bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of shortest sailing distance through random and regular sampling points
Authors: Harbitz Alf , Pennington Michael 
Published: March 2004

Abstract
The shortest sailing distance through n sampling points is calculated for simple theoretical sampling domains (square and circle) as well as for a rather irregular and concavely shaped real sampling domain in the Barents Sea. The sampling sites are either located at the nodes of a square grid (regular sampling) or they are randomly distributed. For n less than ten, the exact shortest sailing distance is derived. For larger n, a traveling salesman algorithm (simulated annealing) was applied, and its bias (distance from true minimum) was estimated based on a case where the true minimum distance was known. In general, the average minimum sailing distance based on random sampling was considerably shorter than for regular sampling, and the difference increased with sample size until an asymptotic value was reached at about n=60 for a square domain. For the sampling domain in the Barents Sea used for shrimp (Pandalus borealis) abundance surveys (n=118 stations), the cruise-track lengths based on random sampling were approximately normally distributed. The mean sailing distance was 18% shorter than the cruise track for regular sampling and the standard deviation equalled 2.6%.
Kinematics of the ACL‐deficient canine knee during gait: Serial changes over two years
Authors: Tashman Scott , Anderst William , Kolowich Patricia , Havstad Suzanne , Arnoczky Steven 
Published: March 2004

AbstractThe ACL‐deficient dog is a model for investigating the development and progression of mechanically driven osteoarthrosis of the knee. ACL loss creates dynamic instability in the ACL‐deficient knee which presumably leads to progressive joint degeneration, but the nature of this instability over the time course of disease development is not well understood. The goal of this study was to characterize three‐dimensional motion of the canine knee during gait, before and serially for two years after ACL transection.Canine tibial‐femoral kinematics were assessed during treadmill gait before and serially for two years after ACL transection (ACL‐D group; 18 dogs) or sham transection (ACL‐I group; five dogs). Kinematic data was collected at 250 frames/s using a biplane video‐radiographic system. Six degree‐of‐freedom motions of the tibia relative to the femur were calculated, and values immediately prior to pawstrike as well as the maximum, minimum, midpoint and range of motion during early/mid stance were extracted. Between‐group differences relative to baseline (pre‐transection) values, as well as changes over time post‐transection, were determined with a repeated‐measures ANCOVA.In the ACL‐D group, peak anterior tibial translation (ATT) increased by 10 mm (p< 0.001), and did not change over time (p= 0.76). Pre‐pawstrike ATT was similar to ACL‐intact values early on (2–4 months) but then increased significantly over time, by 3.5 mm (p< 0.001). The range of ab/adduction motion nearly doubled after ACL loss (from 3.3° to 6.1°). The magnitude (midpoint) of knee adduction also increased significantly over time (mean increase 3.0°;p= 0.036). All changes occurred primarily between 6 and 12 months. There were no significant differences between groups in the transverse plane, and no significant changes over time in the ACL‐I group.In summary, peak anterior tibial translation and coronal‐plane instability increased immediately after ACL loss, and did not improve with time. ATT just prior to pawstrike and mean knee adduction throughout stance became progressively more abnormal with time, with the greatest changes occurring between 6 and 12 months after ACL transection. This may be due to overload failure of secondary restraints such as the medial meniscus, which has been reported to fail in a similar timeframe in the ACL‐deficient dog. The relationships between these complex mechanical alterations and the rate of OA development/progression are currently under investigation. © 2004 Published by Elsevier Ltd. on behalf of Orthopaedic Research Society.
Playing the Devil's Advocate: the United Nations Security Council is Unbound by Law
Authors: Oosthuizen Gabriël H. 
Published: March 2004

Playing the devil's advocate, it is argued that ultimately there are no international legal limits to the UN Security Council's enforcement powers. The argument is based on a brief analysis of various UN Charter provisions and the rejection of the ius cogens concept and other possible arguments for international legal limits. The conclusion reached is that the UN Security Council has unfettered powers when dealing with maintenance of international peace and security issues.Is it true of the Security Council, that:
[…] because the End of this Institution is the Peace and Defence of […] all; and whosoever has the Right to the End, has the Right to the Means, it belongeth of Right [to him] to be Judge both of the Meanes [sic] of Peace and Defence; and also of the hindrances and disturbances of the same; and to do whatsoever he shall think necessary to be done […]Martti Koskenniemi, quoting from Thomas Hobbes' Leviathan
France and European Integration: From the Schuman Plan to Economic and Monetary Union
Authors: LYNCH FRANCES M. B. 
Published: March 2004

