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R Roberts

Publications and source records attributed to R Roberts.

At least 217 records · Page 12Linked to original sources
PubMed1994

The 8993 mtDNA mutation: heteroplasmy and clinical presentation in three families.

The point mutation at bp 8993 of human mtDNA in the ATPase 6 gene is associated with neurogenic weakness, ataxia and retinitis pigmentosa, and with subacute necrotizing encephalomyelopathy (Leigh disease) when present at high copy number. In this study we describe three new multiplex families with the ATPase 8993 mtDNA mutation and demonstrate a correlation between the percentage heteroplasmy of this mutation and the clinical phenotype. By combining this study with previous data we produce a graph of age of onset of symptoms versus percentage heteroplasmy of the mutation. Finally, we determine that ATP synthesis with NAD-linked substrates in cultured lymphoblast mitochondria from three patients with Leigh disease who had a high percentage heteroplasmy was on average 66% of the rate seen in control lymphoblast mitochondria. Similar rates are observed in lymphoblast mitochondria isolated from patients with Leigh disease due to complex I deficiency. This percentage appears to be independent of the rate of electron transport in mitochondria from patient cell lines with the mtDNA 8993 mutation.

Adenosine Triphosphatases↗
PubMed1994

Earlier diagnosis and treatment of acute myocardial infarction necessitates the need for a 'new diagnostic mind-set'.

Triaging patients suspected of myocardial infarction is performed primarily in the coronary care unit, with infarction determined within 12 to 24 hours, and only about 20% are subsequently shown to have myocardial infarction. Plasma MB CK is not elevated until 8 to 10 hours after onset, and the ECG is unreliable; thus, the need has arisen for a new "diagnostic mind-set." The need is threefold: (1) more effective triaging in the emergency room to prevent unnecessary use of hospital beds, particularly those in the intensive care units, (2) to administer thrombolytic therapy in the early hours, and (3) earlier detection of coronary reocclusion and reinfarction. Diagnostic imaging techniques such as pyrophosphate, thallium-201 technetium sestamibi, or positron emitting agents lack the necessary early diagnostic specificity, but echocardiography has potential although its specificity is limited. Plasma CK isoforms provide diagnostic sensitivity and specificity of 96% and 94%, respectively, within the initial 4 to 6 hours of onset and can be assayed within minutes. In a prospective study of 1100 patients suspected of infarction, with conventional MB CK, 22% of the patients admitted to the coronary care unit would have had infarction, whereas using the CK isoforms, 75% had infarction and about 50% were discharged home. A scenario for the future might be to initiate thrombolytic therapy outside the hospital (eg, recombinant tissue-type plasminogen activator [r-TPA] 20 mg bolus) and upon arrival, confirm or exclude infarction by the MB CK isoform which can be performed in the emergency room in 20 minutes to determine whether thrombolytic therapy and heparin should be continued.

Cardiology↗
PubMed1994

Percutaneous transluminal in vivo gene transfer by recombinant adenovirus in normal porcine coronary arteries, atherosclerotic arteries, and two models of coronary restenosis.

BACKGROUND: Gene therapy has been proposed as a possible solution to the problem of restenosis after coronary angioplasty. The current study was undertaken to assess conventional methods of gene transfer and to develop percutaneous techniques for introducing genes directly into the coronary arteries of large mammals. Since the anticipated targets of gene therapy against restenosis include atherosclerotic and previously instrumented arteries, we also evaluated gene transfer in atherosclerotic coronary arteries and in two porcine models of restenosis: one using intracoronary stents and a second using balloon overstretch angioplasty. METHODS AND RESULTS: The conventional method of using perforated balloon catheters to deliver Lipofectin-DNA complexes directly into the coronary arteries of intact animals was applied to 18 porcine coronary arteries including normal arteries, hypercholesterolemic arteries, and those simulating restenosis. The results of this study were consistent with previously published results indicating that only low levels of luciferase gene expression could be obtained by Lipofectin-mediated gene transfer. We therefore undertook a second, parallel study to evaluate percutaneous transluminal in vivo gene transfer using a replication-deficient adenoviral vector. A comparison of the two studies revealed that the mean level of reporter gene expression in the cohort undergoing adenoviral infection was 100-fold higher than in the cohort undergoing Lipofection. Analysis of luciferase activity over time in normal arteries revealed that recombinant gene expression was half-maximal after 1 day, peaked within 1 week, was still half-maximal at 2 weeks, and declined to low levels by 4 weeks. Histochemical analysis of coronary arteries treated with a second adenovirus expressing a nuclear-localized beta-galactosidase gene demonstrated gene transfer to a limited number of cells in the media and adventitia. Immunohistochemical analysis of Ad5-infused arteries using a monoclonal antibody directed against CD44 identified a periadventitial infiltrate composed of leukocytes. CONCLUSIONS: The recombinant adenoviral vectors proved to be far more effective than Lipofectin at delivering foreign genes directly into the coronary arteries of living mammals. Furthermore, the influences of hypercholesterolemia and arterial injury appeared to have little effect on the levels of gene expression obtained using either method. The results demonstrate that low-level recombinant gene expression, the major obstacle impeding gene therapy for the prevention of restenosis, can potentially be overcome by using adenoviral vectors to mediate coronary gene transfer in vivo. The duration of gene expression provided by these vectors and their effective deployment in atherosclerotic, balloon-overstretched, and stented coronary arteries suggest that recombinant adenovirus may have potential for evaluating gene therapy in the clinically informative porcine models of coronary restenosis.

