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Biomedical subjects

R Roberts

Publications and source records attributed to R Roberts.

At least 73 records · Page 4Linked to original sources
PubMed2000

Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia.

BACKGROUND: Detection of subclinical coronary artery disease (CAD) before the development of life-threatening cardiac complications has great potential clinical relevance. Electron beam computed tomography (EBCT) is currently the only noninvasive test that can detect CAD in all stages of its development and thus has the potential to be an excellent screening technique for identifying asymptomatic subjects with underlying myocardial ischemia. METHODS AND RESULTS: Over 2.5 years, we prospectively studied 3895 generally asymptomatic subjects with EBCT, 411 of whom had stress myocardial perfusion tomography (SPECT) within a close (median, 17 days) time period. SPECT and exercise treadmill results were compared with the coronary artery calcium score (CACS) as assessed by EBCT. The total CACS identified a population at high risk for having myocardial ischemia by SPECT although only a minority of subjects (22%) with an abnormal EBCT had an abnormal SPECT. No subject with CACS <10 had an abnormal SPECT compared with 2.6% of those with scores from 11 to 100, 11.3% of those with scores from 101 to 399, and 46% of those with scores >/=400 (P<0.0001). CACS predicted an abnormal SPECT regardless of subject age or sex. CONCLUSIONS: CACS identifies a high-risk group of asymptomatic subjects who have clinically important silent myocardial ischemia. Our results support the role of EBCT as the initial screening tool for identifying individuals at various stages of CAD development for whom therapeutic decision making may differ considerably.

Adult↗
PubMed2000

Factors predictive of bone mineral density in eating-disordered women: a longitudinal study.

OBJECTIVE: Osteoporosis in eating-disordered women is well established, but factors predictive of this condition have proved elusive. The roles of behavioral factors, weight, menstrual status, and the degree of bone mineral density change over the clinical course of the eating disorder were investigated METHOD: A cohort of 56 eating-disordered women was subjected to bone mineral density measurement at Scan 1 and were followed up between 9 and 51 months later for repeat measurement (n = 10) at Scan 2. RESULTS: High levels of reduced bone mineral density were observed. Total duration of amenorrhea, body mass index, frequency of vomiting, and cigarette and alcohol consumption accounted for 40% of the variance in spinal bone mineral density measurement at Scan 1. No significant changes in bone mineral density were observed at Scan 2 despite increases in body mass index. DISCUSSION: The results suggest that increases in weight appear not to be sufficient to increase bone mineral density.

Absorptiometry, Photon↗
PubMed2000

Genetic aspects of arrhythmias.

Advances in the treatment and prevention of heart disease have led to consistently declining morbidity and mortality rates over the past 30 years. Despite these advances, therapy remains largely palliative. The development of curative therapies is limited by our lack of knowledge of the basic mechanisms of disease. In the next decade, we will probably change many of these current approaches from treating the crisis to preventing the disease. Molecular biology and genetics have elucidated several basic pathways. It is hoped that targeted therapies will prevent or arrest many of these cardiac diseases, in particular, arrhythmias and sudden death. With the discovery of the genes causing familial diseases like long QT, hypertrophic cardiomyopathy, and Brugada syndrome, we have identified several substrates responsible for triggering malignant arrhythmias.

Adolescent↗
PubMed2000

Rapid and comprehensive determination of cytochrome P450 CYP2D6 poor metabolizer genotypes by multiplex polymerase chain reaction.

The liver enzyme cytochrome P450 CYP2D6 (debrisoquine 4-hydroxylase) metabolizes numerous drugs, including many antidepressants, neuroleptics, antiarrhythmics, and antihypertensive agents. Variability in the gene that encodes this enzyme is an important factor underlying variable drug treatment responses. Some 5-10% of Caucasians lack functional CYP2D6, and the genetic basis of most of these "poor metabolizer" alleles is now well defined. As the CYP2D6 status of a patient can have profound effects on response to drug treatment, it is important to devise methods that permit rapid and economical determination of CYP2D6 genotype. We have developed a robust polymerase chain reaction method that simultaneously identifies the variants CYP2D6 *3, *4, *6, *8, *11, *12, *14, *15, *19, and *20. This constitutes most of the poor metabolizer alleles described in Caucasian and Asian populations. Separate PCR reactions or Southern blots are required for *7, the *5 deletion, and the hybrid alleles *13 and *16. The multiplex assay was validated on 100 individuals previously genotyped by specific polymerase chain reaction-restriction fragment length polymorphism analysis, and proved 100% accurate in this sample. The assay performed consistently with Taq DNA polymerases from various suppliers, within a broad range of temperatures and MgCl(2) concentrations, and using genomic DNA prepared by a range of methods including extraction from dried blood spots on card. This multiplexed, amplification refractory mutation system (ARMS) method is reliable, rapid, relatively cheap, amenable to automation, and offers the advantages of minimal sample handling with no requirement for restriction enzymes as in earlier CYP2D6 assays.

