bluuebunny/crossref_metadata_2025_split huggingface dataset:
United States – Anti-Dumping Measures on Oil Country Tubular Goods (OCTG) from Mexico: a legal-economic assessment of sunset reviews
Authors: BOWN CHAD P. , WAUTERS JASPER 
Published: April 2008

AbstractThis paper reviews the WTO Appellate Body Report on United States – Anti-Dumping Measures on Oil Country Tubular Goods (OCTG) from Mexico (WT/DS282/AB/R 2 November 2005). This dispute concerns the disciplines imposed by the Anti-Dumping Agreement on WTO Members seeking to extend their anti-dumping measures beyond the original five-year period through a so-called sunset review. Our analysis focuses on the Appellate Body's finding in this case that no causation analysis is required in sunset reviews, and addresses the AB's approach towards the legal instrument that provides for the US policy in terms of sunset reviews, the Sunset Policy Bulletin. We conclude that the Anti-Dumping Agreement, as interpreted by the Appellate Body in this and other similar cases, imposes only minimal disciplines of a general nature on Members wishing to extend the anti-dumping measure beyond its original five-year period. We argue that the ‘textual’ argument relied on to support this deferential approach is weak and has resulted in undermining the practical effect of, what was considered to be, one of the major achievements of the Uruguay Round Anti-Dumping Agreement: limiting the life span of an anti-dumping measure to five years. From an economic perspective, Panels and the Appellate Body are simply debating the wrong type of questions. The prospective nature required by a sunset review analysis raises questions such as why exporters engaged in dumping in the first place, and what the conditions of the industry were so that the dumped imports caused injury. At the moment, sunset reviews seem adrift as panels and the Appellate Body fail to give guidance to Members on how to do a more economically sound and informed review.
Addiction: the clinical interface
Authors: Nutt D , Lingford‐Hughes A 
Published: April 2008

This review gives an overview of what we see as the key issues in the human pharmacology of drugs of addiction. We review evidence of efficacy and mechanisms by which treatments act and point out areas where further work is needed. The role of agonist, partial agonist and antagonist treatments for opioid addiction is detailed and current issues relating to the mechanisms of actions at the receptor level and how to improve on compliance are discussed. The role of the brain dopamine and GABA‐A systems in drug dependence is considered in relation to the growing pharmacology of these receptor systems, and the current status of novel preclinical targets reviewed. In addition, the different roles of dynamic and kinetic factors in both addiction and its treatment are discussed in relation to the underlying neuropharmacology of the disorders as defined from human and preclinical studies. Finally, some pointers to future research and especially to drug development by pharma are elaborated.British Journal of Pharmacology (2008) 154, 397–405; doi:fn1; published online 14 April 2008
Oxidative stress and COX cause hyper‐responsiveness in vascular smooth muscle of the femoral artery from diabetic rats
Authors: Shi Y , Vanhoutte P M 
Published: April 2008

