bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in extracellular pH and myocardial ischaemia alter the cardiac effects of diadenosine tetraphosphate and pentaphosphate
Authors: Stavrou Brigitte M , Beck Caroline , Flores Nicholas A 
Published: January 2005

The structural conformation of diadenosine tetraphosphate (Ap4A) and pentaphosphate (Ap5A) has been reported to alter as pH is reduced. As such, it is possible that the cardiac effects of Ap4A and Ap5A vary during acidosis and myocardial ischaemia due to changes in ligand structure, receptor proteins or intracellular signalling.
We investigated whether the cardiac electrophysiological and coronary vasomotor effects of Ap4A and Ap5A are preserved under conditions of extracellular acidosis (pH 6.5) and alkalosis (pH 8.5) and whether Ap4A has any electrophysiological or antiarrhythmic effects during ischaemia.
Transmembrane right ventricular action potentials, refractory periods and coronary perfusion pressure were recorded from isolated, Langendorff‐perfused guinea‐pig hearts under constant flow conditions. The effects of 1 nM and 1 μM Ap4A and Ap5A were studied at pH 7.4, 6.5 and 8.5. The effects of 1 μM Ap4A were studied during global low‐flow ischaemia and reperfusion.
At pH 7.4, Ap4A and Ap5A increased action potential duration (APD95) and refractory period (RP) and reduced coronary perfusion pressure. The electrophysiological effects were absent at pH 6.5 while the reductions in perfusion pressure were attenuated. At pH 8.5, Ap4A increased RP but the effects of Ap4A and Ap5A on perfusion pressure were attenuated. During ischaemia, Ap4A had no antiarrhythmic or electrophysiological effects.
These data demonstrate the importance of extracellular pH in influencing the effects of Ap4A and Ap5A on the heart and indicate that any potentially cardioprotective effects of these compounds during normal perfusion at physiological pH are absent during ischaemia.

British Journal of Pharmacology (2001) 134, 639–647; doi:10.1038/sj.bjp.0704288
Induction of cyclooxygenase‐2 protein by lipoteichoic acid from Staphylococcus aureus in human pulmonary epithelial cells: involvement of a nuclear factor‐κB‐dependent pathway
Authors: Lin Chien‐Huang , Kuan I‐Hui , Lee Horng‐Mo , Lee Wen‐Sen , Sheu Joen‐Rong , Ho Yuan‐Soon , Wang Chun‐Hua , Kuo Han‐Pin 
Published: January 2005

This study investigated the role of protein kinase C (PKC) and transcription factor nuclear factor‐κB (NF‐κB) in cyclooxygenase‐2 (COX‐2) expression caused by lipoteichoic acid (LTA), a cell wall component of the gram‐positive bacterium Staphylococcus aureus, in human pulmonary epithelial cell line (A549).
LTA caused dose‐ and time‐dependent increases in COX‐2 expression and COX activity, and a dose‐dependent increase in PGE2 release in A549 cells. The LTA‐induced increases in COX‐2 expression and COX activity were markedly inhibited by dexamethasone, actinomycin D or cyclohexamide, but not by polymyxin B, which binds and inactivates endotoxin.
The phosphatidylcholine‐phospholipase C (PC‐PLC) inhibitor (D‐609) and the phosphatidate phosphohydrolase inhibitor (propranolol) reduced the LTA‐induced increases in COX‐2 expression and COX activity, while phosphatidylinositol‐phospholipase C inhibitor (U‐73122) had no effect. The PKC inhibitors (Go 6976, Ro 31‐8220 and GF 109203X) and NF‐κB inhibitor, pyrrolidine dithiocarbamate (PDTC), also attenuated the LTA‐induced increases in COX‐2 expression and COX activity.
Treatment of A549 cells with LTA caused an increase in PKC activity in the plasma membrane; this stimulatory effect was inhibited by D‐609, propranolol, or Go 6976, but not by U‐73122.
Exposure of A549 cells to LTA caused a translocation of p65 NF‐κB from the cytosol to the nucleus and a degradation of IκB‐α in the cytosol. Treatment of A549 cells with LTA caused NF‐κB activation by detecting the formation of NF‐κB‐specific DNA‐protein complex in the nucleus; this effect was inhibited by dexamethasone, D‐609, propranolol, Go 6976, Ro 31‐8220, or PDTC.
These results suggest that LTA might activate PC‐PLC and phosphatidylcholine‐phospholipase D to induce PKC activation, which in turn initiates NF‐κB activation, and finally induces COX‐2 expression and PGE2 release in human pulmonary epithelial cell line.