Craig Parsons, A Certain Idea of Europe (Ithaca, NY, and London: Cornell University Press, 2003), 255pp., $39.95 (hb), ISBN 0-8014-4086-6.David J. Howarth, The French Road to European Monetary Union (New York and London: Palgrave, 2001), 256pp., £42.50 (hb), ISBN 0-333-92096-1.Mairi MacLean, Economic Management and French Business from de Gaulle to Chirac (New York and London: Palgrave, 2001), 256pp., £42.50 (hb), ISBN 0-333-76148-0.
Pharmacokinetic study on the utilisation of 5‐methyltetrahydrofolate and folic acid in patients with coronary artery disease
Authors: Willems Frank F , Boers Godfried H J , Blom Henk J , Aengevaeren Wim R M , Verheugt Freek W A 
Published: March 2004

Methylenetetrahydrofolate reductase (MTHFR) is a regulating enzyme in folate‐dependant homocysteine remethylation, because it catalyses the reduction of 5,10 methylenetetrahydrofolate to 5‐methyltetrahydrofolate (5‐MTHF).
Subjects homozygous for the 677C → T mutation in the MTHFR enzyme suffer from an increased cardiovascular risk. It can be speculated that the direct administration of 5‐MTHF instead of folic acid can facilitate the remethylation of homocysteine in methionine.
The aim of this study was to determine the pharmacokinetic properties of orally administered 6[R,S] 5‐MTHF versus folic acid in cardiovascular patients with homozygosity for 677C → T MTHFR.
This is an open‐controlled, two‐way, two‐period randomised crossover study. Patients received a single oral dose of either 5 mg folic acid or 5 mg 5‐MTHF in each period. The concentrations of the 6[S] 5‐MTHF and 6[R] 5‐MTHF diastereoisomers were determined in venous blood samples.
All pharmacokinetic parameters demonstrate that the bioavailability of 5‐MTHF is higher compared to folic acid. The peak concentration of both isomers following the administration of 6[R,S] 5‐MTHF is almost seven times higher compared to folic acid, irrespective of the patient's genotype. However, at 1 week after the administration of a single dosage 6[R,S] 5‐MTHF, we detected 6[R] 5‐MTHF following the administration of folic acid, indicating storage of this isomer in the body.
Our results demonstrate that oral 5‐MTHF has a different pharmacokinetic profile with a higher bioavailability compared to folic acid, irrespective of the patient's genotype. Detrimental effects of the storage of high levels of the non‐natural isomer 6[R] 5‐MTHF cannot be excluded.

British Journal of Pharmacology (2004) 141, 825–830. doi:10.1038/sj.bjp.0705446
Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice
Authors: Ferreira Juliano , Da Silva Gisele L , Calixto João B 
Published: March 2004

The vanilloid receptor (TRPV1) is viewed as a molecular integrator of several nociceptive stimuli. In the present study, we have investigated the role played by TRPV1 in the nociceptive response induced by the peripheral activation of kinin B2 receptor in mice.
The intraplantar (i.pl.) administration of bradykinin (BK) and the selective B2 agonist Tyr8‐BK, or the vanilloid agonists resiniferatoxin and capsaicin, into the mouse paw induced a dose‐related overt nociception of short duration. The B2 receptor antagonist Hoe 140 inhibited BK‐induced, but not capsaicin‐induced, nociceptive response. On the other hand, the TRPV1 antagonist capsazepine inhibited both capsaicin‐ and BK‐mediated nociception.
Repeated injections of BK or capsaicin produced desensitization to their nociceptive response. Capsaicin desensitization greatly reduced BK‐induced nociception, but in contrast, the desensitization to BK increased the capsaicin response.
Administration of low doses of capsaicin or acidified saline did not produce nociception when administered alone, but caused a pronounced effect when administered in association with a subthreshold dose of BK. Moreover, the degeneration of the subset of primary afferent fibers, sensitive to capsaicin, abolished both capsaicin‐ and BK‐induced nociception.
The inhibition of phospholipase C (PLC), protein kinase C or phospholipase A2 markedly decreased the nociception caused by BK, but not that of capsaicin. BK administration increased leukotriene B4 levels in the injected paw. Likewise, BK‐induced overt nociception was decreased by lipoxygenase (LOX) inhibition.
These results demonstrate that BK produces overt nociception mediated by TRPV1 receptor stimulation, via PLC pathway activation and LOX product formation.