Background and purpose:To investigate the dysfunction of vascular smooth muscle in streptozotocin‐induced diabetic rats.Experimental approach:Rings without endothelium of femoral arteries were suspended in organ chambers for isometric tension recording. The production of oxygen‐derived free radicals was measured with 2′,7′‐dichlorodihydrofluorescein diacetate using confocal microscopy. The protein expressions were measured by western blotting.Key results:The concentration–response curves to U46619 and phenylephrine, but not that to KCl, were shifted to the left, suggesting a hypersensitivity of cell membrane receptors in diabetes. Exogenous oxygen‐derived free radicals induced greater vasoconstrictions in the femoral artery from diabetic rats. Chronic treatment with apocynin (inhibitor of NADPH oxidase) and acute exposure to MnTMPyP (SOD/catalase mimetic) normalized the response. The catalase activity and the total glutathione level were reduced in arteries from streptozotocin‐treated rats, confirming a redox abnormality. The basal oxidative state was higher in arteries from streptozotocin‐treated rats and reduced in arteries from apocynin‐ and streptozotocin‐treated rats, suggesting that the functional changes in diabetes are due to a chronic increase in oxidative stress. In the arteries of streptozotocin‐treated rats, inhibitors of COX‐1 and/or COX‐2 prevented the hypersensitivity and reduced the increase in oxidative stress caused by phenylephrine and U46619, suggesting that both isoforms contribute to the smooth muscle dysfunction. The expression of proteins for COX‐1 and COX‐2 was increased in arteries of streptozotocin‐treated rats and reduced in preparations of apocynin‐ and streptozotocin‐treated rats.Conclusions and implications:Chronic diabetes and the resulting increased oxidative stress activate the production of COX‐derived vasoconstrictor prostanoids causing hypersensitivity of vascular smooth muscle.British Journal of Pharmacology (2008) 154, 639–651; doi:10.1038/bjp.2008.110; published online 14 April 2008
Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures
Authors: Albus K , Wahab A , Heinemann U 
Published: April 2008

Background and purpose:Earlier studies had demonstrated that tonic–clonic seizure‐like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds.Experimental approach:OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4‐aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed.Key results:In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2–P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABAA‐agonist muscimol.Conclusions and implications:We present a simple to establish in vitro model of tonic–clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non‐responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy.British Journal of Pharmacology (2008) 154, 709–724; doi:10.1038/bjp.2008.112; published online 14 April 2008
Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice
Authors: Drouin A , Gendron M‐È , Thorin E , Gillis M‐A , Mahlberg‐Gaudin F , Tardif J‐C 
Published: April 2008

Background and purpose:High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with coronary artery disease. We tested the hypothesis that a reduction of resting heart rate with the cardiac pacemaker If current inhibitor ivabradine prevents the endothelial dysfunction associated with dyslipidaemia.Experimental approach:Three‐month‐old dyslipidaemic (DL) male mice expressing the human ApoB‐100 were assigned or not (DL, n=16), to treatment for 3 months with ivabradine (10 mg kg−1 d−1, n=17). Wild‐type C57Bl/6 mice (WT, n=15) were used as controls. Heart rate was measured at 3, 4.5 and 6 months. Dilatation to acetylcholine (ACh) of isolated cerebral and renal arteries was investigated at 6 months.Key results:Heart rate remained stable in anaesthetized WT mice, increased (25%, P<0.05) with age in DL mice but was limited (11%, P<0.05) by ivabradine. At 6 months, left ventricular maximal pressure was similar in all groups. The minimal and end‐diastolic left ventricular pressures were increased (P<0.05) in DL (10.2±1.0 and 18.7±1.4 mm Hg) compared to WT (−0.4±0.7 and 6.3±1.0 mm Hg) and reduced (P<0.05) by ivabradine (4.2±1.3 and 11.5±1.5 mm Hg). ACh‐induced maximal dilatation was impaired (P<0.05) in renal and cerebral arteries isolated from DL compared to WT (56±7 versus 83±3% in renal arteries; 22±2 versus 42±2% in cerebral arteries). Ivabradine completely prevented (P<0.05) this dysfunction in renal and cerebral arteries.Conclusions and implications:Selective heart rate reduction with ivabradine limits cardiac dysfunction and prevents the renovascular and cerebrovascular endothelial dysfunction associated with dyslipidaemia.British Journal of Pharmacology (2008) 154, 749–757; doi:fn2; published online 14 April 2008
The endocannabinoid system in brain reward processes
Authors: Solinas M , Goldberg S R , Piomelli D 
Published: April 2008

Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB1 receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB1 receptors by plant‐derived, synthetic or endogenous CB1 receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB1 receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2‐arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine‐tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes.British Journal of Pharmacology (2008) 154, 369–383; doi:10.1038/bjp.2008.130; published online 14 April 2008
Neuropharmacology of addiction—setting the scene
Authors: Lawrence A J , Beart P M , Kalivas P W 
Published: April 2008