British Journal of Pharmacology (2001) 134, 543–552; doi:10.1038/sj.bjp.0704290
Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction‐induced chronic left ventricular dysfunction
Authors: Duncker D J , Haitsma D B , Liem D A , Heins N , Stubenitsky R , Verdouw P D 
Published: January 2005

It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca2+‐sensitizer/phosphodiesterase‐III inhibitor pimobendan.
Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction.
MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dtmax (18%), and a doubling of LV end‐diastolic pressure, compared to normal pigs (N, n=13).
In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg−1 min−1) increased LVdP/dtmax (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O2‐consumption, similar to N.
In MI, the effects of EMD 57033 (0.4 mg kg−1 min−1, IV) on stroke volume and LVdP/dtmax were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise.
Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg−1 min−1, IV) were blunted in MI both at rest and during exercise compared to N.
In conclusion, the positive inotropic actions of the Ca2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca2+‐sensitizer/phosphodiesterase‐III inhibitor pimobendan are blunted.

British Journal of Pharmacology (2001) 134, 553–562; doi:10.1038/sj.bjp.0704292
Anandamide induces cardiovascular and respiratory reflexesviavasosensory nerves in the anaesthetized rat
Authors: Smith Paula J W , McQueen Daniel S 
Published: January 2005

We tested the hypothesis that sensory nerves innervating blood vessels play a role in the local and systemic regulation of the cardiovascular and respiratory (CVR) systems. We measured CVR reflexes evoked by administration of anandamide (86 – 863 nmoles) and capsaicin (0.3 – 10 nmoles) into the hindlimb vasculature of anaesthetized rats.Anandamide and capsaicin each caused a rapid dose‐dependent reflex fall in blood pressure and an increase in ventilation when injected intra‐arterially into the hindlimb.Action of both agonists at the vanilloid receptor (VR1) on perivascular sensory nerves was investigated using capsazepine (1 mg kg−1i.a.) a competitive VR1 antagonist, ruthenium red (1 mg kg−1i.a.), a non‐competitive antagonist at VR1, or a desensitizing dose of capsaicin (200 nmoles i.a.). The cannabinoid receptor antagonist SR141716 (1 mg kg−1i.a.) was used to determine agonist activity at the CB1receptor.Capsazepine, ruthenium red, or acute VR1 desensitization by capsaicin‐pretreatment, markedly attenuated the reflex CVR responses evoked by anandamide and capsaicin (P<0.05; paired Student'st‐test). Blockade of CB1had no significant effect on the responses to anandamide.Local sectioning of the femoral and sciatic nerves attenuated CVR responses to anandamide and capsaicin (P<0.05). Vagotomy or carotid sinus sectioning had no significant effect on anandamide‐ or capsaicin‐induced responses.These data demonstrate that both the endogenous cannabinoid, anandamide, and the vanilloid, capsaicin, evoke CVR reflexes when injected intra‐arterially into the rat hindlimb. These responses appear to be mediated reflexlyviaVR1 located on sensory nerve endings within the hindlimb vasculature.British Journal of Pharmacology(2001)134, 655–663; doi:10.1038/sj.bjp.0704296
Inhibition of interleukin‐12 production by auranofin, an anti‐rheumatic gold compound, deviates CD4+ T cells from the Th1 to the Th2 pathway
Authors: Kim T S , Kang B Y , Lee M H , Choe Y K , Hwang S Y 
Published: January 2005

