Search PubMed⌕ Search

Biomedical subjects

J L Reid

Publications and source records attributed to J L Reid.

At least 37 records · Page 2Linked to original sources
PubMed1999

Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium.

The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.

Animals↗
PubMed1999

Does potassium channel opening contribute to endothelium-dependent relaxation in human internal thoracic artery?

Opening of potassium channels can cause hyperpolarization and relaxation of vascular smooth muscle cells. The aim of this work was to investigate the contribution of potassium channel activation to vasorelaxation in internal thoracic artery taken from patients undergoing coronary artery bypass graft surgery. Relaxations to carbachol and sodium nitroprusside were studied in isolated rings of internal thoracic artery in the absence and presence of nitric oxide synthase inhibitors and potassium channel blockers. The nitric oxide synthase inhibitors Nomega-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine abolished relaxations to carbachol. Relaxations to both carbachol and sodium nitroprusside were attenuated in the presence of raised extracellular potassium and the potassium channel blockers charybdotoxin, iberiotoxin and tetraethylammonium. Neither apamin nor glibenclamide modified relaxation. ODQ (1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one), an inhibitor of soluble guanylate cyclase, abolished relaxation to carbachol in rings from some but not all subjects. These results suggest that potassium channel opening may make a small contribution to endothelium-dependent vasorelaxation in internal thoracic artery. The potassium channels had characteristics consistent with those of large-conductance calcium-dependent potassium channels.

Aged↗
PubMed1998

E1A directly binds and regulates the P/CAF acetyltransferase.

The P/CAF protein has intrinsic histone acetyltransferase (HAT) activity and is capable of binding the transcriptional co-activator CBP. Here we show that P/CAF can regulate transcription and that this function is independent of its binding to CBP. The HAT domain of P/CAF has transcriptional activation potential in yeast. In mammalian cells P/CAF can stimulate transcription of the RSV promoter, using the activity of its HAT domain. We show that the adenovirus protein E1A targets P/CAF and sequesters its transcriptional activity. Binding of E1A to P/CAF is direct, independent of CBP and requires residues within E1A conserved region 1. We find that the P/CAF binding residues in E1A are within a motif shown to be essential for efficient disruption of myogenesis by E1A. The fact that E1A can directly bind and regulate the activity of P/CAF, independently of its regulation of CBP, highlights an important role for P/CAF in the process of cell differentiation.

Acetyltransferases↗
PubMed1998

Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?

BACKGROUND: Previous studies have reported an increased risk of cancer with calcium-channel blockers in man. Other work in animals suggests that inhibitors of angiotensin-I-converting enzyme (ACE) protect against cancer. We aimed to assess the risk of cancer in hypertensive patients receiving ACE inhibitors or other antihypertensive drugs. METHODS: Our retrospective cohort study was based on the records of 5207 patients who attended the Glasgow Blood Pressure Clinic between Jan 1, 1980, and Dec 31, 1995. The patients' records are linked with the Registrar General Scotland and the West of Scotland Cancer Registry. FINDINGS: Compared with the West of Scotland controls, the relative risks of incident and fatal cancer among the 1559 patients receiving ACE inhibitors were 0.72 (95% CI 0.55-0.92) and 0.65 (0.44-0.93). Among the 3648 patients receiving antihypertensive drugs other than ACE inhibitors (calcium-channel blockers 1416, diuretics 2099, beta-blockers 2681), the corresponding relative risks were 110 (0.97-1.22) and 1.03 (0.87-1.20). The relative risk of cancer was lowest in women on ACE inhibitors: 0.63 (0.41-0.93) for incident cancer; 0.48 (0.23-0.88) for fatal cancer; and 0.37 (0.12-0.87) for female-specific cancers. The reduced relative risk of cancer in patients on ACE inhibitors was greatest with follow-up of longer than 3 years. Calcium-channel blockers, diuretics, and beta-blockers had no apparent effect on risk of cancer. INTERPRETATION: Long-term use of ACE inhibitors may protect against cancer. The status of this finding is more that of hypothesis generation than of hypothesis testing; randomised controlled trials are needed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Retinoblastoma protein recruits histone deacetylase to repress transcription.

