Morphometrics of the human thumb metacarpal bone: interest for developing an osseointegrated prosthesis.

INTRODUCTION: Amputation of the thumb presents a serious insult to the hand and diminished quality of life for a patient physically, vocationally, and possibly psychologically. The aim of this study was to define the geometry of the thumb metacarpal in order to help create a standardized set of transcutaneous osseointegrated prostheses to treat patients who have suffered amputation of the thumb at the level of the metacarpophalangeal joint. MATERIALS AND METHODS: A total of 80 metacarpals from 46 cadavers were studied. All soft tissues were removed and the thumb metacarpals were imaged using computed tomography. Three-dimensional models were constructed using images from the coronal, sagittal, and axial planes. Using HyperMesh™ CAD software, the bones were analyzed for overall length, radius of curvature, medullary canal diameter, cortical thickness, and distance to the isthmus, defined as the narrowest portion of the intramedullary canal. RESULTS: The average length of the first metacarpal was 47.6 mm (±3.3 mm, 39.2-56.9 mm). The average radius of curvature was 55.5 mm (±10.7 mm, 33-78.9 mm). Inner bone diameter, measured in two axes, was 10.5 mm (±1.3 mm, 5.4-18.7 mm) for the major axis and 7.7 mm (±0.9 mm, 4.3-17.8 mm) for the minor axis. The average cortical thickness was 1.4 mm (±0.3 mm, 0.7-3.1 mm). The distance to the center of the isthmus from the distal end had an average length of 21.3 mm (±1.9 mm, 17-25 mm). CONCLUSIONS: Using these findings a standardized set of intramedullary stems can be developed as a base for a transcutaneous osseointegrated prosthesis, helping to create a reliable method for treating patients with amputated thumbs.

Invited review: An evaluation of the likely effects of individualized feeding of concentrate supplements to pasture-based dairy cows.

In pasture-based dairy systems, supplementary feeds are used to increase dry matter intake and milk production. Historically, supplementation involved the provision of the same amount of feed (usually a grain-based concentrate feed) to each cow in the herd during milking (i.e., flat-rate feeding). The increasing availability of computerized feeding and milk monitoring technology in milking parlors, however, has led to increased interest in the potential benefits of feeding individual cows (i.e., individualized or differential feeding) different amounts and types of supplements according to one or more parameters (e.g., breeding value for milk yield, current milk yield, days in milk, body condition score, reproduction status, parity). In this review, we consider the likely benefits of individualized supplementary feeding strategies for pasture-based dairy cows fed supplements in the bail during milking. A unique feature of our review compared with earlier publications is the focus on individualized feeding strategies under practical grazing management. Previous reviews focused primarily on research undertaken in situations where cows were offered ad libitum forage, whereas we consider the likely benefits of individualized supplementary feeding strategies under rotational grazing management, wherein pasture is often restricted to all or part of a herd. The review provides compelling evidence that between-cow differences in response to concentrate supplements support the concept of individualized supplementary feeding.

Mother knows best, even when stressed? Effects of maternal exposure to a stressor on offspring performance at different life stages in a wild semelparous fish.

The environment mothers are exposed to has resonating effects on offspring performance. In iteroparous species, maternal exposure to stressors generally results in offspring ill-equipped for survival. Still, opportunities for future fecundity can offset low quality offspring. Little is known, however, as to how intergenerational effects of stress manifest in semelparous species with only a single breeding episode. Such mothers would suffer a total loss of fitness if offspring cannot survive past multiple life stages. We evaluated whether chronic exposure of female sockeye salmon (Oncorhynchus nerka) to a chase stressor impaired offspring performance traits. Egg size and early offspring survival were not influenced by maternal exposure to the repeated acute stressor. Later in development, fry reared from stressed mothers swam for shorter periods of time but possessed a superior capacity to re-initiate bouts of burst swimming. In contrast to iteroparous species, the mechanisms driving the observed effects do not appear to be related to cortisol, as egg hormone concentrations did not vary between stressed and undisturbed mothers. Sockeye salmon appear to possess buffering strategies that protect offspring from deleterious effects of maternal stress that would otherwise compromise progeny during highly vulnerable stages of development. Whether stressed sockeye salmon mothers endow offspring with traits that are matched or mismatched for survival in the unpredictable environment they encountered is discussed. This study highlights the importance of examining intergenerational effects among species-specific reproductive strategies, and across offspring life history to fully determine the scope of impact of maternal stress.