Interleukin‐12 (IL‐12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN‐γ and low IL‐4 production. In this study we investigated the effect of auranofin (AF), an anti‐rheumatic gold compound, on IL‐12 production in mouse macrophages and dendritic cells, and studied whether AF‐mediated inhibition of IL‐12 production could regulate a cytokine profile of antigen (Ag)‐primed CD4+ Th cells.
Treatment with AF significantly inhibited IL‐12 production in lipopolysaccharide (LPS)‐stimulated macrophages and also in CD40L‐stimulated dendritic cells. AF‐pretreated macrophages reduced their ability to induce IFN‐γ and increased the ability to induce IL‐4 in Ag‐primed CD4+ T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86.
Addition of recombinant IL‐12 to cultures of AF‐pretreated macrophages and CD4+ T cells restored IFN‐γ production in Ag‐primed CD4+ T cells.
The in vivo administration of AF resulted in the inhibition of IL‐12 production by macrophages stimulated in vitro with LPS or heat‐killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN‐γ and increased IL‐4 production) in Ag‐primed CD4+ T cells.
These findings may explain some known effects of AF including anti‐rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1‐mediated immune diseases such as autoimmune diseases.

British Journal of Pharmacology (2001) 134, 571–578; doi:10.1038/sj.bjp.0704298
Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats
Authors: Kagota Satomi , Tamashiro Akiko , Yamaguchi Yu , Sugiura Reiko , Kuno Takayoshi , Nakamura Kazuki , Kunitomo Masaru 
Published: January 2005

Cyclic guanosine monophosphate (cyclic GMP)‐mediated mechanism plays an important role in vasodilatation and blood pressure regulation. We investigated the effects of high salt intake on the nitric oxide (NO) – cyclic GMP signal transduction pathway regulating relaxation in aortas of spontaneously hypertensive rats (SHR).
Four‐week‐old SHR and normotensive Wistar‐Kyoto rats (WKY) received a normal salt diet (0.3% NaCl) or a high salt diet (8% NaCl) for 4 weeks.
In aortic rings from SHR, endothelium‐dependent relaxations in response to acetylcholine (ACh), adenosine diphosphate (ADP) and calcium ionophore A23187 were significantly impaired by the high salt intake. The endothelium‐independent relaxations in response to sodium nitroprusside (SNP) and nitroglycerin were also impaired, but that to 8‐bromo‐cyclic GMP remained unchanged. On the other hand, high salt diet had no significant effects on the relaxations of aortic rings from WKY.
In aortas from SHR, the release of NO stimulated by ACh was significantly enhanced, whereas the production of cyclic GMP induced by either ACh or SNP was decreased by the high salt intake.
Western blot analysis showed that the protein level of endothelial NO synthase (eNOS) was slightly increased, whereas that of soluble guanylate cyclase (sGC) was dramatically reduced by the high salt intake.
These results indicate that in SHR, excessive dietary salt can result in downregulation of sGC followed by decreased cyclic GMP production, which leads to impairment of vascular relaxation in responses to NO. It is notable that chronic high salt intake impairs the sGC/cyclic GMP pathway but not the eNOS/NO pathway.

British Journal of Pharmacology (2001) 134, 737–744; doi:10.1038/sj.bjp.0704300
Adenosine‐mediated hypotension in in vivo guinea‐pig: receptors involved and role of NO
Authors: Nieri P , Martinotti E , Calderone V , Breschi M C 
Published: January 2005