The retinoblastoma protein (Rb) silences specific genes that are active in the S phase of the cell cycle and which are regulated by E2F transcription factors. Rb binds to the activation domain of E2F and then actively represses the promoter by a mechanism that is poorly understood. Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb 'pocket' domain. Association with the deacetylase is reduced by naturally occurring mutations in the pocket and by binding of the human papilloma virus oncoprotein E7. We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cycle protein cyclin E. Inhibition of histone deacetylase activity by trichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter. Our results indicate that histone deacetylases are important for regulating the cell cycle and that active transcriptional repression by Rb may involve the modification of chromatin structure.

Amino Acid Sequence↗
PubMed1998

Topographic detection of photorefractive keratectomy.

PURPOSE: This study aimed to evaluate the sensitivity and specificity of subjective review of corneal topography to detect patients who have undergone photorefractive keratectomy (PRK). METHODS: Topographic maps from 3 different devices were obtained from 19 patients with postoperative PRK and 9 control subjects with emmetropia and 10 control subjects with myopia. Each image was printed in an absolute and relative scale (total of 228 maps) and graded for overall shape and pattern. Fifteen masked reviewers independently rated each map as either postoperative PRK or not. RESULTS: The overall sensitivity (ability to detect PRK) and specificity rates (ability to exclude control subjects) by reviewers were 65% and 93%, respectively. Sensitivity was influenced independently by the scale (relative, 68%; absolute, 62%; P < 0.01), experience of reviewer (experienced, 77%; inexperienced, 53%; P < 0.001), and device (Alcon, 67 +/- 29.9; Eyesys, 75 +/- 29.4%; and Tomey, 54 +/- 31.7%; P < 0.001). Low levels of preoperative myopia were consistently more difficult to detect than higher levels (low myopia -1.50 to -2.99 diopters [D] sensitivity: 53 +/- 34.5%; medium level -3.00 to -4.49 D: 67 +/- 28.9%; and high level -4.50 to -6.00 D: 77 +/- 21.1%; P < 0.0001). Differences in specificity between experienced and inexperienced reviewers were obtained when maps had a homogeneous topographic pattern (97 +/- 5.6% and 85 +/- 13.7%, respectively; P < 0.05). Several control topography patterns (e.g., homogeneous, focal, and keyhole) were disproportionately more difficult to correctly identify on the Eyesys device. CONCLUSIONS: Topographic experience is a significant factor influencing the correct identification of PRK. Techniques also can be used to enhance detection, such as the use of different devices and scales. However, if subjective review of topography is used as the only method of detection, many patients with PRK will not be identified properly. In addition, the most prevalent preoperative myopic category in the general population (myopia < -3.00 D) also is the most difficult to detect after treatment. This reduces the usefulness of topography as a screening tool. Other techniques are needed to improve the detection of patients with postoperative PRK.

Adult↗
PubMed1998

Determinants of the blood pressure response to the first dose of ACE inhibitor in mild to moderate congestive heart failure.

AIMS: To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables. METHODS: We studied individual placebo-corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis. RESULTS: BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2 = 5.8%, P = 0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2 = 14.4%, P = 0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r = 23.6%, P < 0.01) but left the majority of the variability in response unexplained. CONCLUSIONS: The first-dose blood pressure response to ACE inhibition cannot be accurately predicted from baseline pathophysiological variables in patients with mild to moderate CHF. The choice of ACE inhibitor accounts for a small proportion of the variability in response but wide inter-individual variability exists in the response to each treatment.

Aged↗
PubMed1998

The distribution of human TCR junctional region lengths shifts with age in both CD4 and CD8 T cells.

