bluuebunny/crossref_metadata_2025_split huggingface dataset:
Congenital quadricuspid aortic valve in children
Authors: Di Pino Alfredo , Gitto Placido , Silvia Antonio , Bianca Innocenzo 
Published: April 2008

AbstractQuadricuspid aortic valves are rare congenital anomalies, usually diagnosed in adult patients affected by severe aortic regurgitation. We have now encountered three such valves in children undergoing transthoracic echocardiography. All children were asymptomatic. The first child possessed a valve with two larger leaflets, and smaller leaflets of equal size. In the second child, 3 leaflets were of equal size, with 1 small accessory leaflet. The third child had a valve with four leaflets of approximately equal size. In one child, the aortic valve was functioning normally, and came to attention because of mitral valvar prolapse causing mild regurgitation. In the remaining two children, central mild aortic regurgitation was detected using colour flow analysis, and associated dilation of the aortic root was revealed by measurements of the cross-sectional images.
United States – Sunset Reviews of Anti-Dumping Measures on Oil Country Tubular Goods from Argentina: a cloudy sunset
Authors: GROSSMAN GENE M. , WAUTERS JASPER 
Published: April 2008

AbstractWe review the WTO Appellate Body report on United States – Sunset Reviews of Anti-Dumping Measures on Oil Country Tubular Goods from Argentina (WT/DS268/AB/R, 29 November 2004). This dispute is one of several that deals with sunset reviews of antidumping-duty orders. In its ruling, the AB reasserts a rigid distinction between mandatory and discretionary law, and sets a very high standard for Member challenges to laws or practices that allow for violations of WTO obligations but do not mandate such behavior. We argue that this ruling is unfortunate, because it diminishes scope of and incentives for ‘as-such’ challenges to laws and practices, which have a potentially useful role to play in the world trading system. The AB ruling also overlooks the purpose and objectives of sunset reviews – to ensure that duty orders are not extended when their removal would generate no harm to an import competing industry – by failing to impose sufficient discipline on their conduct. We argue that a sunset review requires an evaluation of competitive conditions in the industry and of the reasons and incentives for dumping, in order that the investigating authority can judge whether the removal of a duty order would lead to a continuation or recurrence of dumping and injury. The Appellate Body's rulings in this and other similar cases have the effect of relieving the investigating authority of this responsibility and thereby render the sunset review process virtually meaningless.
Measures Affecting the Cross-Border Supply of Gambling and Betting Services (DS 285)
Authors: IRWIN DOUGLAS A. , WEILER JOSEPH 
Published: April 2008

AbstractThe controversial gambling decision of the Appellate Body is mostly important because of examination of the nature of Access under Article XVI GATS, the relationship of that Article to Articles XIV and XVII GATS, and the parallels with Articles III, XI, and XX GATT. Notably, the Appellate Body took the position that an apparant internal regulatory measure, which, nonetheless, had equivalent effect to a zero quota, violated Article XVI GATS. A similar measure in the area of goods would have been examined under Article III GATT and require a showing of discrimination. The facts of the case would have allowed the decision to be based on Article XVII GATS. Most of this paper deals with this issue. We agree with this interpretation of Article XVI by the Appellate Body but are critical of its hermeneutics, suffering from a textual fetish and a policy phobia. Some other elements in the decision are also examined critically.
Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction
Authors: Christie M J 
Published: April 2008

A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the μ‐opioid receptor itself, cellular tolerance and withdrawal in opioid‐sensitive neurons, systems tolerance and withdrawal in opioid‐sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element‐binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid‐sensitive neurons is great but some candidate neuropeptide systems that interact with μ‐opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.British Journal of Pharmacology (2008) 154, 384–396; doi:10.1038/bjp.2008.100; published online 14 April 2008
Gonadotropins in doping: pharmacological basis and detection of illicit use
Authors: Stenman U‐H , Hotakainen K , Alfthan H 
Published: April 2008

