Tetrahydrobiopterin metabolism in depression and senile dementia of Alzheimer type

Excretion of biopterin and the related pteridines neopterin and pterin was measured in urine samples from a group of 76 male and female unipolar and bipolar depressed outpatients receiving lithium therapy, and compared to 61 male and female control subjects. The ratio of neopterin to biopterin excreted (N/B) was significantly higher in the patients than the controls. The significant positive correlation between urinary neopterin and biopterin shown by the controls was absent in the patients, indicating disrupted biosynthesis of tetrahydrobiopterin.Urinary cortisol excretion in depressed patients was similar to controls, implying normal hypothalmus-pituitary-adrenal axis function in these patients, Serum folate was shown to correlate with urinary total biopterin excretion in female unipolar patients. Two groups of elderly females with senile dementia of Alzheimer type (SDAT) were examined for urinary pteridine excretion. In the first study of 10 patients, the N/B ratio was significantly higher than in 24 controls and the ratio B/B+ N significantly lower. A second study of 30 SDAT patients and 21 controls confirmed these findings. However, neopterin correlated with biopterin in both patients and controls, indicating that the alteration in tetrahydrobiopterin metabolism may be different to that shown in depression. Lithium had no effect in vivo or in vitro on Wistar rat brain or liver biosynthesis of tetrahydrobiopterin at a range of concentrations and duration of dosing period, showing that lithium was not responsible for the lowered biopterin excretion by depressed patients. No significant effects on tetrahydrobiopterin metabolism in the rat were shown by the tricyclic antidepressant imipramine, the anticonvulsant sodium valproate, the vitamin folic acid, the anticatecholaminergic agent amethylparatyrosine, the synthetic corticosteroid dexamethasone, or stimulation of natural cortisol by immobilisation stress. Scopolamine, an ant ichol inergic drug, lowered rat brain pterin which may relate to the tetrahydrobiopterin deficits shown in SDAT.

The relationship between alexithymia and salivary cortisol levels in somatoform disorders

The purpose of this study was to investigate cortisol levels as a function of the hypothalamic-pituitary-adrenal axis (HPA) in relation to alexithymia in patients with somatoform disorders (SFD). Diurnal salivary cortisol was sampled in 32 patients with SFD who also underwent a psychiatric examination and filled in questionnaires (Toronto Alexithymia Scale, TAS scale; Screening for Somatoform Symptoms, SOMS scale; Hamilton Depression Scale, HAMD). The mean TAS total score in the sample was 55.69.6, 32% of patients being classified as alexithymic on the basis of their TAS scores. Depression scores were moderate (HAMD=13.2, Beck Depression Inventory, BDI=16.5). The patients' alexithymia scores (TAS scale Difficulty identifying feelings) correlated significantly positively with their somatization scale scores (Symptom Checklist-90 Revised, SCL-90-R); r=0.3438 (P0.05) and their scores on the Global Severity Index (GSI) on the SCL-90-R; r=0.781 (P0.01). Regression analysis was performed with cortisol variables as the dependent variables. Cortisol levels [measured by the area under the curve-ground (AUC-G), area under the curve-increase (AUC-I) and morning cortisol (MCS)] were best predicted in a multiple linear regression model by lower depressive scores (HAMD) and more psychopathological symptoms (SCL-90-R). No significant correlations were found between the patients' alexithymia scores (TAS) and cortisol levels. The healthy control group (n=25) demonstrated significantly higher cortisol levels than did the patients with SFD; in both tests P0.001 for AUC-G and AUC-I. However, the two groups did not differ in terms of their mean morning cortisol levels (P0.05). The results suggest that pre-existing hypocortisolism might possibly be associated with SFD.

