Signal intensity and volume of carotid intraplaque hemorrhage on magnetic resonance imaging and the risk of ipsilateral cerebrovascular events: The Plaque At RISK (PARISK) study.

BACKGROUND: The Plaque At RISK (PARISK) study demonstrated that patients with a carotid plaque with intraplaque hemorrhage (IPH) have an increased risk of recurrent ipsilateral ischemic cerebrovascular events. It was previously reported that symptomatic carotid plaques with IPH showed higher IPH signal intensity ratios (SIR) and larger IPH volumes than asymptomatic plaques. We explored whether IPH SIR and IPH volume are associated with future ipsilateral ischemic cerebrovascular events beyond the presence of IPH. METHODS: Transient ischemic attack and ischemic stroke patients with mild-to-moderate carotid stenosis and an ipsilateral IPH-positive carotid plaque (n = 89) from the PARISK study were included. The clinical endpoint was a new ipsilateral ischemic cerebrovascular event during 5 years of follow-up, while the imaging-based endpoint was a new ipsilateral brain infarct on brain magnetic resonance imaging (MRI) after 2 years (n = 69). Trained observers delineated IPH, a hyperintense region compared to surrounding muscle tissue on hyper T1-weighted magnetic resonance images. The IPH SIR was the maximal signal intensity in the IPH region divided by the mean signal intensity of adjacent muscle tissue. The associations between IPH SIR or volume and the clinical and imaging-based endpoint were investigated using Cox proportional hazard models and logistic regression, respectively. RESULTS: During 5.1 (interquartile range: 3.1-5.6) years of follow-up, 21 ipsilateral cerebrovascular ischemic events were identified. Twelve new ipsilateral brain infarcts were identified on the 2-year neuro MRI. There was no association for IPH SIR or IPH volume with the clinical endpoint (hazard ratio (HR): 0.89 [95% confidence interval: 0.67-1.10] and HR: 0.91 [0.69-1.19] per 100-µL increase, respectively) nor with the imaging-based endpoint (odds ratio (OR): 1.04 [0.75-1.45] and OR: 1.21 [0.87-1.68] per 100-µL increase, respectively). CONCLUSION: IPH SIR and IPH volume were not associated with future ipsilateral ischemic cerebrovascular events. Therefore, quantitative assessment of IPH of SIR and volume does not seem to provide additional value beyond the presence of IPH for stroke risk assessment. TRIAL REGISTRATION: The PARISK study was registered on ClinicalTrials.gov with ID NCT01208025 on September 21, 2010 (https://clinicaltrials.gov/study/NCT01208025).

Determination of the proliferative fractions in differentiating hematopoietic cell lineages of normal bone marrow.

Because of the proven prognostic value of Ki-67 as a proliferation marker in several types of solid cancers, our goal is to develop and validate a multiparameter flow cytometric assay for the determination of the Ki-67 expression in hemato-oncological diseases. The aim of the present study was to establish the reference values for the fraction of Ki-67 positive cells in and during maturation of individual hematopoietic cell lineages present in normal bone marrow. Aspirates derived from femoral heads of 50 patients undergoing a hip replacement were used for the flow cytometric quantification of Ki-67 expression in the different hematopoietic cell populations of healthy bone marrow. Furthermore, the proliferative index was investigated in detail for the maturation steps during erythro-, myelo-, and monopoiesis using recently described immunophenotypic profiles in combination with a software-based maturation tool. Reference values for the proliferative index were established for different relevant hematopoietic cell populations in healthy bone marrow. During maturation, the size of the Ki-67 positive fraction was the highest in the most immature compartment of the myeloid, monocytic, and erythroid cell lineages, followed by a steady decline upon cell maturation. While proerythroblasts showed a proliferative activity of almost 100%, the myelo- and monoblast showed a lower proliferative index of on average of 50%, indicating that a relatively large proportion of these cells exist in a quiescent state. In conclusion, we can state that when using a novel combination of immunophenotypic markers, the proliferation marker (Ki-67) and a software-based maturation tool, it was possible to determine the proliferative fractions in the diverse hematopoietic cell lineages in bone marrow, in particular during maturation. Using this approach, the proliferative indices for the normal myelo-, mono-, and erythropoiesis were determined, which can be used as a reference in future studies of hematologic malignancies originating from bone marrow. © 2018 International Society for Advancement of Cytometry.