British Journal of Pharmacology (2004) 141, 787–794. doi:10.1038/sj.bjp.0705546
ATP‐induced vasodilation in human skeletal muscle
Authors: Van Ginneken E E M , Meijer P , Verkaik N , Smits P , Rongen G A 
Published: March 2004

The purine nucleotide adenosine‐5′‐triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium‐derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique.
Adenosine 5′‐triphosphate (0.2, 0.6, 6 and 20 nmol dl−1 forearm volume min−1) evoked a dose‐dependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 μg dl−1 min−1, n=10), the blocker of Na+/K+‐ATPase ouabain (0.2 μg dl−1 min−1, n=8), the blocker of KCa channels tetraethylammonium chloride (TEA, 0.1 μg dl−1 min−1, n=10), nor by the KATP‐channel blocker glibenclamide (2 μg dl−1 min−1, n=10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and L‐NMMA (n=6) significantly increased the baseline forearm vascular resistance. The ATP‐induced relative decreases in forearm vascular resistance were 48±5, 67±3, 88±2, and 92±2% in the absence and 23±7, 62±4, 89±2, and 93±1% in the presence of the combination of TEA, indomethacin and L‐NMMA (P<0.05, repeated‐measures ANOVA, n=6). A similar inhibition was obtained for sodium nitroprusside (SNP, P<0.05 repeated‐measures ANOVA, n=6), indicating a nonspecific interaction due to the blocker‐induced vasoconstriction.
ATP‐induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and L‐NMMA. Endothelium‐independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.

British Journal of Pharmacology (2004) 141, 842–850. doi:10.1038/sj.bjp.0705589
Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes
Authors: Han Suhua , Espinoza Luis A , Liao Hongling , Boulares A Hamid , Smulson Mark E 
Published: March 2004

The mechanism of toxicity of sulphur mustard was investigated by examining the biochemical effects of the analog 2‐chloroethylethyl sulphide (CEES) in both human Jurkat cells as well as normal human lymphocytes.
Exposure of both types of cells to CEES resulted in a marked decrease in the intracellular concentration of the reduced form of glutathione (GSH), and CEES‐induced cell death was potentiated by L‐buthionine sulphoximine, an inhibitor of GSH synthesis.
CEES increased the endogenous production of reactive oxygen species (ROS) in Jurkat cells, and CEES‐induced cell death was potentiated by hydrogen peroxide.
CEES induced various hallmarks of apoptosis, including collapse of the mitochondrial membrane potential, proteolytic processing and activation of procaspase‐3, and cleavage of poly (ADP‐ribose) polymerase.
The effects of CEES on the accumulation of ROS, the intracellular concentration of GSH, the mitochondrial membrane potential, and caspase‐3 activity were all inhibited by pretreatment of cells with the GSH precursor N‐acetyl cysteine or with GSH‐ethyl ester. Furthermore, CEES‐induced cell death was also prevented by these antioxidants.
CEES toxicity appears to be mediated, at least in part, by the generation of ROS and consequent depletion of GSH. Given that sulphur mustard is still a potential biohazard, the protective effects of antioxidants against CEES toxicity demonstrated in Jurkat cells and normal human lymphocytes may provide the basis for the development of a therapeutic strategy to counteract exposure to this chemical weapon.