Adenosine produced a biphasic lowering of the mean BP with a drastic bradycardic effect at the highest doses. The first phase hypotensive response was significantly reduced by the nitric oxide (NO) synthase inhibitor L‐NAME.
The A2a/A2b agonist NECA produced hypotensive and bradycardic responses similar to those elicited by adenosine, which were not significantly modified by the A2b antagonist enprofylline.
The A2a agonist CGS 21680 did not significantly influence basal HR while induced a hypotensive response antagonized by the A2a selective antagonist ZM 241385, and reduced by both L‐NAME and the guanylate cyclase inhibitor methylene blue.
The A1 agonist R‐PIA showed a dose‐dependent decrease in BP with a drastic decrease in HR at the highest doses. The A1 selective antagonist DPCPX significantly reduced the bradycardic activity and also the hypotensive responses obtained with the lowest doses while it increased those obtained with the highest ones.
The A1/A3 agonist APNEA, in the presence of the xanthinic non‐selective antagonist 8‐pSPT, maintained a significant hypotensive, but not bradycardic, activity, not abolished by the histamine antagonist diphenhydramine.
The selective A3 agonist IB‐MECA revealed a weak hypotensive and bradycardic effect, but only at the highest doses.
In conclusion, in the systemic cardiovascular response to adenosine two major components may be relevant: an A2a‐ and NO‐mediated hypotension, and a bradycardic effect with a consequent hypotension, via atypical A1 receptors. Finally, an 8‐pSPT‐resistant hypotensive response not attributable to A3 receptor‐stimulation or to release of histamine by mastocytes or other immune cells was observed.

British Journal of Pharmacology (2001) 134, 745–752; doi:10.1038/sj.bjp.0704301
Pravastatin suppresses the interleukin‐8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase
Authors: Takata Michiyo , Urakaze Masaharu , Temaru Rie , Yamazaki Katsuya , Nakamura Norio , Nobata Yuhko , Kishida Mika , Sato Akira , Kobayashi Masashi 
Published: January 2005

3‐Hydroxy‐3‐methylglutaryl co‐enzyme A reductase inhibitors (statins) prevent the progression of atherosclerosis by lowering cholesterol. However, the effect of statins on the synthesis of pro‐inflammatory cytokines from endothelial cells has not yet been fully investigated. Here, we examined the effect of pravastatin, one of the statins, on IL‐8 synthesis induced by thrombin in human aortic endothelial cells (AoEC) cultured with high glucose concentrations.
Pravastatin significantly decreased the IL‐8 synthesis induced by thrombin.
Pravastatin inhibited the p44/42 MAP kinase activity induced by thrombin, but did not inhibit the p38 MAP kinase activity.
Translocation of ras protein from the cytosol to plasma membrane was inhibited by pravastatin.
Pravastatin inhibit the activator protein‐1 activity, but did not inhibit the activation of IκB‐α.
Dominant negative ras inhibited the p44/42 MAP kinase activity induced by PMA.
Our results suggest that pravastatin inhibits IL‐8 synthesis by blocking the ras‐MAP (p44/42) kinase pathway rather than nuclear factor‐κB. Pravastatin may prevent atherosclerosis not only by lowering cholesterol levels, but also by suppressing IL‐8 synthesis in AoEC through the inhibition of p44/42 MAP kinase, and this may be more beneficial in diabetic patients than in non‐diabetics.

British Journal of Pharmacology (2001) 134, 753–762; doi:10.1038/sj.bjp.0704305
Effects of dantrolene and its derivatives on Ca2+ release from the sarcoplasmic reticulum of mouse skeletal muscle fibres
Authors: Ikemoto Takaaki , Hosoya Takamitsu , Aoyama Hiroshi , Kihara Yasutaka , Suzuki Masaaki , Endo Makoto 
Published: January 2005

