Endothelial dysfunction in cardiovascular disease: risk factor, risk marker, or surrogate end point?

Endothelial dysfunction is a feature of the early stages of atherosclerotic cardiovascular disease. It also is almost invariably associated with recognized cardiovascular risk factors, including those that are irreversible (such as age and family history) and those that are reversible (such as hypertension and hypercholesterolemia). It remains the subject of debate whether endothelial dysfunction can be considered an independent risk factor or, perhaps more plausibly, an intermediate or surrogate end point.

Role of Surface Precipitation in Copper Sorption by the Hydrous Oxides of Iron and Aluminum.

Isotherms were developed at pH 6.9 for adsorption (ADS) and coprecipitation (CPT) of Cu by hydrous oxides of Fe (HFO) and Al (HAO) to study the role of sorbate/sorbent ratio in metal cation removal. For low sorbate/sorbent conditions, HFO had a higher Cu retention capacity than HAO regardless of contact methodology.

ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans.

Background: We have investigated the possible effects of contrasting ACE (I/D) genotypes on the responses to the ACE inhibitor enalaprilat in normotensive men.

Methods And Results: Subjects with DD (n=12) and II (n=11) ACE genotypes received an intravenous infusion of enalaprilat or placebo. Pressor responses to stepwise, incremental doses of angiotensin I were measured at 1 and 10 hours after dosing.

Renal and haemodynamic effects of amlodipine and nifedipine in hypertensive renal transplant recipients.

Background: Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal allografts, but is associated with renal vasoconstriction and hypertension. Previous reports suggest that the calcium-channel blockers nifedipine and amlodipine may improve graft function in CsA-treated patients. We have compared the effects of amlodipine (5-10 mg once daily) and nifedipine retard (10-40 mg twice daily) on renal function and blood pressure in renal transplant recipients treated with CsA.

Population pharmacokinetics of gentamicin in patients with cancer.

Aims: The purpose of this study was to describe the population pharmacokinetics of gentamicin in patients with cancer, to identify possible relationships between clinical covariates and population pharmacokinetic parameter estimates and to examine the relevance of existing dosage nomograms in light of the population model developed in these patients.

Methods: Data were collected prospectively from 210 patients with cancer and were analysed with package NONMEM. Data were split into two sets: a population data set and an evaluation set.

Lacidipine: effects on vascular pressor responses throughout the dosage interval in normotensive subjects.

Aims: To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine.

Methods: Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline.

Angiotensin II antagonists: efficacy, duration of action, comparison with other drugs.

The benefits of anti-hypertensive drug treatment have been established by clinical trials demonstrating significant reductions in cardiovascular morbidity and mortality. Thiazide diuretics predominated in these trials but it is reasonable to conclude that the benefits were attributable to the blood pressure (BP) reduction per se and not to specific pharmacological characteristics. Furthermore, it can be calculated that even greater benefits would probably have accrued if the magnitude of the BP reduction had been greater.

A 3-year audit of thyroid fine needle aspirates.

Fine needle aspiration (FNA) cytology is an important adjunct to the preoperative management of thyroid swellings. It is a simple and highly cost effective procedure with a higher sensitivity for the detection of malignancy than ultrasound and radio-isotope scans. We audited a total of 208 aspirates performed over a 3-year period.

The vasodilating effect of insulin is dependent on local glucose uptake: a double blind, placebo-controlled study.

During systemic hyperinsulinemia in man, skeletal muscle vasodilation has consistently been demonstrated. However, most studies that have examined the vascular effect of local hyperinsulinemia have reported either no effect or only weak vasodilation, and all of these have been open in design. The present studies were designed in a double blind, placebo-controlled manner to evaluate the direct (local) vascular effect of insulin alone and in association with physiological concentrations of D-glucose.

Insulin as a vascular hormone: implications for the pathophysiology of cardiovascular disease.

1. Metabolic disorders, such as obesity and non-insulin-dependent diabetes mellitus, and cardiovascular disorders, such as essential hypertension, congestive cardiac failure and atherosclerosis, have two features in common, namely relative resistance to insulin-mediated glucose uptake and vascular endothelial dysfunction. 2.

Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets.

How reproducible is bilateral forearm plethysmography?