British Journal of Pharmacology (2004) 141, 795–802. doi:10.1038/sj.bjp.0705591
Modulation of the baroreceptor reflex by α2A‐adrenoceptors: a study in α2A knockout mice
Authors: Niederhoffer Nathalie , Hein Lutz , Starke Klaus 
Published: March 2004

Our objective was to determine whether α2A‐adrenoceptors modulate the baroreceptor reflex. The efficacy of the reflex was evaluated by measuring the spontaneous blood pressure and heart rate variability at rest and the heart rate responses to evoked changes in blood pressure. Experiments were carried out in conscious, unrestrained, and anaesthetized α2A‐adrenoceptor‐deficient (α2A‐KO) mice and WT mice.
In conscious α2A‐KO mice, the spontaneous blood pressure variability was greater, and the spontaneous heart rate variability was lower than in conscious WT mice. This was also observed in anaesthetized animals.
The reflex bradycardia after intravenous injection of phenylephrine was greatly attenuated in conscious α2A‐KO compared to conscious WT mice; the baroreceptor reflex gain (ratio maximal change in heart rate/maximal change in mean arterial pressure) was decreased by 40%.
Similar results were obtained when reflex bradycardia was elicited by intra‐arterial volume loading of conscious WT and α2A‐KO mice. The baroreceptor reflex gain upon volume loading was also low in anaesthetized α2A‐KO mice.
The reflex tachycardia evoked by intravenous sodium nitroprusside injection was also significantly less in α2A‐KO mice as compared to WT, conscious as well as anaesthetized; the baroreceptor reflex gains were decreased by 50 and 65%, respectively.
Direct stimulation of cardiac β‐adrenoceptors by the agonist isoprenaline produced similar cardioacceleration in α2A‐KO and WT animals.
Our results show that the baroreceptor reflex function is impaired in mice lacking α2A‐adrenoceptors. We conclude that central α2A‐adrenoceptors facilitate the reflex response to both loading and unloading of the arterial baroreceptors.

British Journal of Pharmacology (2004) 141, 851–859. doi:10.1038/sj.bjp.0705636
Characterisation of the vasorelaxant properties of the novel endocannabinoid N‐arachidonoyl‐dopamine (NADA)
Authors: O'Sullivan Saoirse E , Kendall David A , Randall Michael D 
Published: March 2004

We have investigated the vascular effects of N‐arachidonoyl‐dopamine (NADA), a novel endocannabinoid/vanilloid. NADA caused vasorelaxant effects comparable to those of anandamide in small mesenteric vessels (G3), the superior mesenteric artery (G0) and in the aorta.
In G3, addition of NG‐nitro‐L‐arginine methyl ester (300 μM) or the dopamine (D1) receptor antagonist (SCH23390, 1 μM) did not affect responses to NADA. In the presence of 60 mM KCl, after de‐endothelialisation, or after K+ channel inhibition with charybdotoxin (100 nM) and apamin (500 nM), relaxant responses to NADA were inhibited.
In G3, pretreatment with the vanilloid receptor (VR) agonist capsaicin (10 μM) or the VR antagonist capsazepine (10 μM) reduced vasorelaxation to NADA.
In G3, application of the CB1 antagonist SR141716A at 1 μM but not 100 nM reduced the potency of NADA. Another CB1 antagonist, AM251 (100 nM and 1 μM), did not affect vasorelaxation to NADA. After endothelial denudation, SR141716A (1 μM) did not reduce the responses further. A combination of capsaicin and SR141716A (1 μM) reduced vasorelaxation to NADA further than with capsaicin pretreatment alone. The novel endothelial cannabinoid (CB) receptor antagonist O‐1918 opposed vasorelaxation to NADA in G3.
In the superior mesenteric artery (G0), vasorelaxation to NADA was not dependent on an intact endothelium and was not sensitive to O‐1918, but was sensitive to capsaicin and SR141716A or AM251 (both 100 nM).
The results of the present study demonstrate for the first time that NADA is a potent vasorelaxant. In G3, the effects of NADA are mediated by stimulation of the VR and the novel endothelial CB receptor, while in G0, vasorelaxation is mediated through VR1 and CB1 receptors.