We analysed the effect of dantrolene (Dan) and five newly synthesized derivatives (GIFs) on Ca2+ release from the sarcoplasmic reticulum (SR) of mouse skeletal muscle.
In intact muscles, GIF‐0185 reduced the size of twitch contraction induced by electrical stimulation to the same extent as Dan. GIF‐0082, an azido‐functionalized Dan derivative, also inhibited twitch contraction, although the extent of inhibition was less than that of Dan and of GIF‐0185.
In skinned fibres, Dan inhibited Ca2+‐induced Ca2+ release (CICR) under Mg2+‐free conditions at room temperature. In contrast, GIF‐0082 and GIF‐0185 showed no inhibitory effect on CICR under the same conditions.
Dan‐induced inhibition of CICR was not affected by the presence of GIF‐0082, whereas it was diminished in the presence of GIF‐0185.
GIF‐0082 and GIF‐0185 significantly inhibited clofibric acid (Clof)‐induced Ca2+ release, as did Dan.
Several Dan derivatives other than GIF‐0082 and GIF‐0185 showed an inhibitory effect on twitch tension but not on the CICR mechanism. All of these derivatives inhibited Clof‐induced Ca2+ release.
The magnitudes of inhibition of Clof‐induced Ca2+ release by all Dan derivatives were well correlated with those of twitch inhibition. This supports the notion that the mode of Clof‐induced opening of the RyR‐Ca2+ release channel may be similar to that of physiological Ca2+ release (PCR).
These results indicate that the difference in opening modes of the RyR‐Ca2+ release channel is recognized by certain Dan derivatives.

British Journal of Pharmacology (2001) 134, 729–736; doi:10.1038/sj.bjp.0704307
α2‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator
Authors: Orito Kensuke , Kishi Masami , Imaizumi Takashi , Nakazawa Toru , Hashimoto Ayako , Mori Toyoki , Kambe Toshimi 
Published: January 2005

Antagonistic properties of OPC‐28326 ([4‐(N‐methyl‐2‐phenylethylamino)‐1‐(3,5‐dimethyl‐4‐propionyl‐aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to α2‐adrenoceptor subtypes.
Using a human recombinant receptor and rat kidney cortex, we found that OPC‐28326 displays affinities to α2A‐, α2B‐ and α2C‐adrenoceptors with Ki values of 2040, 285, and 55 nM, respectively. The Ki values of yohimbine for α2A‐, α2B‐, and α2C‐adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively.
B‐HT 920, an α2‐adrenoceptor agonist, produced a pressor response via peripheral postsynaptic α2‐adrenoceptor stimulation (thought to be an α2B‐subtype) in a reserpine‐pretreated pithed rat preparation. OPC‐28326 (3 – 30 mg kg−1, i.v.) and yohimbine (0.3 – 3 mg kg−1, i.v.) caused dose‐dependent rightward shift in the pressor dose‐response curve induced by B‐HT 920. The apparent pA2 values were 1.55 (0.87 – 2.75, 95% confidence interval) and 0.11 (0.06 – 0.21) mg kg−1, respectively. The potency of OPC‐28326 was about 14 times less than that of yohimbine.
Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic α2A/D‐adrenoceptor action. OPC‐28326 (1 – 100 μM) and yohimbine (10 – 1000 nM) caused a rightward shift in the concentration‐response curve of clonidine. The pA2 values were 5.73 (5.54 – 5.91) and 7.92 (7.84 – 8.01), respectively, providing evidence for a potency of OPC‐28326 of about 155 times less than that of yohimbine.
Mydriasis was induced by brimonidine via stimulation of central α2A/D‐adrenoceptors in anaesthetized rats. Intravenous OPC‐28326 had no effect on this action, even at a very high dose of 10 mg kg−1 i.v., while yohimbine (0.1 – 0.3 mg kg−1 i.v.) inhibited mydriasis in a dose‐dependent manner, indicating that OPC‐28326 was at least 100 times less potent than yohimbine in regard to the anti‐mydriatic effect.
These data suggest that OPC‐28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the α2B‐ and α2C‐adrenoceptor subtypes.

