The effects of metformin on the vascular system

Macrovascular contraction and relaxation effects of metformin were measured using a Mulvany Halpern myograph. Mouse aortic ring sections were treated for 1 and 4 hours in vitro with metformin at 10-5M, and for 2, 4 and 8 weeks in vivo with metformin at 250mg/kg/day. The rings were contacted with increasing concentrations of noradrenaline (10-9M, 10-8M, 10-7M, 10-6M) in the absence and presence of metformin. Maximally contracted tissue was then relaxed using increasing acetylcholine concentrations (10-9M, 10-8M, 10-7M, 10-6M). Meformin increased the sensitivity of the aorta to noradrenaline-induced contraction. The maximal effect in vitro was seen after 4 hours giving a 221% increase in contraction after 4 hours at noradrenaline 10-6M. Acetylcholine-stimulated relaxation via endothelium also increased with metformin after 4 hours by 36.85%. The maximal effect of metformin treatment in vivo was seen on aortic contraction after 8 weeks: the effect of melformin treatment on relaxation was less marked at this time. Metformin also increased passive tension generated by the aortic vessel wall after 4 hours, which was reversed by administration of papaverine, which acts directly on vascular smooth muscle. Metformin was shown not to alter nitric oxide production by the mouse aortic wall after 1 and 4 hours in vitro. Metformin lowered basal calcium concentrations, as measured by FURA/2AM, generating a slow sustained increase in calcium release induced by noradrenaline during contraction. This research programme has shown that metformin can increase both the contraction and relaxation capabilities of aortic sections treated both in vitro and in vivo with therapeutic concentrations of metformin at 10-5M. Metformin has been shown to act directly in the vascular wall to alter vascular contractility via effects on both vascular smooth muscle and endothelium, and to influence calcium movements independently of nitric oxide.

Stanley Hoffmann: a political life:a political life

Stanley Hoffmann is one of the most eminent political scholars of our age—a renowned authority in the study of French, European, and world politics over half a century, an influential theorist of international relations, a critical analyst of US foreign policy, and a voice of moral conscience in many public debates of his time. Hoffmann has always asked big questions—and to those questions he brings an encyclopedic mind that crosses boundaries between politics, history, sociology, law, philosophy, ethics, and literature. This brief article highlights some aspects of his life and work, and introduces a symposium in his honor bringing together five leading scholars on France, Europe, international relations, and international law—each with an enduring debt to the teaching, writings and example of Stanley Hoffmann.

EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries

1 Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E2 (PGE2) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2 In the presence of indomethacin (3μM) and the TP receptor antagonist GR32191 (1 μM), PGE2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC50 8.0 ± 0.1, n = 5). 3 Establishment of a rank order of potency using the EP4 > EP2 agonist 11-deoxy PGE1, and the EP2 > EP4 agonist PGE1-OH (mean pEC 50 of 7.6 ± 0.1 (n = 6) and 6.4 ± 0.1 (n = 4), respectively), suggested the presence of functional EP4 receptors. Furthermore, the selective EP2 receptor agonist butaprost at concentrations < 1 μM failed to relax the tissues. 4 Blockade of EP 4 receptors with the EP4 receptor antagonists AH23848 and EP4A caused significant rightward displacements in PGE2 concentration-response curves, exhibiting pA2 and pKB values of 5.7 ± 0.1, n = 3, and 8.4, n = 3, respectively. 5 The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC50 values 8.3 ± 0.1 (n = 4) and 8.1 ± 0.1 (n = 9), respectively). In contrast, the DP and FP receptor agonists PGD2 and PGFα2 failed to cause appreciable relaxation or contraction at concentrations of up to 30 μM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC50 7.4 ± 0.3, n = 3). 6 These data demonstrate the presence of prostanoid EP4 receptors mediating PGE2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

The role of social agents in the translation into English of the novels of Naguib Mahfouz

This research investigates the field of translation in an Egyptain context around the work of the Egyptian writer and Nobel Laureate Naguib Mahfouz by adopting Pierre Bourdieu’s sociological framework. Bourdieu’s framework is used to examine the relationship between the field of cultural production and its social agents. The thesis includes investigation in two areas: first, the role of social agents in structuring and restructuring the field of translation, taking Mahfouz’s works as a case study; their role in the production and reception of translations and their practices in the field; and second, the way the field, with its political and socio-cultural factors, has influenced translators’ behaviour and structured their practices. In this research, it is argued that there are important social agents who have contributed significantly to the structure of the field and its boundaries. These are key social agents in the field namely; the main English language publisher in Egypt, the American University in Cairo Press (AUCP); the translators: Denys Johnson-Davies, Roger Allen and Trevor Le Gassick; and the author, Naguib Mahfouz. Their roles and contributions are examined and discussed through the lens of Bourdieu’s sociology. Particular focus is given to the author Mahfouz and his award of the Nobel Prize, and how this award has influenced the field of cultural production and its social agents. Also, it is argued that socio-cultural factors in the field, in the period between 1960s and 2000s, affected the translators’ practices in terms of modes of production of Mahfouz’s works. To investigate the influence of these factors on translators’ practices in the field, empirical examination is conducted, at the textual level, on a corpus of six translated novels written by the same author, Mahfouz. It is shown that the translators have an increased tendency, over time, towards applying a foreignising approach in their translations of culture-specific items. The translators’ behaviour, which is a result of their habitus, is correlated to political and socio-cultural factors in the field of translation. That is, based on interviews conducted with the translators, it has been found that there are particular factors influenced their translational habitus and, thus, their practices during the production process of the translations.

Do R&D strategies in high-tech sectors differ from those in low-tech sectors? An alternative approach to testing the pooling assumption

Most studies investigating the determinants of R&D investment consider pooled estimates. However, if the parameters are heterogeneous, pooled coefficients may not provide reliable estimates of individual industry effects. Hence pooled parameters may conceal valuable information that may help target government tools more efficiently across heterogeneous industries. There is little evidence to date on the decomposition of the determinants of R&D investment by industry. Moreover, the existing work does not distinguish between those R&D determinants for which pooling may be valid and those for which it is not. In this paper, we test the pooling assumption for a panel of manufacturing industries and find that pooling is valid only for output fluctuations, adjustment costs and interest rates. Implementing the test results into our model, we find government funding is significant only for low-tech R&D. Foreign R&D and skilled labour matter only in high-tech sectors. These results suggest important implications for R&D policy.