Adenoviridae↗
PubMed1994

The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial.

In the randomized, placebo-controlled, physician-blinded Canadian cooperative trial of cyclophosphamide and plasma exchange, neither active treatment regimens (group I: i.v. cyclophosphamide and prednisone; group II: weekly plasma exchange, oral cyclophosphamide, and prednisone) were superior to placebo (group III: sham plasma exchange and placebo medications) using the blinded, evaluating neurologists' assessments of disease course (primary analysis). All patients were examined by both a blinded and an unblinded neurologist at each assessment in this trial. We compared the blinded and unblinded neurologists' judgment of treatment response and analyzed the clinical behavior of patients who correctly guessed their treatment. The unblinded (but not the blinded) neurologists' scores demonstrated an apparent treatment benefit at 6, 12, and 24 months for the group II patients (not group I or placebo; p < 0.05, two-tailed). There were no significant differences in the time to treatment failure or in the proportions of patients improved, stable, or worse between the group II and group III patients who correctly guessed their treatment assignments and those who did not. Physician blinding prevented an erroneous conclusion about treatment efficacy (false positive, type 1 error).

Cyclophosphamide↗
PubMed1994

Reduced receptor aggregation and altered cytoskeleton in cultured myocytes after space-flight.

We carried out parallel experiments first on the slow clinostat and then in space-flight to examine the effects of altered gravity on the aggregation of the nicotinic acetylcholine receptors and the structure of the cytoskeleton in cultured Xenopus embryonic muscle cells. By examining the concordance between results from space flight and the clinostat, we tested whether the slow clinostat is a relevant simulation paradigm. Space-flown cells showed marked changes in the distribution and organization of actin filaments and had a reduced incidence of acetylcholine receptor aggregates at the site of contact with polystyrene beads. Similar effects were found after clinostat rotation. The sensitivity of synaptic receptor aggregation and cytoskeletal morphology suggests that in the microgravity of space cell behavior may be importantly altered.

Acetylcholine↗
PubMed1994

PSA screening.

Explore the source record for details and available documents.