Alleles↗
PubMed2000

Identification of P gene mutations in individuals with oculocutaneous albinism in sub-saharan africa; robyn kerr, gwynneth stevens, prashiela manga, sarah salm, premila john, tabitha haw, and michele ramsay; (Article was originally published in human mutation 15:166-172, 2000)

The authors wish to correct a mistake which occurred in the reporting of one of the mutations. The mutation reported as 683insT is actually an insertion G mutation, and should thus be called 683insG.

Journal Article↗
PubMed2000

Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q(92), responsible for human hypertrophic cardiomyopathy.

The causality of mutant sarcomeric proteins in hypertrophic cardiomyopathy (HCM) is well established. The current emphasis is to elucidate the pathogenesis of HCM in transgenic animal models. We determined the left ventricular ejection fraction (LVEF) in transgenic mice expressing mutant cardiac troponin T (cTnT)-Q(92), known to cause HCM in humans. Transgenes were constructed by placing wild-type (R(92)) or mutant (Q(92)) full-length human cTnT cDNAs 3' into a 5.5-kb murine [alpha -myosin heavy chain (MyHC)] promoter injected into fertilized zygotes. Three wild-type and six mutant lines were produced. Transgene mRNA and proteins, detected using transgene-specific probes were expressed at high levels in all wild-type and three mutant lines. The total cTnT mRNA pool was increased by up to five-fold in transgenic mice, but the total cTnT protein remained unchanged. The mean values of LVEF, determined by(178)Ta radionuclide angiography, were 57.8+/-6% (n=4) in non-transgenic littermate (NLM), 53.3+/-10 (n=6) in wild-type and 39. 4+/-6 (n=5) in mutant transgenic mice (P=0.009). The heart/body weight ratios and the number of cells stained with terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling were similar among the groups. Three mutant mice had myocyte disarray and excess interstitial collagen and two had normal myocardial structure despite having reduced LVEF. Thus, in vivo expression of the mutant cTnT-Q(92)protein, responsible for human HCM, impaired global cardiac systolic function in transgenic mice, which also occurred in the absence of myocyte disarray and increased interstitial collagen.

Animals↗
PubMed2000

Variants of trophic factors and expression of cardiac hypertrophy in patients with hypertrophic cardiomyopathy.

Patients with hypertrophic cardiomyopathy (HCM) exhibit variable expression of left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity, which is partly due to the diversity of causal mutations, genetic background (modifier genes), and probably environmental factors. We determined association of functional variants of tumor necrosis factor (TNF)- alpha, interleukin-6 (IL6), insulin-like growth factor-2 (IGF2), transforming growth factor- beta 1 (TGFB1), and aldosterone synthase (CYP11B2) genes, all previously implicated in cardiac hypertrophy, with the severity of LVH in patients with HCM. Two-dimensional echocardiography was performed and demographic variables were recorded in 142 genetically independent patients. Indices of LVH including interventricular septal thickness (IVST), left ventricular mass index (LVMI), and LVH score were measured/calculated. TNF-alpha-308G/A, IL6-174G/C, IGF2 820G/A, TGFB1-509C/T, and CYP11B2-344T/C genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotypes were identified by the presence of specific electrophoretic patterns and their distributions were according to the Hardy-Weinberg equilibrium. Demographic variables were not significantly different among the genotypes. Subjects with the AA genotype of TNF-alpha (n=8) were approximately 13 years younger at the time of clinical diagnosis. Despite a younger age, they had a greater mean LVMI than those with the GG (n=94) or GA (n=33) genotypes (191.8+/-59.5 v 139.1+/-47.3 v 132.1+/-34.3, respectively, P=0.004). TNF-alpha-308G/A genotypes accounted for 6.0% of variability of LVMI (P=0.002). Mean IVST, LVEDD, and LVH score were not significantly different. Variants of IL6, IGF2, TGFB1, and CYP11B2 were not associated with indices of LVH. The uncommon allele of TNF-alpha-308G/A polymorphism, known to produce more TNF- alpha, was associated with greater LVMI and clinical diagnosis at a younger age in patients with HCM. Functional variants of other trophic factors, previously implicated in cardiac hypertrophy, were not associated with the indices of LVH. These results suggest that TNF-alpha is a modifier gene for HCM.