Nutritional influences on cognitive function:mechanisms of susceptibility

The impact of nutritional variation, within populations not overtly malnourished, on cognitive function and arousal is considered. The emphasis is on susceptibility to acute effects of meals and glucose loads, and chronic effects of dieting, on mental performance, and effects of cholesterol and vitamin levels on cognitive impairment. New developments in understanding dietary influences on neurohormonal systems, and their implications for cognition and affect, allow reinterpretation of both earlier and recent findings. Evidence for a detrimental effect of omitting a meal on cognitive performance remains equivocal: from the outset, idiosyncrasy has prevailed. Yet, for young and nutritionally vulnerable children, breakfast is more likely to benefit than hinder performance. For nutrient composition, despite inconsistencies, some cautious predictions can be made. Acutely, carbohydrate-rich–protein-poor meals can be sedating and anxiolytic; by comparison, protein-rich meals may be arousing, improving reaction time but also increasing unfocused vigilance. Fat-rich meals can lead to a decline in alertness, especially where they differ from habitual fat intake. These acute effects may vary with time of day and nutritional status. Chronically, protein-rich diets have been associated with decreased positive and increased negative affect relative to carbohydrate-rich diets. Probable mechanisms include diet-induced changes in monoamine, especially serotoninergic neurotransmitter activity, and functioning of the hypothalamic pituitary adrenal axis. Effects are interpreted in the context of individual traits and susceptibility to challenging, even stressful, tests of performance. Preoccupation with dieting may impair cognition by interfering with working memory capacity, independently of nutritional status. The change in cognitive performance after administration of glucose, and other foods, may depend on the level of sympathetic activation, glucocorticoid secretion, and pancreatic β-cell function, rather than simple fuelling of neural activity. Thus, outcomes can be predicted by vulnerability in coping with stressful challenges, interacting with nutritional history and neuroendocrine status. Functioning of such systems may be susceptible to dietary influences on neural membrane fluidity, and vitamin-dependent cerebrovascular health, with cognitive vulnerability increasing with age.

Pituitary volume in patients with bipolar disorder and their first-degree relatives

Background: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been reported in bipolar disorder (BD), but previous magnetic resonance imaging (MRI) studies of pituitary gland volume in BD have yielded inconsistent findings. In addition, the contribution of genetic factors to the pituitary changes in BD remains largely unknown. Method: We used MRI to investigate the pituitary volume in 29 remitted patients with BD, 49 of their first-degree relatives (of whom 15 had a diagnosis of Major Depressive Disorder), and 52 age- and gender-matched healthy controls. Results: BD patients had a significantly larger pituitary volume compared with their relatives and healthy controls. Pituitary volume did not differ between controls and healthy relatives or relatives diagnosed with major depression. Limitations: Direct measures of HPA function (i.e., hormonal levels) were not available. Conclusions: These findings suggest that enlarged pituitary volume is associated with disease expression but not genetic susceptibility to BD. © 2009 Elsevier B.V. All rights reserved.

Down-regulation of central glucocorticoid receptor expression using antisense oligonucleotide technology

Endogenous glucocorticoids and serotonin have been implicated in the pathophysiology of depression, anxiety and schizophrenia. This thesis investigates the potential of downregulating expression of central Type II glucocorticoid receptors (GR) both in vitro and in vivo, with empirically-designed antisense oligodeoxynucleotides (ODN), to characterise GR modulation of 5-HT2A receptor expression using quantitative RT-PCR, Western blot analysis and radioligand binding. The functional consequence of GR downregulation is also determined by measuring 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane hydrochloride (DOI) mediated 5-HT2A receptor specific headshakes. Using a library of random antisense ODN probes, RNAse H accessibility mapping of T7-primed, in vitro transcribed GR mRNA revealed several potential cleavage sites and identified an optimally effect GR antisense ODN sequence of 21-mer length (GRAS5). In vitro efficacy studies using rat C6 glioma cells showed a 56% downregulation in GR mRNA levels and 80% downregulation in GR protein levels. In the same cells a 29% upregulation in 5-HT2A mRNA levels and 32% upregulation in 5-HT2A protein levels was revealed. This confirmed the optimal nature of the GRAS5 sequence to produce marked inhibition of GR gene expression, and also revealed GR modulation of the 50-HT2A receptor subtype in C6 glioma cells to be a tonic repression of receptor expression. The distribution of a fluorescently-labelled GRAS5 ODN was detected in diverse areas of the rat brain after single ICV administration, although this fluorescence signal was not sustained over a period of 5 days. However, fluorescently-labelled GRAS5 ODN, when formulated in polymer microspheres, showed diverse distribution in the brain which was maintained for 5 days following a single ICV administration. This produced no apparent neurotoxic effects on rat behaviour and hypothalamic-pituitary-adrenal (HPA) axis homeostasis. Furthermore, a single polymer microsphere injection ICV proved to be an effective means of delivering antisense ODNs and this was adopted for the in vivo efficacy studies. In vivo characterisation of GRAS5 revealed marked downregulation of GR mRNA in rat brain regions such as the frontal cortex (26%), hippocampus (35%), and hypothalamus (39%). Downregulation of GR protein was also revealed in frontal cortex (67%), hippocampus (76%), and hypothalamus (80%). In the same animals upregulation of 5-HT2A mRNA levels was shown in frontal cortex (13%), hippocampus (7%), and hypothalamus (5%) while upregulation in 5-HT2A protein levels was shown in frontal cortex (21 %). This upregulation in 5-HT2A receptor density as a result of antisense-mediated inhibition of GR was further confirmed by a 55% increase in DOl-mediated 5-HT2A receptor specific headshakes. These results demonstrate that GR is involved in tonic inhibitory regulation of 5-HT2A receptor expression and function in vivo, thus providing the potential to control 5-HT2A-linked disorders through corticosteroid manipulation. These experiments have therefore established an antisense approach which can be used to investigate pharmacological characteristics of receptors.