Quantification of carotid plaque composition with a multi-contrast atherosclerosis characterization (MATCH) MRI sequence.

Background and purpose: Carotid atherosclerotic plaques with a large lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and a thin or ruptured fibrous cap are associated with increased stroke risk. Multi-sequence MRI can be used to quantify carotid atherosclerotic plaque composition. Yet, its clinical implementation is hampered by long scan times and image misregistration. Multi-contrast atherosclerosis characterization (MATCH) overcomes these limitations. This study aims to compare the quantification of plaque composition with MATCH and multi-sequence MRI. Methods: MATCH and multi-sequence MRI were used to image 54 carotid arteries of 27 symptomatic patients with ≥2 mm carotid plaque on a 3.0 T MRI scanner. The following sequence parameters for MATCH were used: repetition time/echo time (TR/TE), 10.1/4.35 ms; field of view, 160 mm × 160 mm × 2 mm; matrix size, 256 × 256; acquired in-plane resolution, 0.63 mm2× 0.63 mm2; number of slices, 18; and flip angles, 8°, 5°, and 10°. Multi-sequence MRI (black-blood pre- and post-contrast T1-weighted, time of flight, and magnetization prepared rapid acquisition gradient echo; acquired in-plane resolution: 0.63 mm2 × 0.63 mm2) was acquired according to consensus recommendations, and image quality was scored (5-point scale). The interobserver agreement in plaque composition quantification was assessed by the intraclass correlation coefficient (ICC). The sensitivity and specificity of MATCH in identifying plaque composition were calculated using multi-sequence MRI as a reference standard. Results: A significantly lower image quality of MATCH compared to that of multi-sequence MRI was observed (p < 0.05). The scan time for MATCH was shorter (7 vs. 40 min). Interobserver agreement in quantifying plaque composition on MATCH images was good to excellent (ICC ≥ 0.77) except for the total volume of calcifications and fibrous tissue that showed moderate agreement (ICC ≥ 0.61). The sensitivity and specificity of detecting plaque components on MATCH were ≥89% and ≥91% for IPH, ≥81% and 85% for LRNC, and ≥71% and ≥32% for calcifications, respectively. Overall, good-to-excellent agreement (ICC ≥ 0.76) of quantifying plaque components on MATCH with multi-sequence MRI as the reference standard was observed except for calcifications (ICC = 0.37-0.38) and fibrous tissue (ICC = 0.59-0.70). Discussion and conclusion: MATCH images can be used to quantify plaque components such as LRNC and IPH but not for calcifications. Although MATCH images showed a lower mean image quality score, short scan time and inherent co-registration are significant advantages.

Emerging Role of Carotid MRI for Personalized Ischemic Stroke Risk Prediction in Patients With Carotid Artery Stenosis.

Rupture of a vulnerable carotid plaque is an important cause of ischemic stroke. Prediction models can support medical decision-making by estimating individual probabilities of future events, while magnetic resonance imaging (MRI) can provide detailed information on plaque vulnerability. In this review, prediction models for medium to long-term (>90 days) prediction of recurrent ischemic stroke among patients on best medical treatment for carotid stenosis are evaluated, and the emerging role of MRI of the carotid plaque for personalized ischemic stroke prediction is discussed. A systematic search identified two models; the European Carotid Surgery Trial (ECST) medical model, and the Symptomatic Carotid Atheroma Inflammation Lumen stenosis (SCAIL) score. We critically appraised these models by means of criteria derived from the CHARMS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modeling Studies) and PROBAST (Prediction model Risk Of Bias ASsessment Tool). We found both models to be at high risk of bias. The ECST model, the most widely used model, was derived from data of large but relatively old trials (1980s and 1990s), not reflecting lower risks of ischemic stroke resulting from improvements in drug treatment (e.g., statins and anti-platelet therapy). The SCAIL model, based on the degree of stenosis and positron emission tomography/computed tomography (PET/CT)-based plaque inflammation, was derived and externally validated in limited samples. Clinical implementation of the SCAIL model can be challenging due to high costs and low accessibility of PET/CT. MRI is a more readily available, lower-cost modality that has been extensively validated to visualize all the hallmarks of plaque vulnerability. The MRI methods to identify the different plaque features are described. Intraplaque hemorrhage (IPH), a lipid-rich necrotic core (LRNC), and a thin or ruptured fibrous cap (TRFC) on MRI have shown to strongly predict stroke in meta-analyses. To improve personalized risk prediction, carotid plaque features should be included in prediction models. Prediction of stroke in patients with carotid stenosis needs modernization, and carotid MRI has potential in providing strong predictors for that goal.

