FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.     

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.     

Low temperature thermal expansion behavior in the Kondo system La1−x Ce x Al2

The thermal expansion coefficient for La_1–x Ce _x Al₂ has been measured from 4 to 50 K and compared to recent calculations based on a valence fluctuation model. The experimental results were found to be inconsistent with the predictions assuming valence fluctuations, even though the predictions of this model for the specific heat and magnetic susceptibility are in striking agreement with the measured quantities. The thermal expansion coefficient was not determined with sufficient precision to allow a quantitative comparison with prediction assuming resonant scattering-Kondo behavior.Work Supported by National Science Foundation Grant No. DMR-76-16433.     

Active symbols and internal models: Towards a cognitive connectionism

In the first section of the article, we examine some recent criticisms of the connectionist enterprise: first, that connectionist models are fundamentally behaviorist in nature (and, therefore, non-cognitive), and second that connectionist models are fundamentally associationist in nature (and, therefore, cognitively weak). We argue that, for a limited class of connectionist models (feed-forward, pattern-associator models), the first criticism is unavoidable. With respect to the second criticism, we propose that connectionist modelsare fundamentally associationist but that this is appropriate for building models of human cognition. However, we do accept the point that there are cognitive capacities for which any purely associative model cannot provide a satisfactory account. The implication that we draw from is this is not that associationist models and mechanisms should be scrapped, but rather that they should be enhanced.In the next section of the article, we identify a set of connectionist approaches which are characterized by active symbols — recurrent circuits which are the basis of knowledge representation. We claim that such approaches avoid criticisms of behaviorism and are, in principle, capable of supporting full cognition. In the final section of the article, we speculate at some length about what we believe would be the characteristics of a fully realized active symbol system. This includes both potential problems and possible solutions (for example, mechanisms needed to control activity in a complex recurrent network) as well as the promise of such systems (in particular, the emergence of knowledge structures which would constitute genuine internal models).     

Stimulus-based priming of task choice during voluntary task switching.

Two voluntary task-switching experiments probed the influence of previous exposures to stimuli and categorizations of these stimuli on task choice during subsequent exposures to the same stimuli. Subjects performed origin and size judgments under standard voluntary task-switching instructions to perform the tasks equally often in a random order. Both when subjects voluntarily selected the task on the first exposure (Experiment 1) and when the experimenter manipulated the task on the first exposure (Experiment 2), subjects chose to perform the same task on subsequent exposures significantly more often than would be expected on the basis of the instructions to perform tasks in a random order. Presentation of a previously encountered stimulus may result in the retrieval of a stimulus–task binding or event file that biases task selection as well as task readiness. The pattern of data across the 2 experiments suggests that stimulus-based priming influences task choice through both retrieval of episodes within the context of the experiment and semantic memory mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Post‐buckling optimization of composite structures using Koiter's method

Thin‐walled structures, when compressed, are prone to buckling. To fully utilize the capabilities of such structures, the post‐buckling response should be considered and optimized in the design process. This work presents a novel method for gradient‐based design optimization of the post‐buckling performance of structures. The post‐buckling analysis is based on Koiter's asymptotic method. To perform gradient‐based optimization, the design sensitivities of the Koiter factors are derived, and new design optimization formulations based on the Koiter factors are presented. The proposed optimization formulations are demonstrated on a composite square plate and a curved panel where the post‐buckling stability is optimized. Copyright © 2016 John Wiley & Sons, Ltd.     

Detection and identification of aqueous saccharides by using surface-enhanced Raman spectroscopy

The sensitive detection and characterization of carbohydrates by means of a strategy based on surface-enhanced Raman spectroscopy is demonstrated. Spectra are obtained after injecting a small amount of saccharide solution onto a roughened silver substrate, with subsequent deposition of silver colloid. The sensitivity achieved by this two-step approach enables high-quality Raman spectra to be obtained for small amounts of aqueous saccharides (5 microL of a 10(-2) M solution) utilizing minimal laser power and small signal acquisition times (a few seconds). Spectral "fingerprints" obtained for seven structurally similar monosaccharides demonstrate clearly an effective means by which each sugar can be identified. The application to more complex analyses is demonstrated for monosaccharide mixtures and a disaccharide, whereby the SERS fingerprints aid in the determination of components.