Several normal and pathological antigen-driven immune responses are associated with limited TCR usage. CDR3 sequence and to some extent length represent clonal markers which can be used to follow the course of an immune response. We investigated whether differences exist in the CDR3 length distribution in the CD4 versus CD8 populations which might reflect the HLA class restriction of the T cell subpopulation. We showed that the range is similar in both the CD4 and CD8 populations for most BV families. Differences exist between CDR3 length distributions of adult versus cord blood CD4 and CD8 T cells. The percentage expressing CDR3 of 10 amino acids or more across all BV families was significantly lower in the cord blood T cells compared to the adults for both CD4 and CD8 populations. This is likely to reflect either differences in the development of the T cell population such as increased N region length post-partum or may be the result of foreign antigen exposure. To address this issue, samples of TCRBV sequences from cord and adult T cell populations were compared. No significant differences were found in either exonucleolytic removal or N region addition between the adult and cord blood samples suggesting that the population shift is the result of antigen exposure. No spectratype distortions existed for any BV family in the adult or cord blood CD4 populations; however, distortions were seen in CD8 populations from all the adults and much less frequently in the cord blood T cells. We investigated the ability to detect clonality at frequencies that one would expect to find antigen-specific T cells in the peripheral repertoire. It was possible to identify a clone at a frequency of 0.1% in a polyclonal CD4 population. This frequency corresponds to that of some individual clones after antigen-driven T cell expansion and establishes parameters within which T cell immune responses may be tracked ex vivo.

Adult↗
PubMed1998

Meeting the needs of women living with HIV.

HIV research, treatment, and support programs in North America have been based on the premise that HIV is a gay man's disease. HIV also affects women. The purposes of this study were to: (1) examine the feelings, concerns, and needs of HIV infected women in a mid-sized Canadian city; and (2) determine whether a community agency for HIV positive persons was adequately supporting women. With informed consent, HIV positive women attending the community agency or a regional medical care facility were interviewed using qualitative research methods to elicit their lived experience. Eight women were interviewed (20% of the women who are HIV positive in this center). Four areas of concern were identified: (1) the impact of diagnosis on women and their children; (2) need for supports specific to HIV positive women; (3) differences in needs and supports available to men and women; and (4) lack of comfort with, or knowledge about, currently available facilities. These results are consistent with previously reported research. HIV positive women who are neither drug-users nor promiscuous feel stigmatized and less supported than HIV positive males. Recommendations for practice included: formulation of self-help groups for women, a more female friendly atmosphere, presence of female staff and other HIV positive women to support these women, and improved inter-agency cooperation. Many recommendations have been implemented and exceeded. The community agency now includes a child's play area, the hiring of a female social worker, and the establishment of an off-site support group for HIV positive women.

Canada↗
PubMed1998

Vascular smooth muscle cell polyploidy and cardiomyocyte hypertrophy due to chronic NOS inhibition in vivo.

To assess the vascular and cardiac response to NO (nitric oxide) synthase (NOS) blockade in vivo, Wistar-Kyoto rats (WKY) were treated for 3 wk with NG-nitro-L-arginine methyl ester (L-NAME; 10 mg.kg-1.day-1). L-NAME treatment induced hypertension that was associated with increased plasma renin activity. Flow cytometry cell cycle DNA analysis showed that aortic vascular smooth muscle cells (VSMC) from L-NAME-treated WKY had a significantly higher polyploid population compared with WKY controls. Using organ bath experiments, we have shown that aortic rings from L-NAME-treated WKY have an increased contractile response to phenylephrine and impaired relaxation to carbachol compared with control rings. NOS blockade in vivo caused a significant increase in cardiac and left ventricular hypertrophy. Northern mRNA analysis of the myocardium showed that L-NAME treatment caused reexpression of the fetal skeletal alpha-actin isoform without alterations in collagen type I expression, a pattern indicating true hypertrophy of the cardiomyocytes. These studies provide further insight to confirm that NO deficiency in vivo results in the development of vascular and cardiac hypertrophy.

Actins↗
PubMed1998

Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait.

BACKGROUND AND PURPOSE: Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1 hybrids derived from a SHRSP/WKY cross. METHODS: The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume. RESULTS: Infarct volumes measured by MRI in adult SHRSP (19.5 +/- 2.0%) and F1 hybrid rats (19.4 +/- 1.9%) were significantly greater than in WKY (11.1 +/- 2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F1 hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001). CONCLUSIONS: Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F1 hybrid rats and indicates a dominant mode of inheritance for this phenotype.

Animals↗
PubMed1998

Endothelium dependent and independent relaxation of aortic rings from Watanabe heritable hyperlipidemic rabbits after exposure to free radical generating system.