Aims: In studies using strain-gauge forearm plethysmography to measure changes in forearm blood flow (FBF) during intra-arterial infusions of vasoactive substances, measurements are often made in both arms simultaneously and the change in ratio of the infused and control arms used to express responses. However, the reproducibility of bilateral plethysmography in this setting has not been addressed in published studies. The unilateral technique remains in use, and forearm vascular resistance (FVR), an alternative method of expressing responses, is used by some investigators.

Clinical pharmacokinetics of nifedipine. Implications for the care of the elderly.

Nifedipine, the prototype for the dihydropyridine class of calcium antagonists, has been available for 20 years and its efficacy as a vasodilator and an antihypertensive agent is well recognised. The development of the so-called nifedipine gastrointestinal therapeutic system (GITS), which allows once-daily administration, has modified and improved the overall therapeutic profile of nifedipine to such a significant extent that it might almost be considered a new drug entity. The nifedipine GITS is associated with distinct improvements in terms of patient compliance and convenience, and a reduced incidence of adverse effects.

Oocyte determination and the origin of polarity in Drosophila: the role of the spindle genes.

The two main body axes in Drosophila become polarised as a result of a series of symmetry-breaking steps during oogenesis. Two of the sixteen germline cells in each egg chamber develop as pro-oocytes, and the first asymmetry arises when one of these cells is selected to become the oocyte. Anterior-posterior polarity originates when the oocyte then comes to lie posterior to the nurse cells and signals through the Gurken/Egfr pathway to induce the adjacent follicle cells to adopt a posterior fate.

The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology.

1. The recognition of the role of insulin resistance in disease states and the recent development of new drugs that modify insulin-dependent metabolism has led to increased use of the euglycaemic hyperinsulinaemic clamp to measure in vivo insulin sensitivity, but several key aspects of the technique are poorly documented in the literature. 2.

The mago nashi gene is required for the polarisation of the oocyte and the formation of perpendicular axes in Drosophila.

Background: Drosophila axis formation requires a series of inductive interactions between the oocyte and the somatic follicle cells. Early in oogenesis, Gurken protein, a member of the transforming growth factor alpha family, is produced by the oocyte to induce the adiacent follicle cells to adopt a posterior cell fate. These cells subsequently send an unidentified signal back to the oocyte to induce the formation of a polarised microtubule array that defines the anterior-posterior axis.

A 3 year audit of fine needle aspirates from a symptomatic breast clinic.

A total of 2431 fine needle aspirates of symptomatic breast lumps was performed on 2096 patients over the last three years at the weekly head, neck and breast clinic at the Belfast City Hospital Trust. Diagnostic accuracy was achieved within the recommended standards although the "insufficient" rate was high at 31.8%.

Identifying individuals with high fat levels and low P:S ratios, in their diets, for intensive dietary intervention.

Objectives: To assess whether simple scores from a dietary questionnaire could identify those with high dietary fat or low P:S ratio intakes, for intensive dietary intervention.

Design: Cross-sectional and longitudinal studies.

Setting: Community setting in the Hunter Region of New South Wales, Australia.

Investigation into the concanavalin A reactivity, fucosylation and oligosaccharide microheterogeneity of alpha 1-acid glycoprotein expressed in the sera of patients with rheumatoid arthritis.

alpha 1-Acid glycoprotein (AGP) exists as an heterogeneous population of glycosylated variants (glycoforms) in plasma. The concentration of AGP increases some 2-5 fold in certain pathophysiological states exemplified by the chronic inflammatory disease, rheumatoid arthritis (RA). Moreover, the expressed glycosylation pattern alters in such conditions, indicating functional significance that is likely to be related to the oligosaccharide heterogeneity.

Evaluation of endpoints in hypertension: blood pressure.

The benefits of antihypertensive therapy in reducing both cerebrovascular and cardiac events have been clearly demonstrated in the meta-analysis of randomised outcome trials. Whilst the use of diuretics and beta-blockers have tended to predominate in these trials, other agents were also included and thus it is reasonable to suggest that the benefit of treatment is not attributable to any particular class of agent but rather to a reduction in blood pressure per se. It may therefore, be reasonably argued that blood pressure itself is the only validated surrogate marker of cardiovascular outcome.