PubMed Health⌕ Search

Biomedical subjects

Graham Jackson

Publications and source records attributed to Graham Jackson.

At least 19 recordsLinked to original sources
PubMed2003

Aspirin modifies nitric oxide synthase activity in platelets: effects of acute versus chronic aspirin treatment.

OBJECTIVE: We examined the effects of aspirin on basal and beta-adrenoceptor (beta-AR)-mediated nitric oxide synthase (NOS) activity in normal platelets. METHODS: NOS activity was determined from the conversion of L-[3H]arginine to L-[3H]citrulline, both basally and following beta-AR stimulation, in platelets from healthy human subjects following both short- and long-term aspirin administration. RESULTS: Basal L-[3H]citrulline increased following aspirin 800 mg administered intravenously in vivo, from 0.31+/-0.12 to 0.76+/-0.14 pmol/10(8) platelets (P<0.01). Isoproterenol at 1 micromol/l increased platelet NOS activity before but not following intravenous aspirin. After short-term in vitro treatment with aspirin 10 micromol/l, 400 micromol/l or 4 mmol/l, basal platelet L-[3H]citrulline increased similarly, an effect not seen with indomethacin 100 micromol/l or ibuprofen 10 micromol/l. Platelet NOS activity was not increased by albuterol 1 micromol/l, in the presence of indomethacin, ibuprofen or aspirin in vitro. By contrast, oral aspirin 75 mg daily for 14 days did not affect basal platelet NOS activity, but abolished beta-adrenergic NOS activation. CONCLUSIONS: Aspirin activates basal platelet NOS acutely, but not chronically, through a mechanism independent of cyclooxygenase (COX) inhibition. By contrast, both short- and long-term aspirin treatment inhibit platelet beta-adrenergic NOS activation by a COX-dependent mechanism. This indicates that aspirin exerts divergent effects on basal and beta-AR-stimulated platelet NOS activity, which are likely to be of clinical relevance.

Adrenergic beta-Agonists↗
PubMed2003

Regional heterogeneity of cellular prion protein isoforms in the mouse brain.

Prion diseases are a group of invariably fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, and bovine spongiform encephalopathy in cattle. The infectious agent or prion is largely composed of an abnormal isoform (PrPSc) of a host encoded normal cellular protein (PrPc). The conversion of PrPc to PrPSc is a dynamic process and, for reasons that are not clear, the distribution of spongiform change and PrPSc deposition varies among prion strains. An obvious explanation for this would be that the transformation efficiency in any given brain region depends on favourable interactions between conformations of PrPc and the prion strain being propagated within it. However, identification of specific PrPc conformations has until now been hampered by a lack of suitable panels of antibodies that discriminate PrPc subspecies under native conditions. In this study, we show that monoclonal antibodies raised against recombinant human prion protein folded into alpha or beta conformations exhibit striking heterogeneity in their specificity for truncations and glycoforms of mouse brain PrPc. We then show that some of these PrPc isoforms are expressed differentially in certain mouse brain regions. This suggests that variation in the expression of PrPc conformations in different brain regions may dictate the pattern of PrPSc deposition and vacuolation, characteristic for different prion strains.

Animals↗
PubMed2003

Changes in the human mitochondrial genome after treatment of malignant disease.

Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in human cells. The mitochondrial genome encodes essential information for the synthesis of the mitochondrial respiratory chain. Inherited defects of this genome are an important cause of human disease. In addition, the mitochondrial genome seems to be particularly prone to DNA damage and acquired mutations may have a role in ageing, cancer and neurodegeneration. We wished to determine if radiotherapy and chemotherapy used in the treatment of cancer could induce changes in the mitochondrial genome. Such changes would be an important genetic marker of DNA damage and may explain some of the adverse effects of treatment. We studied samples from patients who had received radiotherapy and chemotherapy for point mutations within the mtDNA control region, and for large-scale deletions. In blood samples from patients, we found a significantly increased number of point mutations compared to the control subjects. In muscle biopsies from 7 of 8 patients whom had received whole body irradiation as well as chemotherapy, the level of a specific mtDNA deletion was significantly greater than in control subjects. Our studies have shown that in patients who have been treated for cancer there is an increased level of mtDNA damage.

Adolescent↗
PubMed2002

Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.

CONTEXT: Percutaneous coronary intervention (PCI) is associated with excellent short-term improvements in ischemic symptoms, yet only three fifths of PCI patients at 5 years and one third of patients at 10 years remain free of major adverse cardiac events (MACE). OBJECTIVE: To determine whether treatment with fluvastatin reduces MACE in patients who have undergone PCI. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted at 77 referral centers in Europe, Canada, and Brazil. PATIENTS: A total of 1677 patients (aged 18-80 years) recruited between April 1996 and October 1998 with stable or unstable angina or silent ischemia following successful completion of their first PCI who had baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0 mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5 mmol/L). INTERVENTIONS: Patients were randomly assigned to receive treatment with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at hospital discharge for 3 to 4 years. MAIN OUTCOME MEASURE: Survival time free of MACE, defined as cardiac death, nonfatal myocardial infarction, or reintervention procedure, compared between the treatment and placebo groups. RESULTS: Median time between PCI and first dose of study medication was 2.0 days, and median follow-up was 3.9 years. MACE-free survival time was significantly longer in the fluvastatin group (P =.01). One hundred eighty-one (21.4%) of 844 patients in the fluvastatin group and 222 (26.7%) of 833 patients in the placebo group had at least 1 MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95; P =.01). This result was independent of baseline total cholesterol levels (above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02] the median). In subgroup analysis, the risk of MACE was reduced in patients with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91; P =.01) who received fluvastatin compared with those who received placebo. There were no instances of creatine phosphokinase elevations 10 or more times the upper limit of normal or rhabdomyolysis in the fluvastatin group. CONCLUSION: Fluvastatin treatment in patients with average cholesterol levels undergoing their first successful PCI significantly reduces the risk of major adverse cardiac events.