Addiction is a complex disorder, affecting not only the individual addict, but also their family and the community at large. While therapeutic strategies are available for the treatment of some forms of substance abuse/dependence, these are not without problems and are not universally efficacious. Moreover, in some instances (for example, cocaine addiction), there are still no medications specifically registered as treatment options. In this themed issue of the British Journal of Pharmacology, we highlight a number of addictions from a pharmacological perspective, with an emphasis on both mechanism and potential therapeutic approaches that are either under development or reflect preclinical work. As such, the authors endeavour to describe the latest thinking on the neural theory of addiction and corresponding novel pharmacotherapeutic targets, and in this way to set the stage for future advances in research and drug development. In addition, we have also attempted to draw attention to the clinicians' perspective in terms of the interface between basic science and care provision.British Journal of Pharmacology (2008) 154, 259–260; doi: 10.1038/bjp.2008.131; published online 14 April 2008
AM3, a natural glycoconjugate, induces the functional maturation of human dendritic cells
Authors: Martín‐Vilchez S , Molina‐Jiménez F , Alonso‐Lebrero J L , Sanz‐Cameno P , Rodríguez‐Muñoz Y , Benedicto I , Roda‐Navarro P , Trapero M , Aragoneses‐Fenoll L , González S , Pivel J P , Corbí A L , López‐Cabrera M , Moreno‐Otero R , Majano P L 
Published: April 2008

Background and purpose: Dendritic cells (DCs) are dedicated antigen‐presenting cells able to initiate specific immune responses and their maturation is critical for the induction of antigen‐specific T‐lymphocyte responses. Here, we have investigated the effects of Inmunoferon‐active principle (AM3), the active agent of a commercial immunomodulatory drug, on human monocyte‐derived DCs (MDDCs).Experimental approach: MDDCs derived from healthy and hepatitis C virus (HCV)‐infected patients were stimulated with AM3. We analysed the expression of cell surface proteins by flow cytometry, that of cytokine production by ELISA, and the expression of chemokines and chemokine receptors by RNase protection assays. T‐lymphocyte proliferation was assessed in mixed lymphocyte reactions, protein expression by western blot and luciferase‐based reporter methods, and Toll‐like receptor (TLR)‐blocking antibodies were employed to analyse TLR activity.Key results: In MDDCs, AM3 induced or enhanced expression of CD54, CD83, CD86, HLA‐DR, chemokines and chemokine receptors, interleukin (IL)‐12p70 and IL‐10. Furthermore, AM3 stimulated MDDCs to increase proliferation of allogenic T cells. AM3 triggered nuclear translocation of NF‐κB and phosphorylation of p38 mitogen‐activated protein kinase. AM3 promoted NF‐κB activation in a TLR‐4‐dependent manner, and blocking TLR‐4 activity attenuated the enhanced expression of CD80, CD83 and CD86 induced by AM3. AM3 enhanced the expression of maturation‐associated markers in MDDCs from HCV‐infected patients and increased the proliferation of T lymphocytes induced by these MDDCs.Conclusions and implications: These results underline the effects of AM3 in promoting maturation of MDDCs and suggest that AM3 might be useful in regulating immune responses in pathophysiological situations requiring DC maturation.British Journal of Pharmacology (2008) 154, 698–708; doi:10.1038/bjp.2008.87; published online 14 April 2008
Effects of imatinib mesylate on spontaneous electrical and mechanical activity in smooth muscle of the guinea‐pig stomach
Authors: Hashitani H , Hayase M , Suzuki H 
Published: April 2008