British Journal of Pharmacology (2001) 134, 763–770; doi:10.1038/sj.bjp.0704309
The role of sensory nerve endings in nerve growth factor‐induced airway hyperresponsiveness to histamine in guinea‐pigs
Authors: Vries Annick de , Rijnsoever Carolien van , Engels Ferdi , Henricks Paul A J , Nijkamp Frans P 
Published: January 2005

Nerve growth factor induces an airway hyperresponsiveness in vivo in guinea‐pigs, as we have shown previously. Since antagonizing the neurokinin‐1 (NK1) receptor can prevent this NGF‐induced airway hyperresponsiveness and since sensory nerves release tachykinins, we investigated the role of sensory nerves in the NGF‐induced airway hyperresponsiveness.
We used isolated tracheal rings from guinea‐pigs to measure tracheal contractility. In these rings sensory nerve endings are present, but these endings lack any contact with their cell bodies.
In this in vitro system, NGF dose‐dependently induced a tracheal hyperresponsiveness to histamine. The NK1 receptor antagonist SR140333 could block the induction of tracheal hyperresponsiveness.
To further investigate the involvement of sensory nerve endings we used the cannabinoid receptor 1 (CB1) agonist R‐methanandamide to inhibit excitatory events at the nerve terminal. The CB1 receptor agonist was capable of blocking the tracheal hyperresponsiveness to NGF in the isolated system, as well as the airway hyperresponsiveness to NGF in vivo.
This indicates that NGF can induce an increase in airway responsiveness in the absence of sensory nerve cell bodies. NGF may act by increasing substance P release from sensory nerve endings, without upregulation of substance P in the neurons. Substance P in its turn is responsible for the induction of the NGF‐induced airway hyperresponsiveness.

British Journal of Pharmacology (2001) 134, 771–776; doi:10.1038/sj.bjp.0704310
Pharmacological comparison of LTB4‐induced NADPH oxidase activation in adherent and non‐adherent guinea‐pig eosinophils
Authors: Lynch Oonagh T , Giembycz Mark A , Barnes Peter J , Lindsay Mark A 
Published: January 2005

Leukotriene B4 (LTB4) stimulation of guinea‐pig peritoneal eosinophils, induced a biphasic activation of the NADPH oxidase composed of a rapid (<3 min) phase mediated by non‐adherent cells and a sustained (3 – 120 min) phase mediated by CD11b/CD18 adherent eosinophils. Studies were undertaken to compare the intracellular mechanism that mediate these responses.
SB 203580 and PP1, inhibitors of p38 mitogen‐activated protein (MAP) kinase and the src‐family protein tyrosine kinases, respectively caused concentration‐dependent attenuation of both the rapid (SB203580: pD2=−6.31; PP1: pD2=−5.50) and sustained (SB203580: pD2=−6.50; PP1: pD2=−5.73) phases. Similarly, the MAP kinase kinase‐1 inhibitor, PD098059 produced partial inhibition of the both phases of superoxide generation.
The protein kinase C (PKC) inhibitors Ro‐31 8220, GF 109203X and Gö 6976 attenuated the rapid NADPH oxidase response (pD2s=−6.10, −6.72, −6.15 respectively) and, to a lesser extent, (pD2s=−5.54, −6.02, −6.51 respectively) the sustained phase.
An inhibitor of phosphatidylinositol 3‐kinase (PtdIns 3‐kinase), wortmannin caused concentration dependent attenuation of the sustained (pD2=−8.68) but not rapid phase of superoxide generation. In contrast, the syk kinase inhibitor, piceatannol abolished the rapid (pD2=−6.43) but not sustained respiratory responses.
This study demonstrates that LTB4‐induced superoxide generation from adherent and non‐adherent eosinophils is mediated via both common (p38 MAP kinase, MEK‐1, PKC and the src kinases) and divergent intracellular pathways (syk kinases and PtdIns 3‐kinase). This suggests the possibility of therapeutic intervention to selective attenuate activation of adherent tissue eosinophils.

British Journal of Pharmacology (2001) 134, 797–806; doi:10.1038/sj.bjp.0704314