Diagnosis of antiphospholipid syndrome in routine clinical practice.

The updated international consensus criteria for definite antiphospholipid syndrome (APS) are useful for scientific clinical studies. However, there remains a need for diagnostic criteria for routine clinical use. We audited the results of routine antiphospholipid antibodies (aPLs) in a cohort of 193 consecutive patients with aPL positivity-based testing for lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL) and anti-ß(2)glycoprotein-1 antibodies (aß(2)GPI). Medium/high-titre aCL/aß(2)GPI was defined as >99th percentile. Low-titre aCL/aß(2)GPI positivity (>95(th )< 99(th) percentile) was considered positive for obstetric but not for thrombotic APS. One hundred of the 145 patients fulfilled both clinical and laboratory criteria for definite APS. Twenty-six women with purely obstetric APS had persistent low-titre aCL and/or aß(2)GPI. With the inclusion of these patients, 126 of the 145 patients were considered to have APS. Sixty-seven out of 126 patients were LA-negative, of whom 12 had aCL only, 37 had aß(2)GPI only and 18 positive were for both. The omission of aCL or aß(2)GPI testing from investigation of APS would have led to a failure to diagnose APS in 9.5% and 29.4% of patients, respectively. Our data suggest that LA, aCL and aß(2)GPI testing are all required for the accurate diagnosis of APS and that low-titre antibodies should be included in the diagnosis of obstetric APS.

The efficacy of field techniques for obtaining and storing blood samples from fishes.

Prompted by the dramatic increase in the use of blood analyses in fisheries research and monitoring, this study investigated the efficacy of common field techniques for sampling and storing blood from fishes. Three questions were addressed: (1) Do blood samples taken via rapid caudal puncture (the 'grab-and-stab' technique) yield similar results for live v. sacrificed groups of fishes? (2) Do rapidly obtained caudal blood samples accurately represent blood properties of fishes prior to capture? (3) Does storage of whole blood in an ice slurry for a working day (8·5 h) modify the properties of the plasma? It was shown that haematocrit, plasma ions, metabolites, stress hormones and sex hormones of caudal blood samples were statistically similar when taken from live v. recently sacrificed groups of adult coho salmon Oncorhynchus kisutch. Moreover, this study confirmed by using paired blood samples from cannulated O. kisutch that blood acquired through the caudal puncture technique (mean ±s.e. 142 ± 26 s after capture) was representative of fish prior to capture. Long-term (8·5 h) cold storage of sockeye salmon Oncorhynchus nerka whole blood caused significant decreases in plasma potassium and chloride, and a significant increase in plasma glucose. Previous research has suggested that these changes largely result from net movements of ions and molecules between the plasma and erythrocytes, movements that can occur within minutes of storage. Thus, blood samples from fishes should be centrifuged as quickly as practicable in the field for separation of plasma and erythrocytes to prevent potentially misleading data.

Odor differences between enantiomeric isomers.

The enantiomers of R- and S-carvone, R- and S-carvotanacetone, R- and S-trans-dihydrocarvone, and R- and S-cis-dihydrocarvone were synthesized from R- and S-carvone, and all were subjected to gas-liquid chromatographic purification. Sensory analysis of the highly purified compounds revealed odor differences between enantiomeric pairs.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

An immunohistochemical study of the distribution of enteric GABA-containing neurons in the rat and guinea-pig intestine.

gamma-Aminobutyric acid (GABA) antiserum was applied to sections of rat and guinea-pig intestine which were subsequently processed to reveal any immunoreactivity using either fluorescence or peroxidase techniques. Immunopositive fibres were demonstrated in stomach, duodenum, ileum and colon of rat and guinea-pig intestine. Myenteric ganglia and nerve bundles in the circular muscle contained immunopositive nerve fibres, while the longitudinal muscle, submucosa and mucosa were only rarely innervated. In favourable sections, immunopositive fibres could be seen running from the myenteric plexus into the circular muscle, thus suggesting that the GABA-immunopositive nerves in the circular muscle originate from neurons in the myenteric plexus. In both rat and guinea-pig, immunoreactive nerve cell bodies were most numerous in the myenteric plexus of the colon. In the rat, immunopositive fibres in the circular muscle were most abundant in the ileum, whereas in the guinea-pig it was the colon circular muscle that was most richly innervated. The results demonstrate that neurons which show GABA immunoreactivity are present along the length of the gastrointestinal tract. Their distribution in both myenteric ganglia and circular muscle is heterogeneous both within and between the two species studied. It is probable that this heterogeneity reflects the diversity and specificity of function of this class of enteric neurons.