Background and purpose:Effects of imatinib mesylate, a Kit receptor tyrosine kinase inhibitor, on spontaneous activity of interstitial cells of Cajal (ICC) and smooth muscles in the stomach were investigated.Experimental approach:Effects of imatinib on spontaneous electrical and mechanical activity were investigated by measuring changes in the membrane potential and tension recorded from smooth muscles of the guinea‐pig stomach. Its effects on spontaneous changes in intracellular concentration of Ca2+ ([Ca2+]i) (Ca2+ transients) were also examined in fura‐2‐loaded preparations.Key results:Imatinib (1–10 μM) suppressed spontaneous contractions and Ca2+ transients. Simultaneous recordings of electrical and mechanical activity demonstrated that imatinib (1 μM) reduced the amplitude of spontaneous contractions without suppressing corresponding slow waves. In the presence of nifedipine (1 μM), imatinib (10 μM) reduced the duration of slow waves and follower potentials in the antrum and accelerated their generation, but had little affect on their amplitude. In contrast, imatinib reduced the amplitude of antral slow potentials and slow waves in the corpus.Conclusions and implications:Imatinib may suppress spontaneous contractions of gastric smooth muscles by inhibiting pathways that increase [Ca2+]i in smooth muscles rather than by specifically inhibiting the activity of ICC. A high concentration of imatinib (10 μM) reduced the duration of slow waves or follower potentials in the antrum, which reflect activity of ICC distributed in the myenteric layers (ICC‐MY), and suppressed antral slow potentials or corporal slow waves, which reflect activity of ICC within the muscle bundles (ICC‐IM), presumably by inhibiting intracellular Ca2+ handling.British Journal of Pharmacology (2008) 154, 451–459; doi:10.1038/bjp.2008.91; published online 14 April 2008
Inhibition of the rapid component of the delayed rectifier potassium current in ventricular myocytes by angiotensin II via the AT1 receptor
Authors: Wang Y H , Shi C X , Dong F , Sheng J W , Xu Y F 
Published: April 2008

Background and purpose: There is increasing evidence that angiotensin II (Ang II) is associated with the occurrence of ventricular arrhythmias. However, little is known about the electrophysiological effects of Ang II on ventricular repolarization. The rapid component of the delayed rectifier K+ current (IKr) plays a critical role in cardiac repolarization. Hence, the aim of this study was to assess the effect of Ang II on IKr in guinea‐pig ventricular myocytes.Experimental approach: The whole‐cell patch‐clamp technique was used to record IKr in native cardiocytes and in human embryonic kidney (HEK) 293 cells, co‐transfected with human ether‐a‐go‐go‐related gene (hERG) encoding the α‐subunit of IKr and the human Ang II type 1 (AT1) receptor gene.Key results: Ang II decreased the amplitude of IKr in a concentration‐dependent manner with an IC50 of 8.9 nM. Action potential durations at 50% (APD50) and 90% (APD90) repolarization were prolonged 20% and 16%, respectively by Ang II (100 nM). Ang II‐induced inhibition of the IKr was abolished by the AT1 receptor blocker, losartan (1 μM). Ang II decreased hERG current in HEK293 cells and significantly delayed channel activation, deactivation and recovery from inactivation. Moreover, PKC inhibitors, stausporine and Bis‐1, significantly attenuated Ang II‐induced inhibition of IKr.Conclusions and implications: Ang II produces an inhibitory effect on IKr/hERG currents via AT1 receptors linked to the PKC pathway in ventricular myocytes. This is a potential mechanism by which elevated levels of Ang II are involved in the occurrence of arrhythmias in cardiac hypertrophy and failure.British Journal of Pharmacology (2008) 154, 429–439; doi:10.1038/bjp.2008.95; published online 14 April 2008
Novel consequences of voltage‐dependence to G‐protein‐coupled P2Y1 receptors
Authors: Gurung I S , Martinez‐Pinna J , Mahaut‐Smith M P 
Published: April 2008

