What one hand giveth the other taketh away:some unpredicted effects of enantiomers in psychopharmacology

It is well known that many medicines are a mixture of two enantiomers, or mirror-image molecules. Two enantiomers occur when a molecule has a single chiral centre and the two mirror images, called S or L (left handed) and R or D (right handed), are usually found in equal amounts in the parent (racemic) mixture. While for many compounds used in clinical practice the active moiety is found in one of the two enantiomers with the other being seen as an unnecessary and redundant component of the racemic mixture, the difference between enantiomers can mean a difference between therapeutic and adverse effects, as well as in beneficial pharmacological effect and potency. © 2010 The Author(s).

Informational masking and the effects of differences in fundamental frequency and fundamental-frequency contour on phonetic integration in a formant ensemble

This study explored the effects on speech intelligibility of across-formant differences in fundamental frequency (ΔF0) and F0 contour. Sentence-length speech analogues were presented dichotically (left=F1+F3; right=F2), either alone or—because competition usually reveals grouping cues most clearly—accompanied in the left ear by a competitor for F2 (F2C) that listeners must reject to optimize recognition. F2C was created by inverting the F2 frequency contour. In experiment 1, all left-ear formants shared the same constant F0 and ΔF0F2 was 0 or ±4 semitones. In experiment 2, all left-ear formants shared the natural F0 contour and that for F2 was natural, constant, exaggerated, or inverted. Adding F2C lowered keyword scores, presumably because of informational masking. The results for experiment 1 were complicated by effects associated with the direction of ΔF0F2; this problem was avoided in experiment 2 because all four F0 contours had the same geometric mean frequency. When the target formants were presented alone, scores were relatively high and did not depend on the F0F2 contour. F2C impact was greater when F2 had a different F0 contour from the other formants. This effect was a direct consequence of the associated ΔF0; the F0F2 contour per se did not influence competitor impact.

Plasma vascular endothelial growth factor, angiopoietin-2, and soluble angiopoietin receptor tie-2 in diabetic retinopathy:effects of laser photocoagulation and angiotensin receptor blockade

Background: Proliferative diabetic retinopathy (PDR) may be a response to abnormal angiogenic growth factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and the soluble angiopoietin receptor tie-2. The authors hypothesised the following: (a) there are differences in plasma levels of these growth factors in different grades of diabetic retinopathy; and (b) that the effects of intervention with panretinal laser photocoagulation (PRP) for PDR, and angiotensin receptor blockade (using eprosartan) for patients with other grades of diabetic retinopathy will be to reduce levels of the growth factors. Methods: Cross sectional and interventional study (using PRP and eprosartan) in diabetic patients. VEGF, Ang-2, and tie-2 were measured by ELISA. Results: VEGF (p<0.001) and Ang-2 levels (p<0.001) were significantly higher in 93 diabetic patients compared to 20 healthy controls, with the highest levels in grade 2 and grade 3 diabetic retinopathy (p<0.05). Tie-2 was lower in diabetics compared to controls (p = 0.008), with no significant differences between the diabetic subgroups. Overall, VEGF significantly correlated with Ang-2 (p<0.001) and tie-2 (p = 0.004) but the correlation between Ang-2 and tie-2 levels was not significant (p = 0.065). Among diabetic patients only, VEGF levels were significantly correlated with Ang-2 (p<0.001) and tie-2 (p<0.001); the correlation between Ang-2 and tie-2 levels was also significant (p<0.001). There were no statistically significant effects of laser photocoagulation on plasma VEGF, Ang-2, and tie-2 in the 19 patients with PDR, or any effects of eprosartan in the 28 patients with non-proliferative diabetic retinopathy. Conclusion: Increased plasma levels of VEGF and Ang-2, as well as lower soluble tie-2, were found in diabetic patients. The highest VEGF and Ang-2 levels were seen among patients with pre-proliferative and proliferative retinopathy, but there was no relation of tie-2 to the severity of retinopathy. As the majority of previous research into Ang-2 and tie-2 has been in relation to angiogenesis and malignancy, the present study would suggest that Ang-2 and tie-2 may be used as potential indices of angiogenesis in diabetes mellitus (in addition to VEGF) and may help elucidate the role of the angiopoietin/tie-2 system in this condition.

Regional competitiveness, economic growth and stages of development

This paper positions the concept of regional competitiveness within theories concerning regional economic growth and stages of economic development. It examines the sources of regional competitiveness encompassing an analysis based on the particular stage of economic development that the nations within which regions are situated have reached. As a means to achieve this, the paper undertakes an empirical analysis of data stemming from the World Competitiveness Index of Regions, and identifies regional competitiveness as a dual concept that explains relative differences in rates of economic development across regions, as well as an understanding of the future economic growth trajectories of regions at a similar stage of economic development. As with endogenous growth and development theory, the notion of regional competitiveness presented here places knowledge, innovation and entrepreneurship at the forefront of conceptualisations of regional economic differentiation.