Adult↗
PubMed2000

Biofeedback for fecal incontinence using transanal ultrasonography: novel approach.

PURPOSE: Neosphincter procedures may prove to be the treatment of choice for patients with neuropathic fecal incontinence but are rarely proposed for milder forms of the disease. Biofeedback may prove beneficial to these patients but is yet unproven. The objectives of this study were to develop a method of performing biofeedback using transanal ultrasound to teach the patient to contract repetitively and to determine biologic measures of sphincter function using transanal ultrasound in healthy and incontinent patients. METHODS: Initial uncontrolled studies were performed to determine the compliance, normal values, biologic measures of external sphincter strength (isotonic and isometric fatigue times), and early efficacy data using continence scores and visual analog scale scores. RESULTS: Forty-four patients were assessed during three months, with relative improvements in continence scores (St. Mark's Hospital, 40 percent; Pescatori, 20 percent) and patient and investigator visual analog scale scores (38 percent for both) and measurable increase in biologic fatigue times measured by transanal ultrasound. CONCLUSIONS: Transanal ultrasound seems to be a method of teaching external sphincter contraction and measuring sphincter strength with good initial compliance. Clinically and statistically significant improvements in incontinence scores, visual analog scale scores, and biologic strength of the external sphincter were detected in the short-term follow-up with uncontrolled data. The randomized, controlled trial that we have begun will either confirm or refute these results.

Adult↗
PubMed2000

A perspective: the new millennium dawns on a new paradigm for cardiology--molecular genetics.

Western civilization had two great epochs--the sixth century B.C. and the 18th century. The 21st century is likely to be the third great epoch. Although cardiology has advanced more in the last 50 years than in the previous 2,000, it is likely to advance more in the next two or three decades than in the previous 2,000 years, including those 50 golden years. The engines of ingenuity to provide the thrust for the 21th century will come from molecular genetics and the application of recombinant deoxyribonucleic acid (DNA) techniques. Identification of all human genes (50,000 to 100,000) in the next two to three years will help link thousands of etiologies and risk factors with their respective diseases, which represents a new paradigm in medicine. This is illustrated by the implications to be drawn from familial hypertrophic cardiomyopathy and the 50 new genes already identified to be responsible for cardiac disease. The hope for prevention and treatment of human disease is unprecedented. Twenty diseases account for 80% of the deaths in the Western world and are due to 100 to 200 genes, all of which will be available in a couple of years. The Phoenician alphabet (inclusive of the Greek vowels) of 26 letters launched two millenniums of Western civilization, whereas the DNA alphabet of only four letters will launch and dominate the next millennium.

Animals↗
PubMed2000

The role of outbreaks in developing food safety policy: population based surveillance of salmonella outbreaks in Wales 1986-98.

In developing public policy on food safety, systematic identification and thorough investigation of all general outbreaks is necessary in order to avoid bias towards highly publicised outbreaks. In Wales, from 1986 to 1998, 87 general foodborne outbreaks of salmonellosis were identified. Most outbreaks occurred at functions or were associated with small catering outlets such as bakeries and sandwich bars. In 50 outbreaks, a vehicle of infection was confirmed microbiologically and/or epidemiologically. The most common food vehicles were those containing shell eggs. Salmonella enteritidis outbreaks were significantly more likely than outbreaks of other serotypes to be associated with vehicles containing shell eggs, suggesting that eggs were also the source of infection in many outbreaks. The routine use of analytical epidemiological studies to identify vehicles in outbreaks is recommended.