Gamma-aminobutyrate as an autonomic neurotransmitter: release and uptake of [3H]gamma-aminobutyrate in guinea pig large intestine and cultured enteric neurons using physiological methods and electron microscopic autoradiography.

To provide further evidence that some enteric neurons use gamma-aminobutyrate (GABA) as a neurotransmitter, we have demonstrated a depolarization-induced release of [3H]GABA from isolated myenteric ganglia in culture, and from segments of large intestine containing the myenteric plexus. In addition, light and electron microscopic autoradiography has been employed to visualize the putative GABAergic neurons and their projections, both in cultured ganglia and in sections from the gut wall. Explant cultures of the guinea-pig myenteric plexus, containing only neurons and glia intrinsic to the gut, were incubated with 0.14 microM [3H]GABA, washed and then repeatedly depolarized by 62 mM K+. The depolarizations always evoked release of [3H]GABA. The evoked release was reversibly blocked by 5 mM Co2+, suggesting a dependence on Ca2+ influx, a characteristic of neuronal transmitter release. Strips of the guinea-pig taenia coli, containing the myenteric plexus, were incubated with 0.14 or 0.7 microM [3H]GABA, washed and subjected to electrical field stimulation. This caused release of [3H]GABA, which could be evoked successively on repeated stimulation. The release was of neuronal origin and Ca2+ dependent, since it was abolished by 3 microM tetrodotoxin and reversibly blocked by 10 mM Co2+. By combined electrophoresis and chromatography the released tritium was identified as being attached to GABA. Autoradiography, following incubation with low concentrations of [3H]GABA, was used to identify specifically putative GABAergic neurons. Light microscopic autoradiography of cultured ganglia, and electron microscopic autoradiography of sections from the taenia coli including the myenteric plexus, were in good agreement, showing a selective and heavy labelling over a sub-population of neurons, and light labelling over glial cells. The majority of neurons and the non-neural cells were unlabelled. The electron microscopic autoradiographs also showed heavy labelling over some, but not all, axons in the fine axon bundles that innervate the longitudinal muscle of the taenia. These results strongly support our previous suggestion that a population of myenteric neurons are GABAergic, although more work is needed before this is fully established. Our data also suggest that some of the putative GABAergic neurons project out to the gut musculature, where their axons, together with axons from other neurons, run in bundles to form the intramuscular nerves. We therefore propose that one of the roles of these neurons in the gut is the presynaptic modulation of transmitter released from neighbouring axons in these nerves.

A comparison of the relative activities of a number of GABAB antagonists in the isolated vas deferens of the rat.

1. A series of GABAB receptor antagonists were tested against (+/-)-baclofen for activity on the presynaptic GABAB receptor in the rat vas deferens. 2. All the antagonists tested caused a rightward shift in the concentration-response curve to (+/-)-baclofen. 3. pA2 values calculated from full Schild analysis were as follows: phaclofen, pA2 = 4.3; delta-amino valeric acid, pA2 = 4.4; 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), pA2 = 5.0; 3-amino-propyl(n-hexyl)phosphinic acid (3-APHPA), pA2 = 4.5. 4. These results show that none of the above compounds possess potent antagonist activity at the GABAB receptor (i.e. pA2 > 6) in this peripheral tissue. In addition, the more recently available phosphinic acid antagonists, appear to offer no great advance over the GABAB antagonists previously available.

Evidence that the P1-purinoceptor in the guinea-pig taenia coli is an A2-subtype.