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity.

Formation and extinction of aversive memories in the mammalian brain are insufficiently understood at the cellular and molecular levels. Using the novel metabotropic glutamate receptor 7 (mGluR7) agonist AMN082, we demonstrate that mGluR7 activation facilitates the extinction of aversive memories in two different amygdala-dependent tasks. Conversely, mGluR7 knockdown using short interfering RNA attenuated the extinction of learned aversion. mGluR7 activation also blocked the acquisition of Pavlovian fear learning and its electrophysiological correlate long-term potentiation in the amygdala. The finding that mGluR7 critically regulates extinction, in addition to acquisition of aversive memories, demonstrates that this receptor may be relevant for the manifestation and treatment of anxiety disorders.

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)).

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

Habenula lesions alter synaptic plasticity within the fimbria-accumbens pathway in the rat.

Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria-nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria-nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

Progressive age-related impairment of cognitive behavior in APP23 transgenic mice.

Transgenic APP23 mice expressing human APP(751) with the K670N/M671L mutation, were compared at ages 3, 18 or 25 months to non-transgenic littermates in passive avoidance and in a small and large Morris maze. The task in the smaller pool habituated their flight response to the platform. Impairments in passive avoidance and small pool performance in APP23 mice were clearly age-related. In the larger Morris maze APP23 mice at all ages were impaired in latency and distance swum before finding the platform. Identical performance of 18-month APP23 and controls in a visible platform condition indicates that the Morris maze performance deficit was not due to sensory, motor or motivational alterations. At age 3 months both groups initially unexpectedly avoided the visible platform, suggesting that in young mice neophobia may contribute significantly to performance in cognitive tests. In conclusion, APP23 mice exhibit both early behavioral impairment in the large Morris maze as well as impairments in passive avoidance and small pool performance that are marked only in old age.

Effects of serotonergic activity in nucleus accumbens septi on drug-induced circling.

The effects of injections of 5-hydroxytryptamine (5-HT) into the nucleus accumbens and lesions of the nucleus accumbens induced by 5,7-dihydroxytryptamine (5,7-DHT) on drug-induced circling were investigated in rats with unilateral nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Injections of 5-HT (60-120 micrograms in 1 microliter; 1 microliter/min) into the nucleus accumbens caused a significant decrease in the circling response to 5.0 mg/kg of d-amphetamine (s.c.). The distribution of radioactivity after intracerebral injections of [3H]5-HT using these parameters showed that although much of the injected material was retained in the nucleus accumbens there was also considerable spread to the frontal cortex. However, in further behavioural experiments, using an injection procedure (0.5 microliter; 0.11 microliter/min) which caused much greater retention of injected material in the nucleus accumbens, with minimal spread to the frontal cortex, the ability of 5-HT injected into the accumbens to block amphetamine-induced circling was not diminished. Moreover, injections of 5-HT into the frontal cortex did not have any effect on amphetamine-induced circling. Lesions of the nucleus accumbens induced by 5,7-DHT caused a significant enhancement of the contralateral circling response to 1.0 mg/kg of apomorphine and a similar but non-significant tendency to increase the circling responses to several other doses of apomorphine and amphetamine. The results provide evidence that serotonergic mechanisms in the nucleus accumbens inhibit circling behaviour generated by unilateral activation of nigrostriatal dopaminergic mechanisms.

