No abstract

Activation of the endothelin A receptor (ET A ) by endothelin-1 (ET-1) mediates events that regulate mitogenesis, apoptosis, angiogenesis and metastasis in tumours. Specific blockade of ET A may have anticancer effects, while retaining beneficial endothelin B receptor (ET B )-mediated effects such as apoptosis and clearance of ET-1. ZD4054 is an orally active, specific ET A antagonist in clinical development. In receptor-binding studies, ZD4054 specifically bound to ET A with high affinity; no binding was detected at ET B . In a randomised placebo-controlled trial in eight healthy volunteers, a single oral dose of ZD4054 reduced forearm vasoconstriction in response to brachial artery infusion of ET-1, thus providing clinical evidence of ET A blockade. ET B blockade was assessed in an ascending, single-dose, placebo-controlled trial in 28 volunteers. For all doses of ZD4054, mean plasma ET-1 concentrations measured at 4 and 24 h were within the placebo reference range (a rise in ET-1 would indicate ET B blockade) and there was no evidence of dose-related changes. These data confirm the specificity of ZD4054 for ET A , with no activity at ET B in a clinical or preclinical setting. As a result of this specificity, ZD4054 has the potential to block multiple ET A -induced pathological processes, while allowing beneficial ET B -mediated processes to continue, which may, in turn, lead to an effective cancer therapy.

Recently discovered sexual dimorphism within developing brain structures such as the amygdala and hippocampus suggests that biological factors may account for many of the sex differences in stress reactivity. In this study, we have relied on studies of naturally occurring anomalous processes, such as congenital adrenal hyperplasia (CAH) and Klinefelter's syndrome (XXY), to observe the effects of hormones and sex chromosomes on brain structures thought to influence an individual's vulnerability to stress. Brain magnetic resonance imaging (MRI) scans were obtained both from 16 boys with classic CAH and 34 age- and sex-matched controls and from 20 XXY children and 40 age-matched controls. Smaller amygdala volumes were observed in boys with CAH than in matched controls, and in XXY patients than in matched controls. XXY patients were also found to have smaller hippocampus volumes when compared with matched controls. Acknowledging that hormone and sex chromosome effects upon the developing human brain are widespread and complex, it is difficult to conclude, with any certainty, the etiology of the differences found in this study. Future studies that examine longitudinal data and/or other diagnostic groups, however, may help to better elucidate specific hormone and sex chromosome effects upon stress-related structures in the brain.

Refractometry yielded acceptable results for measurement of TP concentration in canine pleural and abdominal fluid specimens, providing a more rapid and convenient method than biuret assay.