Aged↗
PubMed1994

A missense mutation in the beta myosin heavy chain gene is a predictor of premature sudden death in patients with hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease with protean clinical manifestations, ranging from asymptomatic to that of severe heart failure or sudden death. There is no known parameter in individuals with hypertrophic cardiomyopathy (HCM) that predicts a specific clinical event. This is particularly troublesome for premature sudden death that frequently occurs in young athletes without prior symptoms. Recent identification of mutations in the beta myosin heavy chain (beta MHC) gene that co-segregate with the inheritance of the disease provides an opportunity to determine whether certain mutations are more likely to induce a particular clinical event. In this study we analyzed the genotype and phenotype of individuals from two unrelated families with HCM in which the affected individuals have the same missense mutation in exon 13 (G1208A) of the coding sequence for beta MHC. METHODS: Individuals from two unrelated families with the diagnosis of FHCM were screened by history, physical examination, electrocardiography, and two dimensional echocardiography. After extraction of DNA from the blood of these individuals, the exon 13 of the beta MHC gene was amplified by polymerase chain reaction (PCR), and the PCR product was digested with Ddel restriction endonuclease. The digestion products were separated by gel electrophoresis and identified by ethidium bromide staining. RESULTS: We studied 54 individuals from the two families, 21 were affected with HCM of which eleven died prematurely, eight from sudden cardiac death. While most of the nine affected individuals studied had septal hypertrophy, three had concentric hypertrophy and six, left ventricular outflow tract obstruction. Onset of symptoms was in the second decade of life. Electrophoretic separation of the digested DNA (exon 13) from unaffected individuals provided two fragments of 84 and 70 bp in size, as expected. In contrast, DNA from individuals affected with HCM showed four fragments of 84 bp, 70 bp, 52 bp and 32 bp indicating they inherited the mutation. In only one 10 year old male was the mutation present without evidence of HCM which gives an overall penetrance of 86%. CONCLUSIONS: The missense mutation in exon 13 of the beta MHC gene in individuals with FHCM is associated with high penetrance, highly variable expressivity, severe disease, early in onset and a high incidence of premature sudden death. Based on these results we recommend individuals from families with HCM be screened for this missense mutation and if positive, be counselled to avoid combative sports, as it is these activities that often precipitate sudden death.

Adult↗
PubMed1994

Molecular basis of hypertrophic and dilated cardiomyopathy.

Hypertrophic cardiomyopathy is a heterogeneous disease with autosomal dominant Mendelian inheritance. In 1989, the 1st locus for hypertrophic cardiomyopathy was mapped to cardiac myosin genes located on chromosome 14q1. Soon, several mutations that cosegregated with inheritance of the disease were identified in the beta-myosin heavy chain gene, or MHY7. More than 30 missense mutations and 1 deletion mutation in the beta-myosin heavy chain gene have since been described. Recently, expression of both the mutant beta-myosin heavy chain mRNA and the mutant protein has been shown in the cardiac and skeletal muscles of individuals with hypertrophic cardiomyopathy. Characterization of the clinical features of beta-myosin heavy chain mutations has shown that certain mutations, such as Arg403Gln and Arg719Trp mutations, are associated with high rate of sudden cardiac death. In addition to the beta-myosin heavy chain gene, 3 new loci for hypertrophic cardiomyopathy have recently been described, but the candidate genes have not yet been identified. Dilated cardiomyopathy can be inherited as an autosomal dominant, autosomal recessive, and X-linked disease. The familial form of dilated cardiomyopathy comprises approximately 20% of the cases of idiopathic cardiomyopathy. Echocardiographic abnormalities such as left ventricular enlargement are present in 10% of asymptomatic relatives. No gene for familial dilated cardiomyopathy has been identified, but linkage studies using polymorphic, short-tandem repeat markers are ongoing. Dilated cardiomyopathy is a common manifestation of Duchenne/Becker muscular dystrophy. Heart failure is a common cause of death in the affected individuals. The gene responsible for this disease is the dystrophin gene located on X chromosome. There have been reports in these patients of several dystrophin-gene deletion mutations, which result in a decrease in the expression of the dystrophin protein in the cardiac and skeletal tissues. X-linked cardiomyopathy, in which the disease is restricted to the heart, has also been linked to the dystrophin gene. Myotonic dystrophy is an autosomal dominant disease that commonly involves the myocardium and the conduction tissue, resulting in conduction defects and heart failure. Sudden cardiac death is the most common cause of mortality in patients with myotonic dystrophy. Recently, the myotonin protein kinase gene located on chromosome 19 was identified as the gene responsible for this disease. Expansion of the number of trinucleotide repeats in the myotonin protein kinase gene results in myotonic dystrophy. Mutations in mitochondrial DNA have been associated with hypertrophic and dilated cardiomyopathy. The inheritance of mitochondrial cardiomyopathy is maternal and the disease is associated with certain systemic disorders.

Cardiomyopathy, Dilated↗
PubMed1993

Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty.