Regional decreases of cortical choline acetyltransferase after lesions of the septal area and in the area of nucleus basalis magnocellularis.

Choline acetyltransferase and [3H]choline uptake have been measured in neocortical regions and hippocampus one week after lesions which destroyed the septum bilaterally, and after unilateral lesions in the area of nucleus basalis magnocellularis. Lesions of the septal area, which severely decreased choline acetyltransferase in hippocampus, only moderately decreased choline acetyltransferase in a posterior cortical region and had no effect in frontal and parietal regions. In contrast, lesions which included nucleus basalis magnocellularis decreased choline acetyltransferase markedly in frontal and parietal regions and had less of an effect in the posterior cortical regions. Lesion-induced decreases of [3H]choline uptake paralleled those of choline acetyltransferase. Lesion which included nucleus basalis magnocellularis had no effect on choline acetyltransferase in hippocampus, nucleus accumbens, olfactory tubercle, midbrain or pons-medulla. These results suggest that existence of topographically distinct cholinergic inputs to neocortex. In agreement with previous studies, cholinergic projections from the peripallidal region of nucleus basalis magnocellularis are predominantly to frontal and parietal neocortex. In contrast to previous suggestions, cholinergic projections to neocortex from the septal area are limited to the posterior regions of neocortex.

Is ethylcholine mustard aziridinium ion a specific cholinergic neurotoxin?

The histopathologic effects of different doses of ethylcholine mustard aziridinium ion infused into the caudate-putamen complex or nucleus basalis were evaluated in rats. Although no non-specific tissue damage was observed at the lowest doses of ethylcholine mustard aziridinium ion examined--0.01 nmol in 1-microliter vehicle and 0.02 nmol in 2-, 5-, and 10-microliters vehicle in both the striatum and nucleus basalis--minimal but definite non-selective pathology, characterized by gliosis and loss of all neuronal elements in the region affected by the nitrogen mustard, was observed in both targets at a dose of 0.02 nmol 1 microliter and more severely at all doses containing 0.05 and 0.1 nmol ethylcholine mustard aziridinium ion. At doses of ethylcholine mustard aziridinium ion containing 0.2 nmol of the cytotoxin and greater amounts, non-specific cell loss in intact tissue and extensive cavitation became increasingly the most prominent histologic features of drug action. No statistically significant effects of ethylcholine mustard aziridinium ion on striatal choline acetyltransferase activities were found until doses of 0.4 nmol/1 microliter or greater were injected, concentrations of the cytotoxin at which appreciable non-specific pathology was also observed. Levels of dopamine in the caudate-putamen nucleus were reduced by comparatively greater amounts than choline acetyltransferase at doses of 2.5 nmol/2 microliters, 5.0 nmol/2 microliters and 10 nmol/2 microliters cytotoxin, but a significant effect of ethylcholine mustard aziridinium ion on striatal L-glutamate decarboxylase activity was found only at a dose of 10 nmol/2 microliters. As no dose of ethylcholine mustard aziridinium ion was found that reduced choline acetyltransferase without producing considerable non-specific tissue destruction, the usefulness of the cytotoxin in studying the behavioral and physiological consequences of selective cholinergic hypofunction in the brain must be questioned.

The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.

1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism.

Evidence concerning the involvement of 5-hydroxytryptamine in the locomotor activity produced by amphetamine or tranylcypromine plus L-DOPA.

1 Pretreatment of rats with p-chlorophenylalanine (PCPA; 2 X 200 mg/kg) decreased the concentration of 5-hydroxytryptamine (5-HT) in the brain. It also decreased the locomotor activity produced by tranylcypromine plus L-DOPA administration 24 h after the second dose of PCPA. 2 Pretreatment with p-chloroamphetamine, which produced a similar decrease in brain 5-HT concentrations did not decrease the locomotor response to tranylcypromine and L-DOPA. 3 PCPA pretreatment decreased the rise in the concentration of DOPA and dopamine in the brain following tranylcypromine and L-DOPA, suggesting its effect on the dopamine-induced locomotor activity was the result of this drug diminishing dopamine formation in the brain, probably by inhibiting L-DOPA uptake. 4 The locomotor activity produced by tranylcypromine and L-DOPA was not decreased by pretreatment 6 h earlier with disulfiram (400 mg/kg). This argues against the locomotor activity being due to noradrenergic stimulation. 5 PCPA pretreatment did not alter amphetamine-induced stereotypy or the circling behaviour in unilateral nigro-striatal lesioned rats.