Aminoglutethimide-induced leucopenia in a mouse model:effects of metabolic and structural determinates

A model of human leucopenia has been developed further in the female mouse. Following daily administration to female mice of 50 mg/kg of the aromatase inhibitor aminoglutethimide, significant falls in platelet and white cell counts occurred after 2 and 3 weeks. At week 4, drug dosage was stopped and the cell counts recovered at the end of that week, although on rechallenge at the beginning of week 5, both platelet and white cell counts fell rapidly. Administration to the mice of structural analogues of aminoglutethimide, such as WSP-3, glutethimide and 4-nitroglutethimide, showed no reductions in platelet and white cell counts. The haemotoxicity of aminoglutethimide over 21 days was unaffected by the presence of either the P-450 inhibitor SKF-525A or the hepatic P-450 inducer phenobarbitone. However, the co-administration of cimetidine abolished the haemotoxicity of aminoglutethimide in terms of platelet and white cell levels. In in vitro studies, both aminoglutethimide and WSP-3 were oxidised to cytotoxic species, although aminoglutethimide was significantly more cytotoxic than WSP-3. The NADPH-dependent covalent binding of 14C aminoglutethimide to mouse microsomes in vitro was significantly reduced by the presence of cimetidine. The activation of the compound to reactive species in vitro, the inhibitory effects of cimetidine in vivo and in vitro, as well as the rapid fall in the in vivo white cell count on rechallenge with aminoglutethimide suggest that this model illustrates a form of leucopenia which may be related to hapten formation and subsequent immune-mediated platelet and white cell lysis. © 2003 Elsevier B.V. All rights reserved.

Studies on the growth rates of lichens

Progress in the field of lichen growth rates is briefly reviewed. The application of a new method of measuring growth rate to thalli of different size has led to the conclusion that there are changes in the radial growth rate during the life of a lichen thallus. For most of the life of a lichen thallus the radial growth rate is constant and the thallus radius increases linearly. Preceeding the linear phase the radial growth rate increases with time and the thallus radius increases logarithmically. There is no evidence for a postlinear phase in the radial growth of a lichen thallus. Studies on the growth rate of lichens are applied both to the problems of determining the age of a lichen thallus on an undated substratum and to an ecological investigation in the field.

Studies on the growth rates of lichens

Progress in the field of lichen growth rate studies is briefly reviewed. The application of a new method of measuring growth rate to thalli of different size has led to the conclusion that there are changes in the radial growth rate during the life of a lichen thallus. For most of the life of a lichen thallus the radial growth rate is constant and the thallus radius increases linearly. Preceding the linear phase the radial growth rate increases with time and the thallus radius increases logarithmically. There is no evidence for a postlinear phase in the radial growth of a lichen thallus. Studies on the growth rate of lichens are applied both to the problems of determining the age of a lichen thallus on an undated susbtratum and to an ecological investigation in the field.

A comparison of the effects of ocular preservatives on mammalian and microbial ATP and glutathione levels

The aim of this study was to investigate the mechanism of action of the preservative sodium chlorite (NaClO2), and the relationship with intracellular glutathione depletion. A detailed comparison of the dose responses of two cultured ocular epithelial cell types and four species of microorganism was carried out, and comparisons were also made with the quaternary ammonium compound benzalkonium chloride (BAK), and the oxidant hydrogen peroxide (H2O2). The viability of mammalian and microbial cells was assessed in the same way, by the measurement of intracellular ATP using a bioluminescence method. Intracellular total glutathione was measured by reaction with 5,5'-dithiobis-2-nitrobenzoic acid in a glutathione reductase-dependent recycling assay. BAK and H2O2 caused complete toxicity to conjunctival and corneal epithelial cells at similar to25 ppm, in contrast to NaClO2 , where >100 ppm was required. The fungi Candida albicans and Alternaria alternata had a higher resistance to NaClO2 than the bacteria Staphyloccus aureus and Pseudomonas aeruginosa , but the bacteria were extremely resistant to H2O2 NaClO2 caused substantial depletion of intracellular glutathione in all cell types, at concentrations ranging from <10 ppm in Pseudomonas , 25-100 ppm in epithelial cells, to >500 ppm in fungal cells. The mechanisms of cytotoxicity of NaClO2 , H2O2 and BAK all appeared to differ. NaClO2 was found to have the best balance of high antibacterial toxicity with low ocular toxicity. The lower toxicity of NaClO2 to the ocular cells, compared with BAK and H2O2 , is in agreement with fewer reported adverse effects of application in the eye.