Parenteral administration of human chorionic gonadotropin (hCG) or luteinizing hormone (LH) stimulates the production of testosterone in males and these gonadotropins can therefore be used by athletes to enhance muscle strength. However, they are more expensive and less efficient than testosterone and anabolic steroids. Therefore their main use is probably to stimulate gonadal testosterone production during and after self‐administration of testosterone or anabolic steroids. A positive effect of hCG on muscle strength has not been demonstrated in women and elevated concentrations of hCG in females are often caused by pregnancy. The use of gonadotropins is therefore prohibited only in males but not in females. HCG occurs at low but measurable concentrations in plasma and urine of healthy males and can be measured by sensitive methods. However, the characteristics of the method to be used for doping control have not been defined. Virtually all commercially available hCG assays have been designed for determination of hCG in serum rather than urine, which is used for doping control. Methods based on mass spectrometric detection of fragments derived from hCG extracted from urine by immunoadsorption have been developed but their suitability for doping control remains to be determined. The concentrations of LH in serum and urine are variable and more then 10‐fold higher than those hCG. It is therefore difficult to detect illicit use of LH. The characteristics and reference values for hCG and LH assays used in doping control and the cutoff values need to be defined.British Journal of Pharmacology (2008) 154, 569–583; doi:fn1; published online 14 April 2008
Discovery and biological characterization of a novel series of androgen receptor modulators
Authors: Zhou C , Wu G , Feng Y , Li Q , Su H , Mais D E , Zhu Y , Li N , Deng Y , Yang D , Wang M‐W 
Published: April 2008

Background and purpose:Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non‐steroidal androgen receptor modulators discovered in a high‐throughput screening campaign.Experimental approach:Competitive receptor binding, luciferase‐based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts.Key results:Forty‐nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/or antagonist activities in both CV‐1 and MDA‐MB‐453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non‐steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV‐1 co‐transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied.Conclusions and implications:These non‐steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.British Journal of Pharmacology (2008) 154, 440–450; doi:10.1038/bjp.2008.107; published online 14 April 2008
The expression and function of Ca2+‐sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes
Authors: Weston A H , Absi M , Harno E , Geraghty A R , Ward D T , Ruat M , Dodd R H , Dauban P , Edwards G 
Published: April 2008

Background and purpose:The extracellular calcium‐sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate‐conductance, calcium‐sensitive K+ channels (IKCa) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes.Experimental approach:Pressure myography, western blotting, sharp microelectrode and K+‐selective electrode recordings were used to investigate the functional expression of the CaR and IKCa in rat mesenteric arteries.Key results:Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619‐induced vessel contraction elevated the extracellular [K+] around the myocytes, and inhibition of this ‘K+ cloud’ by iberiotoxin was needed to reveal calindol‐induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IKCa expression was also diminished, but IKCa‐generated hyperpolarizations mediated by 1‐EBIO were unaffected.Conclusions and implications:The reduced CaR‐mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IKCa channels. Detection of CaR‐mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long‐term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.British Journal of Pharmacology (2008) 154, 652–662; doi:10.1038/bjp.2008.108; published online 14 April 2008
The existence of a local 5‐hydroxytryptaminergic system in peripheral arteries
Authors: Ni W , Geddes T J , Priestley J R C , Szasz T , Kuhn D M , Watts S W 
Published: April 2008

Background and purpose:5‐HT is a vasoconstrictor exhibiting enhanced effects in systemic arteries from subjects with cardiovascular disease. The effect of endogenous 5‐HT on arteries is controversial, because the concentration of free circulating 5‐HT is low and a 5‐hydroxytryptaminergic system has not been identified in peripheral arteries. We hypothesized that a local 5‐hydroxytryptaminergic system (including 5‐HT synthesis, metabolism, uptake and release) with physiological function exists in peripheral arteries.Experimental approach:The presence of key components of a 5‐hydroxytryptaminergic system in rat aorta and superior mesenteric artery was examined using western blot analyses, immunohistochemistry and immunocytochemistry. The function of the rate‐limiting enzyme in 5‐HT biosynthesis, tryptophan hydroxylase (TPH), and 5‐HT transporter was tested by measuring enzyme activity and 5‐HT uptake, respectively. Isometric contraction of arterial strips was used to demonstrate the function of released endogenous 5‐HT in arterial tissues.Key results:mRNA for TPH‐1 was present in arteries, with low levels of TPH protein and TPH activity. Expression and function of MAO A (5‐HT metabolizing enzyme) was supported by immunohistochemistry, western analyses and the elevation of concentrations of 5‐hydroxyindoleacetic acid (5‐HT metabolite) after exposure to exogenous 5‐HT. The 5‐HT transporter was localized to the plasma membrane of freshly isolated aortic smooth muscle cells. Peripheral arteries actively took up 5‐HT in a time‐dependent and 5‐HT transporter‐dependent manner. The 5‐HT transporter substrate, (+)‐fenfluramine, released endogenous 5‐HT from peripheral arteries, which potentiated noradrenaline‐induced arterial contraction.Conclusions and implications:This study revealed the existence of a local 5‐hydroxytryptaminergic system in peripheral arteries.British Journal of Pharmacology (2008) 154, 663–674; doi:10.1038/bjp.2008.111; published online 14 April 2008
Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart
Authors: Shimoni Y , Chen K , Emmett T , Kargacin G 
Published: April 2008