A polymorphism in the growth hormone (GH)-releasing hormone (GHRH) receptor gene is associated with elevated response to GHRH by human pituitary somatotrophinomas in vitro

A previous study has suggested that a G to A base change at position 169 of the GHRH-receptor gene in human somatotrophinomas is a mutation and confers hypersensitivity to GHRH. The alternative base converts codon 57 from GCG to AGC, resulting in replacement of alanine (Ala) with threonine (Thr). In the present study, two of five human GH-secreting somatotrophinomas were found to possess the codon 57 AGC sequence. The GCG allele was also detected, indicating heterozygosity. However, the patients' normal blood-derived DNA also yielded the same sequence pattern, indicating that the Ala=> Thr amino acid change is a normal polymorphism, and not a somatic mutation. Nevertheless, in vitro, the tumors possessing the Ala=> Thr amino acid change responded very strongly to GHRH in terms of cAMP formation, being increased 40- and 200-fold, in comparison to the 2-fold increases by tumors without the alternative GHRH-receptor sequence. Likewise, the in vitro response of GH secretion to GHRH was elevated. One of the two tumors with the alternative Thr residue, and the highest responder to GHRH, possessed a gsp muration, despite the fact that these defects are thought to reduce responsiveness to GHRH. These results fail to confirm that the GCG => AGC at codon 57 of the GHRH-receptor gene is a mutation, but do support the concept that the alternative form with Thr confers increased sensitivity to GHRH. (C) 2000 Academic Press.

Two-axis temperature-insensitive accelerometer based on multicore fiber Bragg gratings

We report a compact two-dimensional accelerometer based upon a simple fiber cantilever constructed from a short length of multicore optical fiber. Two-axis measurement is demonstrated up to 3 kHz. Differential measurement between fiber Bragg gratings written in the multicore fiber provides temperature- insensitive measurements.

Axis-alignment affects perceptual grouping: evidence from simultanagnosia

We examined the effect of grouping by the alignment of implicit axes on the perception of multiple shapes, using a patient (GK) who shows simultanagnosia as part of Blint's syndrome. Five experiments demonstrated that: (1) GK was better able to judge the orientation of a global configuration if the constituent local shapes were aligned with their major axes than if they were aligned with their edges; (2) this axis information was used implicitly, since GK was unable to discriminate between configurations of axis-aligned and edge-aligned shapes; (3) GK's sensitivity to axis-alignment persisted even when the orientations of local shapes were kept constant, indicating some form of cooperative effect between the local elements; (4) axis-alignment of shapes also facilitated his ability to discriminate single-item from multi-item configurations; (5) the effect of axis-alignment could be attributed, at least partially, to the degree to which there was matching between the orientations of local shapes and the global configuration. Taken together, the results suggest that axis-based grouping can support the selection of multiple objects.