Adult↗
PubMed2002

Cost-effectiveness of preoperative positron emission tomography in ischemic heart disease.

BACKGROUND: Revascularization of patients with ischemic heart disease and poor left ventricular function for surgical procedures is expensive and carries considerable risks, but may improve survival for patients with hibernating myocardium. Positron emission tomography can detect hibernating myocardium, and may be cost-effective if used to select patients for operation. METHODS: An economic model was developed to compare the cost-effectiveness of three management strategies: (1) coronary artery bypass grafting for all patients; (2) using positron emission tomography to select candidates for coronary artery bypass grafting, those without hibernation remaining on medical therapy; and (3) medical therapy for all patients. The model used data from our hospital and the published literature. A sensitivity analysis was also undertaken. RESULTS: Positron emission tomography was cost-effective in selecting patients for operation. In a hypothetical population of 1,000 patients, using positron emission tomography saved marginally more life-years and cost approximately Pound Sterling 3 million less. Using positron emission tomography before coronary artery bypass grafting instead of all patients receiving medical treatment saved lives but was more expensive. The incremental cost per life-year saved was Pound Sterling 77,000. The sensitivity analysis showed that the prevalence of hibernation and the survival rate of patients refused revascularization on the basis of the positron emission tomography scan were the areas most likely to influence cost-effectiveness. CONCLUSIONS: Positron emission tomography may be cost-effective to select patients with poor left ventricular function for coronary artery bypass grafting.

Coronary Artery Bypass↗
PubMed2002

Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease.

Sildenafil citrate is the first oral phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction. The wide use of sildenafil by patients with erectile dysfunction and cardiovascular disease has resulted in a considerable number of independent studies investigating the cardiovascular safety and functional role of the phosphodiesterase type 5-cyclic guanosine monophosphate-nitric oxide pathway in the cardiovascular system. Endothelial dysfunction, defined as a reduction in the bioavailability of nitric oxide, is associated with many of the common risk factors for cardiovascular disease and erectile dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure and diabetes. Hemodynamic studies suggest that sildenafil is a modest vasodilator with the potential to increase coronary blood flow and coronary flow reserve. In patients with ischemic heart disease, sildenafil is associated with reductions in mean arterial and pulmonary pressure with little effect on heart rate, cardiac output, and systemic or pulmonary vascular resistance. The absence of an effect on cardiac output supports the lack of an inotropic effect of sildenafil. This is consistent with the finding that sildenafil has no effect on cyclic adenosine monophosphate levels in the vasculature. Finally, exciting reports have emerged from clinical experience with the use of phosphodiesterase type 5 inhibitors in patients with pulmonary hypertension.

Cardiovascular Diseases↗
PubMed2002

Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis.

OBJECTIVE: To determine the relative efficacy of antianginal drugs administered as monotherapy or in combination in patients with chronic stable angina. METHODS: A meta-analysis was performed on randomized trials, published in English between 1980 and 1999, that directly compared combined treatment and monotherapy. Twenty-two articles were included, all on the comparison of -blocker monotherapies to their combination with a calcium antagonist and 10 on the comparison of calcium antagonist monotherapies to their combination with a -blocker. RESULTS: Time to 1 mm ST-segment depression, total exercise duration and time to onset of anginal pain were significantly increased with the combined therapy compared to -blocker alone (by 8, 5 and 12%, respectively). Only time to 1 mm ST-segment depression was significantly increased with the combined therapy compared to calcium antagonist alone (by 9%). For all these parameters, the adjusted differences were significant only within 6 h following drug intake and were not significant after 6 h. No analysis of safety data could be performed. CONCLUSION: As far as exercise testing is concerned, the combination of a calcium antagonist and a -blocker is statistically more effective than either monotherapy. Further studies are needed to confirm the higher efficacy after the first 6 h following drug intake.

Adrenergic beta-Antagonists↗
PubMed2002

Interpreting small quantities of DNA: the hierarchy of propositions and the use of Bayesian networks.

The dramatic increase in the sensitivity of DNA profiling systems that has occurred over recent years has led to the need to address a wider range of interpretational problems in forensic science. The issues surrounding questions of the kind "whose DNA is this?" have been the subject of considerable controversy but now it is clear that the emphasis is shifting to questions of the kind "how did this DNA get here?" Such issues are discussed in this paper and new insights are provided by two particular recent developments. First, the notion of the "hierarchy of propositions" that has arisen from a project called Case Assessment and Interpretation (CAI) that has been running in the British Forensic Science Service (FSS). Second, a technique for drawing inferences in the face of many interacting considerations, known as "Bayesian networks"--or "Bayes' nets" for short--that has been the subject of an earlier paper in this journal (1). The discussion is carried out by means of case studies, based on actual cases. It is clear that, whereas the inference in relation to the source of the DNA in a crime sample might be overwhelmingly strong, the inference in relation to the propositions that a jury must consider relating to the identity of the actual offender may be much more tentative.

Bayes Theorem↗