British Journal of Pharmacology (2004) 141, 803–812. doi:10.1038/sj.bjp.0705643
Cannabinoids and neuroinflammation
Authors: Walter Lisa , Stella Nephi 
Published: March 2004

Growing evidence suggests that a major physiological function of the cannabinoid signaling system is to modulate neuroinflammation. This review discusses the anti‐inflammatory properties of cannabinoid compounds at molecular, cellular and whole animal levels, first by examining the evidence for anti‐inflammatory effects of cannabinoids obtained using in vivo animal models of clinical neuroinflammatory conditions, specifically rodent models of multiple sclerosis, and second by describing the endogenous cannabinoid (endocannabinoid) system components in immune cells. Our aim is to identify immune functions modulated by cannabinoids that could account for their anti‐inflammatory effects in these animal models.British Journal of Pharmacology (2004) 141, 775–785. doi:10.1038/sj.bjp.0705667
Overexpression of β1‐adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for ‘putative’β4‐adrenoceptor pharmacology
Authors: Lewis Clive J , Gong Haibin , Brown Morris J , Harding Sian E 
Published: March 2004

CGP 12177A mediates cardiostimulation by activation of the ‘putative’ β4‐adrenoceptor; however, it has recently been reported that disruption of the β1‐adrenoceptor gene abolishes this effect. We have adenovirally overexpressed β1‐adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 μM propranolol).
Isoprenaline was a full inotropic agonist at rat ventricular myocytes (pD2 7.69±0.12). CGP 12177A was a nonconventional partial agonist (pD2 6.34±0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol.
β1‐adrenoceptor overexpression enhanced the inotropic potency of isoprenaline by 11.7‐fold (pD2 8.76±0.14) and CGP 12177A by 5.9‐fold (7.11±0.10), respectively. Green fluorescent protein (GFP) overexpression did not alter the potency of isoprenaline or CGP 12177A (pD2 7.41±0.24 and pD2 6.60±0.50, respectively).
The cardiostimulant effects of CGP 12177A were enhanced by IBMX (phosphodiesterase inhibitor) and decreased by Rp‐cAMPS (cAMP antagonist). CGP 12177A also increased cAMP levels. CGP 12177A but not isoprenaline initiated arrhythmias at lower concentrations following β1‐adrenoceptor overexpression.
125I‐Cyanopindolol saturation binding in Adv.β1 myocytes demonstrated ∼18‐fold increase in β1‐adrenoceptors. 3H‐CGP 12177A saturation binding, in the presence of propranolol, increased ∼5‐fold following overexpression of β1‐adrenoceptors.
This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing β1‐adrenoceptors, mediated by a Gs/cAMP signalling pathway. ‘Putative’ β4‐adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the β1‐adrenoceptor.

British Journal of Pharmacology (2004) 141, 813–824. doi:10.1038/sj.bjp.0705668
Molecular analysis of the subtype‐selective inhibition of cloned KATP channels by PNU‐37883A
Authors: Kovalev H , Quayle J M , Kamishima T , Lodwick D 
Published: March 2004

In this study, we have used Kir6.1/Kir6.2 chimeric proteins and current recordings to investigate the molecular basis of PNU‐37883A inhibition of cloned KATP channels.
Rat Kir6.1, Kir6.2 and Kir6.1/Kir6.2 chimeras were co‐expressed with either SUR2B or SUR1, following RNA injection into Xenopus oocytes, and fractional inhibition of KATP currents by 10 μM PNU‐37883A reported.
Channels containing Kir6.1/SUR2B were more sensitive to inhibition by PNU‐37883A than those containing Kir6.2/SUR2B (mean fractional inhibition: 0.70, cf. 0.07).
On expression with SUR2B, a chimeric channel with the Kir6.1 pore and the Kir6.2 amino‐ and carboxy‐terminal domains was PNU‐37883A insensitive (0.06). A chimera with the Kir6.1 carboxy‐terminus and Kir6.2 amino‐terminus and pore was inhibited (0.48). These results, and those obtained with other chimeras, suggest that the C‐terminus is an important determinant of PNU‐37883A inhibition of Kir6.1. Similar results were seen when constructs were co‐expressed with SUR1. Further chimeric constructs localised PNU‐37883A sensitivity to an 81 amino‐acid residue section in the Kir6.1 carboxy‐terminus.
Our data show that structural differences between Kir6.1 and Kir6.2 are important in determining sensitivity to PNU‐37883A. This compound may prove useful in probing the structural and functional differences between the two channel subtypes.

British Journal of Pharmacology (2004) 141, 867–873. doi:10.1038/sj.bjp.0705670