The effects of the xanthine oxidase/hypoxanthine free radical generating system on endothelium dependent and independent relaxation were compared in aortic rings from New Zealand white rabbits and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits with mild atherosclerosis. Studies were carried out in young (3 months) and mature (18 months) animals. Plasma cholesterol levels were significantly higher in both 3 and 18 month WHHL animals. Endothelium independent relaxation to SNP did not differ between groups. However, the attenuation of relaxation to carbachol after xanthine oxidase/hypoxanthine treatment tended to be less in WHHL. This reached significance at 18 but not 3 months. We propose that this could be due to increases in levels of endogenous scavenger enzymes in these WHHL rabbits.

Animals↗
PubMed1997

Left ventricular hypertrophy and arterial blood pressure in experimental models of hypertension.

Cardiac hypertrophy in essential and experimental (genetic) hypertension have been initially attributed to increased pressure load. However, the level of blood pressure does not parallel the degree of cardiac hypertrophy, i.e., a complex relationship rather than a simple dose-response effect has to be suggested. Several non-haemodynamic factors which influence LV mass have been identified with genetic and neuro-hormonal influences playing a major role. The experimental strategies which have been used to highlight one or more of these influences include pharmacological studies of regression or prevention of LVH and studies designed to produce LVH de-novo in normotensive strains. All these studies while confirming an important role of haemodynamic factors also stress the major influence of the renin-angiotensin system and the inter-relationship between angiotensin II and nitric oxide. In contrast, genetic strategies, from simple co-segregation analysis to most complex genome scan studies, suggest the existence of "susceptibility genes" for LV hypertrophy, a finding which deserves further study in large collections of siblings and family groups with essential hypertension.

Animals↗
PubMed1997

Effects of nitric oxide and superoxide on relaxation in human artery and vein.

Endothelium-derived relaxing and contracting factors play an important role in atherosclerosis, re-stenosis and graft survival. Internal thoracic artery (ITA) and saphenous vein (SV) are used as conduit vessels in coronary artery bypass graft surgery (CABG). The long-term graft patency rate is higher with ITA than SV. Effects of nitric oxide and superoxide on vascular relaxation in isolated rings of ITA and SV from patients undergoing CABG were investigated. NG-nitro-L-Argenine methylester (L-NAME) was used to block nitric oxide synthesis and superoxide dismutase (SOD) and tiron to scavenge superoxide. Responses to carbachol were taken as a measure of stimulated nitric oxide release and increased responses to phenylephrine after addition of L-NAME as a measure of basal nitric oxide release. Immunocytochemical demonstration of endothelial nitric oxide synthase was performed using anti-endothelial nitric oxide synthetase (anti-eNOS) NOS antibody. Stimulated nitric oxide release was observed in ITA and SV but basal release was reduced or absent in SV. Treatment with SOD and tiron potentiated carbachol stimulated relaxation in ITA and SV. Tiron treatment resulted in a significant increase in basal nitric oxide in veins. eNOS immunoreactivity was more intense in ITA than SV, compatible with reduced nitric oxide production in veins. This may contribute to the reduced patency of venous grafts.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1997

Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension.

Losartan potassium, an angiotensin II receptor antagonist, is the first of a new class of agents to be introduced for the treatment of hypertension. In this review, we describe the clinical pharmacology of losartan, including its pharmacokinetics in healthy, male volunteers and special patient groups, such as the elderly, patients with liver disease and patients with renal impairment. We also review its pharmacodynamics, including safety and tolerability; specificity of action; and the effect of salt depletion. We then review the studies examining clinical efficacy and safety in hypertension.

Age Factors↗
PubMed1997

From kinetics to dynamics: are there differences between ACE inhibitors?

Angiotensin converting enzyme inhibitors are established treatment for hypertension and heart failure. There are well documented differences between ACE inhibitors both in physicochemical properties and pharmacokinetics. Pharmacodynamic actions are similar for most members of the ACE inhibitor class but there are compounds with additional effects which may reflect protease inhibition or non-enzyme-directed pharmacological properties. Clinically relevant differences are few and far between, particularly in the treatment of hypertension when the optimal dose and dose intervals are used. In heart failure there may be a role for drugs with additional properties such as neutral endopeptidase inhibition. In addition, ACE inhibitors differ in the profile of blood pressure changes after the first dose. Early haemodynamic changes with a fall in blood pressure in heart failure patients may be disadvantageous in terms of subsequent outcome. Thus the haemodynamic effects of the first dose may be relevant to the choice of ACE inhibitors in heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Animals↗