Background and purpose:Aldosterone plays a major role in cardiac pathology. This study was designed to investigate the role of cardiac aldosterone in modulating K+ currents and oxidative stress in the streptozotocin‐induced diabetic rat heart.Experimental approach:Transient and sustained K+ currents were measured in ventricular myocytes by voltage clamp. Plasma and cellular aldosterone were measured by ELISA. Fluorescent dihydroethidium (DHE) was used to assess superoxide ions as markers of oxidative stress.Key results:The mineralocorticoid antagonist spironolactone (1 μM, 5–9 h) significantly augmented both K+ currents in diabetic males, with a concomitant shortening of the action potential but had no effect in myocytes from control males or from diabetic females. Effects of spironolactone were restored in ovariectomized diabetic females and abolished in orchidectomized diabetic males. The aldosterone synthase inhibitor FAD286 (1 μM, 5–9 h) significantly augmented K+ currents in cells from diabetic males, but not females. Spironolactone and FAD286 significantly reduced oxidative stress in cells from diabetic males. Plasma aldosterone content was elevated in diabetic males (relative to control), but not in females. Cellular aldosterone was also elevated, but not significantly. The elevation in aldosterone was only partly dependent on a concomitant increase in cellular angiotensin II.Conclusions and implications:A gender‐related, sex‐hormone‐dependent elevation in plasma and cardiac cell aldosterone contributed to oxidative stress and to attenuation of K+ currents in diabetic male rats. Aldosterone may thus contribute to diabetes‐associated cardiac arrhythmias. Aldosterone elevation was partly related to levels of angiotensin II, but residual, angiotensin II‐independent, aldosterone maintains functional relevance.British Journal of Pharmacology (2008) 154, 675–687; doi:10.1038/bjp.2008.114; published online 14 April 2008
Bone morphogenetic protein signalling is required for the anti‐mitogenic effect of the proteasome inhibitor MG‐132 on colon cancer cells
Authors: Wu W K K , Sung J J Y , Wu Y C , Li Z J , Yu L , Cho C H 
Published: April 2008

Background and purpose:Inhibition of proteasome has been emerging as a promising approach in pathway‐directed cancer therapy. Bone morphogenetic protein (BMP) signalling, which is known to be regulated by the ubiquitin–proteasome pathway in osteoblasts, plays a crucial role in the suppression of gastrointestinal carcinogenesis. Here we sought to elucidate the anti‐mitogenic effect of a proteasome inhibitor in relation to BMP signalling in colon cancer.Experimental approach:The effects of the proteasome inhibitor MG‐132 on proliferation of SW1116 and HT‐29 colon cancer cells were determined by [3H]‐thymidine incorporation and colony‐formation assay. The involvement of BMP signalling in the action of MG‐132 was elucidated by western blot, real‐time PCR, immunofluorescence and RNA interference.Key results:MG‐132 significantly suppressed the proliferation of colon cancer SW1116 and HT‐29 cells. In this regard, MG‐132 activated BMP signalling and this was manifested as an increase in Smad1/5/8 phosphorylation and upregulation of p21Waf1/Cip1 and p27Kip1 expression. Knockdown of BMP receptor II abolished Smad1/5/8 phosphorylation, the induction of p21Waf1/Cip1 and p27Kip1 and inhibition of cell proliferation induced by MG‐132. Further analysis revealed that MG‐132 upregulated the expression of BMP1 and BMP2, which are secreted members of the BMP superfamily. Moreover, the expression of Smad6, an intracellular inhibitor of BMP signalling, was suppressed by MG‐132.Conclusions and implications:These findings suggest that inhibition of proteasome suppresses the proliferation of colon cancer cells via activation of BMP signalling. They also demonstrate a novel aspect of proteasome function in the regulation of colon cancer cell proliferation.British Journal of Pharmacology (2008) 154, 632–638; doi:10.1038/bjp.2008.115; published online 14 April 2008
Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement
Authors: Kadi F 
Published: April 2008