Background and purpose:Emerging evidence suggests that activation of G‐protein‐coupled receptors (GPCRs) can be directly regulated by membrane voltage. However, the physiological and pharmacological relevance of this effect remains unclear. We have further examined this phenomenon for P2Y1 receptors in the non‐excitable megakaryocyte using a range of agonists and antagonists.Experimental approach:Simultaneous whole‐cell patch clamp and fura‐2 fluorescence recordings of rat megakaryocytes, which lack voltage‐gated Ca2+ influx, were used to examine the voltage‐dependence of P2Y1 receptor‐evoked IP3‐dependent Ca2+ mobilization.Results:Depolarization transiently and repeatedly enhanced P2Y1 receptor‐evoked Ca2+ mobilization across a wide concentration range of both weak, partial and full, potent agonists. Moreover, the amplitude of the depolarization‐evoked [Ca2+]i increase displayed an inverse relationship with agonist concentration, such that the greatest potentiating effect of voltage was observed at near‐threshold levels of agonist. Unexpectedly, depolarization also stimulated an [Ca2+]i increase in the absence of agonist during exposure to the competitive antagonists A3P5PS and MRS2179, or the allosteric enhancer 2,2′‐pyridylisatogen tosylate. A further effect of some antagonists, particularly suramin, was to enhance the depolarization‐evoked Ca2+ responses during co‐application of an agonist. Of several P2Y1 receptor inhibitors, only SCH202676, which has a proposed allosteric mechanism of action, could block ADP‐induced voltage‐dependent Ca2+ release.Conclusions and implications:The ability of depolarization to potentiate GPCRs at near‐threshold agonist concentrations represents a novel mechanism for coincidence detection. Furthermore, the induction and enhancement of voltage‐dependent GPCR responses by antagonists has implications for the design of therapeutic compounds.British Journal of Pharmacology (2008) 154, 882–889; doi:10.1038/bjp.2008.97; published online 14 April 2008
Akt substrate TBC1D1 regulates GLUT1 expression through the mTOR pathway in 3T3-L1 adipocytes
Authors: Zhou Qiong L. , Jiang Zhen Y. , Holik John , Chawla Anil , Hagan G. Nana , Leszyk John , Czech Michael P. 
Published: April 2008

Multiple studies have suggested that the protein kinase Akt/PKB (protein kinase B) is required for insulin-stimulated glucose transport in skeletal muscle and adipose cells. In an attempt to understand links between Akt activation and glucose transport regulation, we applied mass spectrometry-based proteomics and bioinformatics approaches to identify potential Akt substrates containing the phospho-Akt substrate motif RXRXXpS/T. The present study describes the identification of the Rab GAP (GTPase-activating protein)-domain containing protein TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1], which is closely related to TBC1D4 [TBC domain family, member 4, also denoted AS160 (Akt substrate of 160 kDa)], as an Akt substrate that is phosphorylated at Thr590. RNAi (RNA interference)-mediated silencing of TBC1D1 elevated basal deoxyglucose uptake by approx. 61% in 3T3-L1 mouse embryo adipocytes, while the suppression of TBC1D4 and RapGAP220 under the same conditions had little effect on basal and insulin-stimulated deoxyglucose uptake. Silencing of TBC1D1 strongly increased expression of the GLUT1 glucose transporter but not GLUT4 in cultured adipocytes, whereas the decrease in TBC1D4 had no effect. Remarkably, loss of TBC1D1 in 3T3-L1 adipocytes activated the mTOR (mammalian target of rapamycin)-p70 S6 protein kinase pathway, and the increase in GLUT1 expression in the cells treated with TBC1D1 siRNA (small interfering RNA) was blocked by the mTOR inhibitor rapamycin. Furthermore, overexpression of the mutant TBC1D1-T590A, lacking the putative Akt/PKB phosphorylation site, inhibited insulin stimulation of p70 S6 kinase phosphorylation at Thr389, a phosphorylation induced by mTOR. Taken together, our data suggest that TBC1D1 may be involved in controlling GLUT1 glucose transporter expression through the mTOR-p70 S6 kinase pathway.