensin-aldosterone system are discussed. Possibly the single most important observation in clinical cardiovascular medicine in 1995 was the reporting of a highly significant interaction between angiotensin-converting enzyme inhibitors and aspirin on mortality in patients with ventricular dysfunction with or without heart failure. This has called into question the safety of aspirin use in heart failure.

Angiotensin II↗
PubMed1996

A systematic evaluation of linkage studies in bipolar disorder.

Genetic factors have long been implicated in the aetiology of bipolar disorder (BD). During the past two decades several linkage studies have been carried out with the aim of identifying major genes. However, remarkable discrepancies in results both between and within studies have constituted a major problem. In order to elucidate some of these conflicts, we assessed the published literature on linkage studies of bipolar disorder, focusing on methodological issues. Studies published between January 1980 and December 1994 were identified by computerized literature searches and subsequent scanning of review articles, and the reference lists of the articles primarily identified. A set of defined inclusion and exclusion criteria was used to select studies for assessment. A total of 31 variables were determined, and pre-defined codes were assigned in a structured manner. More than 200 citations were reviewed, and 60 articles were included in this study. Descriptive statistical analyses of the variables, as well as associations between variables, are presented. The findings are discussed with regard to the possibility that, beyond the genetic complexity of the disorder itself, there are several other similarly complicated study design issues which should be more carefully observed. Moreover, the need for standardization of basic criteria to use and report clinical and analytical parameters employed in linkage studies is strongly suggested.

Bipolar Disorder↗