PURPOSE: To compare the efficacy, safety, and cost-effectiveness of low-molecular-weight heparin with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. DATA IDENTIFICATION: Studies were identified by MEDLINE search and review of bibliographies of retrieved articles. Hospital resources used in treating deep vein thrombosis and bleeding complications after total hip arthroplasty were estimated using retrospectively collected data from 447 patients who participated in a recently completed randomized controlled deep vein thrombosis prophylaxis trial at our center. STUDY SELECTION: Randomized controlled trials directly comparing a low-molecular-weight heparin preparation with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty were potentially eligible for the meta-analysis. DATA EXTRACTION: Data from eligible studies were extracted independently by two of the authors. Multiple regression analysis of data from the patient cohort was used to estimate the effect of deep vein thrombosis and bleeding on length of hospital stay. A hypothetical North American price for low-molecular-weight heparin was determined based on the ratio between low-molecular-weight heparin and standard heparin in France. Costs were based on weighted per-diem hospital expenditures and physician fees for procedures and reported in 1992 U.S. dollars. RESULTS OF DATA SYNTHESIS: Meta-analysis of six eligible trials determined that low-molecular-weight heparin was significantly more effective than standard heparin at preventing deep vein thrombosis after total hip arthroplasty (common odds ratio, 0.72; 95% CI, 0.53 to 0.95). However, this benefit was restricted to the prevention of proximal deep vein thrombosis (common odds ratio, 0.40; CI, 0.28 to 0.59). No significant differences were found in the rates of distal deep vein thrombosis or total, major, or minor bleeding between the two groups. Based on a 2.6 to 1 price ratio between low-molecular-weight heparin and standard heparin, use of low-molecular-weight heparin would save the health care system about $50,000 per 1000 patients treated. Sensitivity analysis shows that if the low-molecular-weight heparin/standard heparin price ratio exceeds 3.7 (the threshold value lies between 0.8 and 5.5 based on the extremes of the 95% CI of the common odds ratios for deep vein thrombosis and bleeding complications), use of low-molecular-weight heparin is more expensive. At a price ratio of 10, it would cost more than $250,000 to treat 1000 patients with low-molecular-weight heparin compared with standard heparin or about $5000 for each additional deep vein thrombosis prevented with low-molecular-weight heparin. CONCLUSIONS: Low-molecular-weight heparin is more effective and is at least as safe as standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Based on the current French price ratio of low-molecular-weight heparin to standard heparin, the use of low-molecular-weight heparin in North America would result in overall savings in cost; however, the relative cost-effectiveness is critically dependent on the price ratio between the two drugs. Further research is needed to compare the cost-effectiveness of low-molecular-weight heparin with other prophylactic regimens and postoperative deep vein thrombosis management strategies.

Cost-Benefit Analysis↗
PubMed1993

Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT): rationale and protocol. CAMIAT Investigators.

The Canadian Amiodarone Myocardial Infarction Trial (CAMIAT) is a multicenter, triple-blind, randomized, placebo-controlled trial. Eligible patients are those found on 24-hour ambulatory electrocardiographic monitoring within 6-45 days of acute myocardial infarction to have ventricular premature depolarizations (VPDs) that are frequent (> or = 10/hr) or repetitive (> or = 1 three-beat run of ventricular tachycardia). Consenting patients are randomized to amiodarone or placebo with an oral loading dose of 10 mg/kg/day for 2 weeks; maintenance dose is 300-400 mg/day for 3.5 months, 200-300 mg/day for 4 months, and 200 mg/day for 5 or 7 days/week for 16 months. Patients are followed by alternate telephone and clinical visit at 2-month intervals for 24 months. The principal outcome is a composite of presumed arrhythmic death or resuscitated ventricular fibrillation. Outcomes are determined by an external validation committee. The anticipated rate of arrhythmic death is 7.5% over 2 years; the sample size is 1,200 patients. CAMIAT began in June 1990 and is anticipated to conclude enrollment by June 1994 and follow-up by June 1995. Recruitment rate is about 92% of projected.

Amiodarone↗
PubMed1993

Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death.

We determined the distribution frequency of angiotensin converting enzyme (ACE) polymorphism in 100 patients with hypertrophic cardiomyopathy and 106 of their unaffected siblings and offspring. The distribution of ACE genotypes was different in the two groups: allele D frequency of 0.69 in patients and 0.57 in relatives (p = 0.021). The frequency of allele D was also higher in hypertrophic cardiomyopathy families with a high incidence of sudden cardiac death than those with a low incidence (0.74 vs 0.55, p = 0.011). In 25 hypertrophic cardiomyopathy patients with a strong family history of sudden cardiac death the frequency of allele D was 0.82 (p = 0.001 vs normals).

Alleles↗