Axis-based grouping reduces visual extinction

We examined the effects on extinction of grouping by collinearity of edges and grouping by alignment of internal axes of shapes, in a patient (GK) with simultanagnosia following bilateral parietal brain damage. GK’s visual extinction was reduced when items (equilateral triangles and angles) could be grouped by base alignment (i.e., collinearity) or by axis alignment, relative to a condition in which items were ungrouped. These grouping effects disappeared when inter-item spacing was increased, though factors such as display symmetry remained constant. Overall, the results suggest that, under some conditions, grouping by alignment of axes of symmetry can have an equal beneficial effect on visual extinction as edge-based grouping; thus, in the extinguished field, there is derivation of axis-based representations from the contours present.

Design methodology for the servo control of high speed multi-axis machinery (BL): decoupling and synchronisation of a generic machine by blockwise decentralised MIMO control

Traditional machinery for manufacturing processes are characterised by actuators powered and co-ordinated by mechanical linkages driven from a central drive. Increasingly, these linkages are replaced by independent electrical drives, each performs a different task and follows a different motion profile, co-ordinated by computers. A design methodology for the servo control of high speed multi-axis machinery is proposed, based on the concept of a highly adaptable generic machine model. In addition to the dynamics of the drives and the loads, the model includes the inherent interactions between the motion axes and thus provides a Multi-Input Multi-Output (MIMO) description. In general, inherent interactions such as structural couplings between groups of motion axes are undesirable and needed to be compensated. On the other hand, imposed interactions such as the synchronisation of different groups of axes are often required. It is recognised that a suitable MIMO controller can simultaneously achieve these objectives and reconciles their potential conflicts. Both analytical and numerical methods for the design of MIMO controllers are investigated. At present, it is not possible to implement high order MIMO controllers for practical reasons. Based on simulations of the generic machine model under full MIMO control, however, it is possible to determine a suitable topology for a blockwise decentralised control scheme. The Block Relative Gain array (BRG) is used to compare the relative strength of closed loop interactions between sub-systems. A number of approaches to the design of the smaller decentralised MIMO controllers for these sub-systems has been investigated. For the purpose of illustration, a benchmark problem based on a 3 axes test rig has been carried through the design cycle to demonstrate the working of the design methodology.

Receptor Activity Modifying Proteins (RAMPs) interact with the VPAC2 Receptor and CRF1 receptors and modulate their function

Background and Purpose Although it is established that the receptor activity modifying proteins (RAMPs) can interact with a number of GPCRs, little is known about the consequences of these interactions. Here the interaction of RAMPs with the glucagon-like peptide 1 receptor (GLP-1 receptor), the human vasoactive intestinal polypeptide/pituitary AC-Activating peptide 2 receptor (VPAC) and the type 1 corticotrophin releasing factor receptor (CRF) has been examined. Experimental Approach GPCRs were co-transfected with RAMPs in HEK 293S and CHO-K1 cells. Cell surface expression of RAMPs and GPCRs was examined by elisa. Where there was evidence for interactions, agonist-stimulated cAMP production, Ca mobilization and GTPγS binding to G, G, G and G were examined. The ability of CRF to stimulate adrenal corticotrophic hormone release in Ramp2 mice was assessed. Key Results The GLP-1 receptor failed to enhance the cell surface expression of any RAMP. VPAC enhanced the cell surface expression of all three RAMPs. CRF enhanced the cell surface expression of RAMP2; the cell surface expression of CRF was also increased. There was no effect on agonist-stimulated cAMP production. However, there was enhanced G-protein coupling in a receptor and agonist-dependent manner. The CRF: RAMP2 complex resulted in enhanced elevation of intracellular calcium to CRF and urocortin 1 but not sauvagine. In Ramp2 mice, there was a loss of responsiveness to CRF. Conclusions and Implications The VPAC and CRF receptors interact with RAMPs. This modulates G-protein coupling in an agonist-specific manner. For CRF, coupling to RAMP2 may be of physiological significance. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Recent advances in antidiabetic drug therapies targeting the enteroinsular axis

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e.g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA. © 2009 Bentham Science Publishers Ltd.