The effects of 5'-N-ethylcarboxamidoadenosine (NECA), L-NECA, 2-chloroadenosine, N6-phenylisopropyladenosine (L-PIA and D-PIA), cyclohexyladenosine (CHA), and adenosine were examined on the guinea-pig taenia coli. All the analogues except L-NECA caused relaxations; the order of potency for the series was: NECA greater than 2-chloroadenosine greater than L-PIA greater than CHA greater than D-PIA greater than adenosine. L-PIA was twice as potent as D-PIA in inducing relaxations of the guinea-pig taenia coli. Adenosine and its analogues that induce relaxation all caused a slow membrane hyperpolarization; differences in the rates of hyperpolarization and latencies were apparent, although not statistically significant. The duration of the response to adenosine was significantly less than that for any adenosine analogue. Ion studies, using the sucrose gap, revealed that responses to the analogues were attenuated in elevated extracellular potassium or reduced extracellular chloride. 8-Phenyltheophylline, a potent P1-purinoceptor antagonist, caused a rightward shift of all the adenosine and analogue concentration-response curves. Dipyridamole, an adenosine uptake inhibitor, potentiated the relaxations to adenosine but had no significant effect on the relaxations induced by the analogues. It is concluded that NECA, 2-chloroadenosine, L-PIA, CHA, D-PIA and adenosine mediate their relaxant effects via an extracellular P1-purinoceptor which displays characteristics of the A2-subtype as determined by the rank order of agonist potency. Electrophysiological analysis of the responses to each of the analogues did not reveal any marked differences in the modes of action even between NECA and L-PIA (preferential A2- and A1-receptor agonists, respectively).

Studies on the stereoselectivity of the P2-purinoceptor.

ATP, 2-chloro-ATP, 2-methylthio-ATP, and their unnatural L-enantiomers, were synthesized and their effects tested on the guinea-pig taenia coli and urinary bladder, and the stimulated frog ventricle. The potent P2-purinoceptor agonists, 2-chloro-ATP and 2-methylthio-ATP were, respectively, 30 and 200 times more effective than ATP in relaxing the guinea-pig taenia, but approximately as effective as ATP in contracting the guinea-pig bladder and augmenting the force of contraction of the frog ventricle. A high degree of stereoselectivity was observed for relaxations of the guinea-pig taenia coli produced by the P2-purinoceptoragonists, and 2-methylthio-ATP was over 700 times more effective than its L-enantiomer. In contrast, stereoselectivity for contraction of the guinea-pig bladder was observed only at low concentrations with each pair of enantiomers, and a similar low stereoselectivity was displayed by the frog ventricle. These results show that P2-purinoceptors mediating inhibitory responses in the guinea-pig taenia coli can show a high degree of stereoselectivity, while P2-purinoceptors mediating excitatory responses in the guinea-pig bladder and in the frog ventricle show little stereoselectivity. The partial stereoselectivity of the P2-purinoceptor in smooth muscle contrasts with the absolute stereospecificity of P1-purinoceptors for adenosine on smooth muscle and autonomic nerve terminals and the absolute stereospecificity of the receptor for ADP on the human platelet.

3-Aminopropylphosphinic acid--a potent, selective GABAB receptor agonist in the guinea-pig ileum and rat anococcygeus muscle.

1. 3-Aminopropylphosphinic acid, a gamma-aminobutyric acid (GABA) analogue, was tested for activity on guinea-pig isolated ileum and rat isolated anococcygeus muscle preparations. The effects of 3-aminopropylphosphinic acid were compared with those of GABA and baclofen. 2. In the electrically stimulated ileum, 3-aminopropylphosphinic acid, like GABA and baclofen, caused a concentration-dependent inhibition of the cholinergic twitch contraction, the IC50 value being 1.84 +/- 0.23 microM (n = 12). Unlike GABA, but like baclofen, 3-aminopropylphosphinic acid did not produce an initial contraction. 3. The inhibitory effects of 3-aminopropylphosphinic acid and baclofen in the guinea-pig ileum were not significantly antagonized by bicuculline (10 microM), phentolamine plus propranolol (both 1 microM), yohimbine (1 microM), naloxone (1 microM), impromidine (1 microM) or 8-phenyltheophylline (10 microM). The inhibitory effects of 3-aminopropylphosphinic acid, but not of baclofen, were however antagonized by phaclofen (500 microM). In addition the effects of 3-aminopropylphosphinic acid were abolished by baclofen desensitization in the guinea-pig ileum. 4. 3-Aminopropylphosphinic acid, GABA and baclofen reduced the twitch contraction evoked by electrical field stimulation in the rat anococcygeus muscle. The IC50 for 3-aminopropylphosphinic acid inhibition of the anococcygeus contraction was 0.89 +/- 0.15 microM (n = 8). 5. It is concluded that 3-aminopropylphosphinic acid is a potent, selective GABAB agonist, being seven times more potent than baclofen in the guinea-pig ileum and five times more potent than baclofen in the rat anococcygues muscle preparations.

Phosphinic acid analogues of GABA are antagonists at the GABAB receptor in the rat anococcygeus.

