No abstract

Corticosteroids exert effects on the hippocampus by binding to intracellular glucocorticoid andlor mineralocorticoid receptors, but the relative importance of each receptor type in mediating corticosteroid effects is poorly understood. There is an extensive serotoninergic (5-HT) innervation of the hippocampus which interacts with corticosteroid-sensitive cells. We have investigated the effect of intracerebroventricular 5,7-dihydroxytryptamine lesions of 5-HT neurons on glucocorticoid and mineralocorticoid receptor messenger ribonucleic acid (mRNA) expression in the rat hippocampus using in situ hybridization histochemistry. In controls, glucocorticoid receptor mRNA was highly expressed in dentate gyrus granule cell neurons, and in pyramidal cells of CA1 and CA2, but levels in CA3 and CA4 were significantly lower. 5,7-dihydroxytryptamine-lesioned animals showed significantly less glucocorticoid receptor mRNA in t h e dentate gyrus (76% decrease), CA1 (42% decrease) and CA2 (52% decrease; all P<0.05 compared with controls). Mineralocorticoid receptor mRNA was expressed at a similar level in all hippocampal subregions in control rats. 5,7-dihydroxytryptamine lesioning led to a significant decrease in rnineralocorticoid receptor mRNA expression in CA3 (56% fall) and CA4 (45% fall; both P<0.05), but not in the other subregions. Thus the 5-HT innervation regulates hippocampal corticosteroid receptor mRNA expression. There are two types of corticosteroid receptor in the CNS. mineralocorticoid (type I) and glucocorticoid (type 11) (I , 2). Glucocorticoid receptors arc widely distributed in neurons and glia throughout the brain, whereas mineralocorticoid receptors are more selectively distributed with the highest levels being found in limbic system neurons (3-6). In the hippocampus both receptor types bind corticosterone as the physiological hgand. Mineral-ocorticoid receptors represent high affinity binding sites that are largely occupied under basal conditions, in vivo, whereas glucocor-ticoid receptors show lower affinity and are able to bind the elevated concentrations of corticosterone associated with stress (1, 7, 8). Corticosterone is thought to have several actions at the hippocampus which are likely to involve changes in neurochemical transmission (6). Clearly, mechanisms which regulate hippocam-pal corticosteroid receptor concentrations could affect these functions. The hippocampus receives a dense serotoninergic (5-HT) innervation arising from the raphe nuclei (9). Depletion of brain 5-HT attenuates negative feedback within the hypothalamo-pituitary -adrenal axis (10). 5-HT levels in the brain vary in parallel with the diurnal rhythm of plasma corticosterone (1 1) and 5-HT agonists activate the hypothalamo-pituitary-adrenal axis (12). Although these data d o not locate the site of interaction between 5-HT and corticosterone, neurophysiological studies have demonstrated that 5-HT inputs to the hippocampus affect corticosterone-concentrating cells (1 3). Furthermore, administration of antidepressants that inhibi...

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule. The fusion has been engineered to deliver sustained peptide activity in vivo in combination with reduced potency, to manage GLP-1 driven adverse effects at high dose, and a favourable manufacturability profile. MEDI4166 showed robust and sustained LDL-C lowering in cynomolgus monkeys and exhibited the anticipated GLP-1 effects in T2D mouse models. We believe MEDI4166 is a novel molecule combining long acting agonist peptide and neutralising antibody activities to deliver a unique pharmacology profile for the management of T2D.

A noncontact optical detection system is developed for the in vivo identification and localization of high-grade cervical intraepithelial neoplasia (CIN 2,3). Diagnostic scans of the entire human cervix are performed following acetic acid application employing three integrated optical measurements: laser-induced fluorescence spectroscopy, white light diffuse reflectance spectroscopy, and video imaging. Full cervical scans comprising 499 interrogation locations at 1-mm spatial resolution are completed in 12 s. Diffuse reflectance and fluorescence spectra with signal-to-noise ratios of better than 100-to-1 are collected between 360 and 720 nm in increments of 1 nm, with an inherent spectral resolution of 8 nm. Glare reduction and optical vignetting are handled with a novel illumination scheme and subsequent spectral arbitration algorithms. The system is designed and found to be well below acceptable safe optical exposure levels. Typical reproducibility across multiple systems is approximately 5%, providing reliable and accurate detection of in vivo cervical neoplasia in normal clinical use.