Vascular compliance versus flow-mediated vasodilation: correlation with cardiovascular risk factors

Cardiovascular risk factors are associated with impaired endothelium dependent vasodilation and reduced vascular compliance. In this study, the correlation with cardiovascular risk factor score of two common techniques for assessing vascular function was compared. Risk factors and vascular function were evaluated in a study population of 122 people with peripheral arterial disease (PAD) or with risk factors for PAD (73 men and 49 women; mean age 69 years). A risk factor score was determined using Framingham criteria. Vascular compliance was assessed by pulse waveform analysis and simultaneous blood pressure measurement. Flow-mediated vasodilation of the brachial artery was measured using duplex ultrasonography. Participants with a high risk factor score had significantly reduced vascular compliance of large and small vessels. By contrast, the difference in flow-mediated vasodilation between those with a high or low risk factor score did not reach statistical significance. There was a significant negative correlation between vascular compliance and risk factor score. There was a similar trend between flow-mediated vasodilation and risk factor score, but this did not reach statistical significance. A measure of vascular compliance was more significantly correlated with cardiovascular risk factor score than was a measure of flow-mediated vasodilation in the study population. Neither technique provided values that were highly correlated with risk factor burden. Although flow-mediated vasodilation is a preferred research tool for assessing vascular function, technical limitations and biological variability may reduce its clinical application in assessing individual cardiovascular risk.     

Endocrine disrupters: a human risk?

Endocrine disrupters (EDs) alter normal hormonal regulation and may be naturally occurring or environmental contaminants. Classically, EDs act genomically, with agonistic or antagonistic effects on steroid receptors and may alter reproductive function and/or cause feminisation by binding to oestrogen or androgen receptors; their binding to the thyroid receptor may dysregulate the neuroendocrine system. Recently, it has been shown that EDs can also act by non-genomic mechanisms, altering steroid synthesis (inhibition of cytochrome P450 isoforms) or steroid metabolism. The alkylphenol and phthalate plasticisers inhibit the inactivation of oestrogens by sulphation (via SULT 1A1 and 1E1 isoforms) and so cause a rise in levels of the free active endogenous oestrogens. A range of ED effects have been shown in mammals, fish, birds, reptiles, amphibia and aquatic invertebrates but it is not yet clear whether these processes also occur in human beings. It is evident that EDs, as well as altering reproduction, can cause changes in neurosteroid levels and so have the potential to affect immune function, behaviour and memory. This may be of long-term concern since traces of EDs such as plasticisers, brominated fire retardants, sunscreen agents and cosmetic ingredients are widely distributed in the environment and in human biofluids.     

Emergency presentation of an elderly female patient with profound hypoglycaemia

We present the case of an elderly non-diabetic female who was admitted to hospital as an emergency due to loss of consciousness. Her clinical presentation was consistent with hypoglycaemia due to a massive insulin overdose. However, the patient refuted the possibility of insulin administration, and the circumstances were reported to the police for investigation. This case demonstrates the clinical and biochemical characteristics of insulin overdose. Furthermore, it serves to illustrate the sequence of events that may be created when foul play is suspected, and the factors related to patient confidentiality that require consideration by the responsible physician.     

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene

Several studies using microarrays have shown that changes in gene expression provide information about the mechanism of toxicity induced by xenobiotic agents. Nevertheless, the issue of whether gene expression profiles are reproducible across different laboratories remains to be determined. To address this question, several members of the Hepatotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute evaluated the liver gene expression profiles of rats treated with methapyrilene (MP). Animals were treated at one facility, and RNA was distributed to five different sites for gene expression analysis. A preliminary evaluation of the number of modulated genes uncovered striking differences between the five different sites. However, additional data analysis demonstrated that these differences had an effect on the absolute gene expression results but not on the outcome of the study. For all users, unsupervised algorithms showed that gene expression allows the distinction of the high dose of MP from controls and low dose. In addition, the use of a supervised analysis method (support vector machines) made it possible to correctly classify samples. In conclusion, the results show that, despite some variability, robust gene expression changes were consistent between sites. In addition, key expression changes related to the mechanism of MP-induced hepatotoxicity were identified. These results provide critical information regarding the consistency of microarray results across different laboratories and shed light on the strengths and limitations of expression profiling in drug safety analysis.     

Incidence of amyotrophic lateral sclerosis and of the parkinsonism-dementia complex of Guam, 1950-1989

Studies representing the accumulated information from the first 30 years of research effort on Guam (1950-1979) have demonstrated a varying degree of decline in the incidence of amyotrophic lateral sclerosis (ALS) and the parkinsonism-dementia complex (PDC) of Guam. Analysis with more complete information for the period 1980-1989 provides more valid estimates of the later patterns in the incidence of ALS and PDC and affords a more extensive assessment of trends over a 40-year period. The annual age-adjusted incidence of ALS was 7/100,000 and the annual age-adjusted incidence of PDC was 22/100,000 in 1989. The incidence was much higher for the period 1980-1989 than suggested in previous reports. These findings provide compelling evidence that this spectrum of neurodegenerative diseases continues to have a significant impact on the health of the Chamorro people of Guam.     

The effect of cysteine analogues on the excretion of urinary sulphate in the rat following cysteine administration

A major pathway for the production of sulphate within the mammalian body is known to be via the oxidative degradation of the sulphur moiety within the amino acid, L-cysteine. The ability of two structurally similar sulphur-containing drugs, the anti-rheumatic agent, D-penicillamine, and the mucoactive compound, S-carboxymethyl-L-cysteine, to interfere with this sulphate production was investigated. Co-administration to the male rat of D-penicillamine (p.o.) and S-carboxymethyl-L-cysteine (p.o.) with [35S]-L-cysteine (i.p.) led to a significant decrease in the subsequent urinary elimination of inorganic sulphate whilst having no measurable effect on organic sulphate excretion. The co-administration of L-valine, an amino acid not containing sulphur, had no effect. It is not known where, within the complex sequence of events surrounding the degradation of cysteine to sulphate, that D-penicillamine or S-carboxymethyl-L-cysteine may interact.     

Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense)

OBJECTIVES: To study the pharmacokinetics of isoflavones from red clover (Trifolium pratense) after long-term administration as a once-daily dietary supplementary. DESIGN: Fourteen (14) subjects who had been consuming a low-isoflavone diet for 2 weeks were given an oral dose of two isoflavone tablets (approximately 80 mg of total isoflavones) daily for 2 weeks and appeared for a study day at 9:00 AM after an overnight fast on the day that they were to receive the last dose. Plasma samples were collected for a 48-hour period after the last dose. Plasma isoflavones were assayed by high-performance liquid chromatography (HPLC). RESULTS: Trough plasma levels were significantly higher for daidzein and genistein after long-term dosing than levels taken prior to the commencement of the study and plasma levels of isoflavones after long-term dosing were in the range previously reported in populations that consume an isoflavone-rich diet. The plasma half-lives observed after long-term administration were, in most cases, consistent with once-daily administration. CONCLUSIONS: Isoflavones have pharmacokinetic characteristics that suggest that once-daily administration is adequate when they are administered long-term as dietary supplements.