Empirical analysis of human capital development and economic growth in Europe

Recent discussion of the knowledge-based economy draws increasingly attention to the role that the creation and management of knowledge plays in economic development. Development of human capital, the principal mechanism for knowledge creation and management, becomes a central issue for policy-makers and practitioners at the regional, as well as national, level. Facing competition both within and across nations, regional policy-makers view human capital development as a key to strengthening the positions of their economies in the global market. Against this background, the aim of this study is to go some way towards answering the question of whether, and how, investment in education and vocational training at regional level provides these territorial units with comparative advantages. The study reviews literature in economics and economic geography on economic growth (Chapter 2). In growth model literature, human capital has gained increased recognition as a key production factor along with physical capital and labour. Although leaving technical progress as an exogenous factor, neoclassical Solow-Swan models have improved their estimates through the inclusion of human capital. In contrast, endogenous growth models place investment in research at centre stage in accounting for technical progress. As a result, they often focus upon research workers, who embody high-order human capital, as a key variable in their framework. An issue of discussion is how human capital facilitates economic growth: is it the level of its stock or its accumulation that influences the rate of growth? In addition, these economic models are criticised in economic geography literature for their failure to consider spatial aspects of economic development, and particularly for their lack of attention to tacit knowledge and urban environments that facilitate the exchange of such knowledge. Our empirical analysis of European regions (Chapter 3) shows that investment by individuals in human capital formation has distinct patterns. Those regions with a higher level of investment in tertiary education tend to have a larger concentration of information and communication technology (ICT) sectors (including provision of ICT services and manufacture of ICT devices and equipment) and research functions. Not surprisingly, regions with major metropolitan areas where higher education institutions are located show a high enrolment rate for tertiary education, suggesting a possible link to the demand from high-order corporate functions located there. Furthermore, the rate of human capital development (at the level of vocational type of upper secondary education) appears to have significant association with the level of entrepreneurship in emerging industries such as ICT-related services and ICT manufacturing, whereas such association is not found with traditional manufacturing industries. In general, a high level of investment by individuals in tertiary education is found in those regions that accommodate high-tech industries and high-order corporate functions such as research and development (R&D). These functions are supported through the urban infrastructure and public science base, facilitating exchange of tacit knowledge. They also enjoy a low unemployment rate. However, the existing stock of human and physical capital in those regions with a high level of urban infrastructure does not lead to a high rate of economic growth. Our empirical analysis demonstrates that the rate of economic growth is determined by the accumulation of human and physical capital, not by level of their existing stocks. We found no significant effects of scale that would favour those regions with a larger stock of human capital. The primary policy implication of our study is that, in order to facilitate economic growth, education and training need to supply human capital at a faster pace than simply replenishing it as it disappears from the labour market. Given the significant impact of high-order human capital (such as business R&D staff in our case study) as well as the increasingly fast pace of technological change that makes human capital obsolete, a concerted effort needs to be made to facilitate its continuous development.

Military spending and economic growth in South Africa

This paper undertakes an empirical analysis of the economic effects of military spending on the South African economy. It estimates a neo-classical model common in the literature at the level of the macroeconomy and at the level of the manufacturing sector. An attempt is made to improve upon the model by allowing the data to determine the dynamic structure of the model through an ARDL procedure. No significant impact of military spending is found in aggregate, but there is a significant negative impact for the manufacturing sector. This suggests that the cuts in domestic military procurement that have occurred since 1989 could lead to improved economic performance in South Africa through their impact on the manufacturing sector.

Impact of FDI, ODA and migrant remittances on economic growth in developing countries:a systems approach

This article seeks to investigate the relative contributions of foreign direct investment, official development assistance and migrant remittances to economic growth in developing countries. We use a systems methodology to account for the inherent endogeneities in these relationships. In addition, we also examine the importance of institutions, not only for growth directly, but for the interactions between institutions and the other sources of growth. It is, we believe, the first article to consider each of these variables together. We find that all sources of foreign capital have a positive and significant impact on growth when institutions are taken into account. © 2013 European Association of Development Research and Training Institutes.

Effects of microstructure on long and short crack growth in nickel base superalloys

The use of engineering materials in critical applications necessitates the accurate prediction of component lifetime for inspection and renewal purposes. In fatigue limited situations, it is necessary to be able to predict the growth rates of cracks from initiation at a defect through to final fracture. To this end, fatigue crack growth data are presented for different microstructures of typical nickel base superalloys used in gas turbine engines. Crack growth behaviour throughout the life history of the crack, i.e. from the short crack through to the long crack propagation regime, is described for each microstructural condition and discussed in terms of current theories of fatigue crack propagation.

Effects of grain size and microstructure on threshold values and near threshold crack growth in powder-formed Ni-base superalloy

Threshold stress intensity values, ranging from ∼6 to 16 MN m −3/2 can be obtained in powder-formed Nimonic AP1 by changing the microstructure. The threshold and low crack growth rate behaviour at room temperature of a number of widely differing API microstructures, with both ‘necklace’ and fully recrystallized grain structures of various sizes and uniform and bimodal γ′-distributions, have been investigated. The results indicate that grain size is an important microstructural parameter which can control threshold behaviour, with the value of threshold stress intensity increasing with increasing grain size, but that the γ′-distribution is also important. In this Ni-base alloy, as in many others, near threshold fatigue crack growth occurs in a crystallographic manner along {111} planes. This is due to the development of a dislocation structure involving persistent slip bands on {111} planes in the plastic zone, caused by the presence of ordered shearable precipitates in the microstructure. However, as the stress intensity range is increased, a striated growth mode takes over. The results presented show that this transition from faceted to striated growth is associated with a sudden increase in crack propagation rate and occurs when the size of the reverse plastic zone at the crack tip becomes equal to the grain size, independent of any other microstructural variables.