Disease Outbreaks↗
PubMed2000

The locus of a novel gene responsible for arrhythmogenic right-ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14.

Arrhythmogenic right-ventricular dysplasia (ARVD), a cardiomyopathy inherited as an autosomal-dominant disease, is characterized by fibro-fatty infiltration of the right-ventricular myocardium. Four loci for ARVD have been mapped in the Italian population, and recently the first locus was mapped in inhabitants of North America. None of the genes have been identified. We have now identified another North American family with early onset of ARVD and high penetrance. All of the children with the disease haplotype had pathological or clinical evidence of the disease at age <10 years. The family spans five generations, having 10 living and 2 dead affected individuals, with ARVD segregating as an autosomal-dominant disorder. Genetic linkage analysis excluded known loci, and a novel locus was identified on chromosome 10p12-p14. A peak two-point LOD score of 3.92 was obtained with marker D10S1664, at a recombination fraction of 0. Additional genotyping and haplotype analysis identified a shared region of 10.6 cM between marker D10S547 and D10S1653. Thus, a novel gene responsible for ARVD resides on the short arm of chromosome 10. This disease is intriguing, since it initiates exclusively in the right ventricle and exhibits pathological features of apoptosis. Chromosomal localization of the ARVD gene is the first step in identification of the genetic defect and the unraveling of the molecular basis responsible for the pathogenesis of the disease.

Adult↗
PubMed2000

Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators.

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 microM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor beta(1)-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor alpha (TNF-alpha) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-alpha and that this process requires p38 MAP kinase activity.

Animals↗
PubMed2000

Role of the dinB gene product in spontaneous mutation in Escherichia coli with an impaired replicative polymerase.

We isolated several new mutator mutations of the Escherichia coli replicative polymerase dnaE subunit alpha and used them and a previously reported dnaE mutation to study spontaneous frameshift and base substitution mutations. Two of these dnaE strains produce many more mutants when grown on rich (Luria-Bertani) than on minimal medium. A differential effect of the medium was not observed when these dnaE mutations were combined with a mismatch repair mutation. The selection scheme for the dnaE mutations required that they be able to complement a temperature-sensitive strain. However, the ability to complement is not related to the mutator effect for at least one of the mutants. Comparison of the mutation rates for frameshift and base substitution mutations in mutS and dnaE mutS strains suggests that the mismatch repair proteins respond differently to the two types of change. Deletion of dinB from both chromosome and plasmid resulted in a four- to fivefold decrease in the rate of frameshift and base substitution mutations in a dnaE mutS double mutant background. This reduction indicates that most mistakes in replication occur as a result of the action of the auxiliary rather than the replicative polymerase in this dnaE mutant. Deletion of dinB from strains carrying a wild-type dnaE had a measurable effect, suggesting that a fraction of spontaneous mutations occur as a result of dinB polymerase action even in cells with a normal replicative polymerase.

Adenosine Triphosphatases↗
PubMed2000

Putting the 'tele' into health-care effectively.

Although the introduction of new technologies has been successful and become accepted practice in many areas of industry, traditional methods have tended to prevail in health-care. Telemedicine has been adopted by enthusiasts who recognize the potential benefits of a 'global health service'. However, the more widespread introduction of telemedicine requires considerable organizational change in the way health-care is delivered. More evaluation is required of clinical outcomes, organizational effects, benefits to health-care providers and users, and quality assurance.

Global Health↗
PubMed2000

The need to ensure that the globalization of information and telematics does not destabilize health-care worldwide.

Modern telecommunication transcends institutional, organizational and cultural boundaries. In the context of health-care, this means that information, enquiries, demands and service provision can be routed anywhere, free of institutional or natural control. The Internet makes information available to anyone regardless of its quality, source or intention. Organizationally initiated applications such as telemedicine are usually intended to reinforce local systems, but their very design and intention indicate a potential rapidly to transcend inherited but electronically ineffectual boundaries. The consequences of such uncontrolled globalization of health-care activities will range from beneficial empowerment and quality improvement, to detrimental effects such as overloading of experts, and undermining of stable health-care systems. The major unplanned societal re-engineering effects in a paper-based culture are likely to be significant and global institutions need to respond by creating positive global frameworks and policies.

Clinical Competence↗