The popularity of testosterone among drug users is due to its powerful effects on muscle strength and mass. Important mechanisms behind the myotrophic effects of testosterone were uncovered both in athletes using steroids for several years and in short‐term controlled studies. Both long‐term and short‐term steroid usage accentuates the degree of fibre hypertrophy in human skeletal muscle by enhancing protein synthesis. A mechanism by which testosterone facilitates the hypertrophy of muscle fibres is the activation of satellite cells and the promotion of myonuclear accretion when existing myonuclei become unable to sustain further enhancement of protein synthesis. Interestingly, long‐term steroid usage also enhances the frequency of fibres with centrally located myonuclei, which implies the occurrence of a high regenerative activity. Under the action of testosterone, some daughter cells generated by satellite cell proliferation may escape differentiation and return to quiescence, which help to replenish the satellite cell reserve pool. However, whether long‐term steroid usage induces adverse effects of satellite cells remains unknown. Testosterone might also favour the commitment of pluripotent precursor cells into myotubes and inhibit adipogenic differentiation. The effects of testosterone on skeletal muscle are thought to be mediated via androgen receptors expressed in myonuclei and satellite cells. Some evidence also suggests the existence of an androgen‐receptor‐independent pathway. Clearly, testosterone abuse is associated with an intense recruitment of multiple myogenic pathways. This provides an unfair advantage over non‐drug users. The long‐term consequences on the regenerative capacity of skeletal muscle are unknown.British Journal of Pharmacology (2008) 154, 522–528; doi:fn1; published online 14 April 2008
Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross‐talk
Authors: Sibilia V , Pagani F , Rindi G , Lattuada N , Rapetti D , De Luca V , Campanini N , Bulgarelli I , Locatelli V , Guidobono F , Netti C 
Published: April 2008

Background and purpose:Ghrelin, a gut‐brain peptide, is considered a gastroprotective factor in gastric mucosa. We investigated the role of prostaglandins (PG) and the possible interplay between PGs and nitric oxide (NO) in ghrelin gastroprotection against ethanol (EtOH)‐induced gastric lesions.Experimental approach:We examined the effects of (1) central ghrelin (4 μg per rat) injection on PGE2 accumulation in normal or EtOH–lesioned gastric mucosa, (2) pretreatment with indomethacin (10 mg kg−1, p.o.), a non‐selective cyclooxygenase (COX) inhibitor, and with a selective COX‐1, SC560 (5 mg kg−1, p.o.) or COX‐2 inhibitor, celecoxib (3.5 mg kg−1, p.o.) on ghrelin gastroprotection against 50% EtOH (1 mL per rat)‐induced gastric lesions, (3) the NO synthase inhibitor, L‐NAME (70 mg kg−1, s.c), on gastric PGE2 content in ghrelin‐treated rats and (4) central ghrelin on the expression of constitutive and inducible NOS and COX mRNA and on the localization of the immunoreactivity for COX‐2 in the gastric mucosa exposed to EtOH.Key results:Ghrelin increased PGE2 in normal mucosa, whereas, it reversed the EtOH‐induced PGE2 surge. Ghrelin had no effect on mucosal COX‐1 expression but reduced the EtOH‐induced increase in COX‐2 expression and immunoreactivity. Indomethacin and SC560, but not celecoxib, removed ghrelin gastroprotection. L‐NAME prevented the PGE2 surge induced by ghrelin and, like indomethacin, reduced EtOH‐induced PGE2 increase. Ghrelin enhanced eNOS expression and reduced iNOS mRNA.Conclusions and implications:This study shows that COX‐1‐derived PGs are mainly involved in ghrelin gastroprotection and that the constitutive‐derived NO together with PGE2 are involved in ghrelin gastroprotective activity.British Journal of Pharmacology (2008) 154, 688–697; doi:10.1038/bjp.2008.120; published online 14 April 2008
Diabetic cardiomyopathy: how much does it depend on AGE?
Authors: Montagnani M 
Published: April 2008

Diabetic cardiomyopathy refers to dysfunction of cardiac muscle in patients with diabetes that cannot be directly ascribed to hypertension, coronary heart disease or other defined cardiac abnormalities per se. The development of diabetic cardiomyopathy may involve several distinct mechanisms, including increased formation of advanced glycation end products (AGEs) secondary to hyperglycaemia. AGEs may alter structural proteins and lead to increased arterial and myocardial stiffness. Therefore, therapies that prevent or retard development of AGEs in diabetes may be valuable strategies to treat or prevent diabetic cardiomyopathy. In this issue of British Journal of Pharmacology, Wu and colleagues demonstrate that aminoguanidine (inhibitor of AGE formation and protein cross‐linking) treatment of a rat model of type I diabetes (rats made insulin deficient with streptozotocin and nicotinamide treatment) ameliorates detrimental changes in left ventricular structure and function. Results from this study are in agreement with previous investigations, suggesting that aminoguanidine is effective in preventing cardiac hypertrophy and arterial stiffening in experimental animal models of diabetes and emphasize the potential pathogenic role of AGEs in diabetic cardiomyopathy.British Journal of Pharmacology (2008) 154, 725–726; doi:10.1038/bjp.2008.121; published online 14 April 2008