CGP 35348 (3-aminopropyl(diethoxymethyl)phosphinic acid) and 3-aminopropyl(n-hexyl)phosphinic acid (3-APHPA) were tested in the rat anococcygeus muscle against CGP 27492 (3-aminopropylphosphinic acid), a selective GABAB agonist, for their antagonist activity. Their antagonist potency was compared with that of 2-hydroxysaclofen. The pA2 values for CGP 35348, 3-APHPA and 2-hydroxysaclofen were 5.38, 4.86, 4.45 respectively in the rat anococcygeus muscle. These results confirm the previous reports of GABAB antagonist activity for these compounds and show a marginal improvement in potency over 2-hydroxysaclofen.

Fragile X syndrome and selective mutism.

This is the first report that details an association between fragile X syndrome (FXS) and selective mutism (SM). This 12-year-old girl with heterozygous full mutation at FMR1 has a long history of social anxiety and shyness in addition to SM. Her sister also has the full mutation and a history of SM that resolved in adolescence. A beneficial response to fluoxetine and psychotherapy is described. The FMR1 mutation appears to be the first gene mutation associated with SM and further studies are recommended to assess what percentage of patients with SM have the FMR1 mutation.

Compound heterozygous female with fragile X syndrome.

We report on a 15-year-old compound heterozygous young woman with fragile X syndrome who has a full mutation of 363 repeats on one X chromosome and a premutation of 103 repeats on the other X chromosome. As predicted, subsequent testing demonstrated that her father carries a premutation (98 repeats) as does her mother (146 repeats). There is only one previous report of a compound heterozygous female with fragile X syndrome. By quantitation of Southern blot signals, the activation ratio for the premutation (the proportion of the premutation on the active X chromosome) was determined to be 0.78. Immunocytochemistry of blood smears showed fragile X mental retardation-1 protein (FMRP) expression in 63.5% of lymphocytes. Cognitively, this woman is functioning in the mid-range of involvement for fragile X females. She attends regular classes and receives supplemental assistance for her learning disabilities. She experiences behavior characteristics typical of females with fragile X syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She has responded very well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attentional problems, and educational therapy.

Fragile X syndrome and an isodicentric X chromosome in a woman with multiple anomalies, developmental delay, and normal pubertal development.

We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. Pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile X syndrome. Age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile X syndrome based on DNA studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to approximately 110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile X syndrome. Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual reinforces the recommendation of obtaining chromosomes on individuals with developmental delay even with a family history of fragile X syndrome.

The effects of vasoactive intestinal polypeptide on the electrical activity of guinea-pig intestinal smooth muscle.

The effect of vasoactive intestinal polypeptide (VIP) on the electrical activity of the smooth muscle of the guinea-pig taenia coli has been examined using the single sucrose gap apparatus. VIP usually caused a slowly developing, long-lasting membrane hyperpolarisation, although sometimes it reduced the frequency of spontaneous spike discharge without hyperpolarising the membrane. In contrast, non-adrenergic, non-cholinergic nerve stimulation initiated rapid membrane hyperpolarisation followed by post inhibitory excitation. In the presence of apamin, the VIP response was little affected, whereas the responses to non-adrenergic, non-cholinergic nerve stimulation were either markedly antagonised or reversed to membrane depolarisation. Consideration is given to the possible role of either VIP or ATP as the neurotransmitter responsible for the inhibitory junction potential elicited in the guinea-pig taenia coli in response to non-adrenergic inhibitory nerve stimulation.

A novel non-adrenergic, non-cholinergic nerve-mediated relaxation of the pig bladder neck: an examination of possible neurotransmitter candidates.

Electrical field stimulation of the isolated pig bladder neck preparation initiated rapid non-adrenergic, non-cholinergic nerve-mediated relaxations. A wide range of substances were examined as possible candidates for the neurotransmitter involved. Of these, only 5-hydroxytryptamine, vasoactive intestinal polypeptide, adenosine and adenosine 5'-triphosphate produced relaxations. Noradrenaline, acetylcholine, substance P, bradykinin and angiotensin II caused contraction, while neurotensin, somatostatin, bombesin and gamma-amino butyric acid were without effect. The nerve response was not blocked by methysergide, ketanserin, chymotrypsin, apamin or 8-phenyltheophylline, although methysergide antagonised the responses to 5-hydroxytryptamine, chymotrypsin blocked the responses to VIP, and 8-phenyltheophylline antagonised the responses to adenosine and ATP.

Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.

For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.