Regional brain atrophy and reductions in glutamate release and uptake after intrastriatal kainic acid.

1 Neurochemical changes and tissue weights were measured following intrastriatal injection of 2.5 microgram of kainic acid in 2 microliter of 0.9% w/v NaCl solution (saline) in the rat. 2 After kainic acid the striatum and neocortex on the injected side showed a progressive reduction in weight, the neocortex showing the greatest absolute weight loss and the striatum the greatest percentage change. 3 Large (80-90%) reduction in choline acetyltransferase (CAT) and L-glutamate decarboxylase (GAD) activities in the striatum occurred within 2-4 days of the injection and persisted at least 10 weeks. At 10 weeks CAT and GAD activities were unaltered in the neocortex. 4 The absolute content of dopamine in the striatum was not different from control 5 days after the injection of kainic acid but was reduced at 2 and 10 weeks. At 2 weeks the concentration (microgram/g wet weight) of dopamine also was reduced but at 10 weeks it was near normal due to atrophy of the striatum. 5 The high affinity glutamate uptake into a crude synaptosomal preparation of the striatum was reduced by 64% 5 days after kainic acid and still reduced by 67% at 10 weeks. 6 The efflux of glutamate from slices of the striatum in the presence of 52 mM K+ was reduced by approximately 75% 5 days and 15 weeks after kainic acid. 7 In vitro kainic acid (10(-4) M) neither altered the high affinity uptake of radiolabelled glutamate into a homogenate of the striatum, nor released endogenous glutamate from slices of striatum.

Mesolimbic dopamine neurons: effects of 6-hydroxydopamine-induced destruction and receptor blockade on drug-induced rotation of rats.

Bilateral injections of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens greatly reduced the dopamine content of this nucleus and the olfactory tubercle and blocked the ipsilateral rotation induced by amphetamine and methamphetamine in rats with unilateral 6-OHDA lesions of the caudate nucleus. In contrast, apomorphine-induced contralateral rotation was enhanced. Similar results were obtained when the destruction of forebrain noradrenergic neurons, normally produced by the nucleus accumbens 6-OHDA lesion, was prevented by desipramine (DMI) pretreatment. Microinjections of the dopamine receptor antagonist heloperidol into the nucleus accumbens did not spread to the olfactory tubercle, as assessed by the distribution of 3H-haloperidol, and blocked circling induced by amphetamine and apomorphine. Amphetamine-induced circling was less effectively blocked by haloperidol injected into the olfactory tubercle. These results suggest that activity at nucleus accumbens dopamine receptors can greatly affect circling behavior, perhaps by amplifying asymmetries of nigrostriatal activity.

Effects of NMDA receptor antagonists on passive avoidance learning and retrieval in rats and mice.

The effects of NMDA antagonists on passive avoidance learning, shock sensitivity and locomotor activity were examined. Pre-training administration of the antagonists 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) in mice and rats resulted in impaired performance in a retention test 24 h later. No such impairment resulted from immediate post-training administration of either compound in either species. In addition neither compound, given only before the retention test, reduced the retention latencies of mice. In rats CPP was similarly ineffective whereas MK-801 reduced retention latencies, but only at a dose which significantly elevated locomotor activity at the time of the retention test. As assessed by vocalization threshold in mice and by the proportion of animals vocalizing in response to the passive avoidance training shock, neither compound produced analgesia. The vocalization threshold was, in fact, slightly reduced by both compounds. MK-801, but not CPP, stimulated locomotor activity in mice. These results indicate that in the passive avoidance task activation of NMDA receptors is involved in memory formation, but is not critical for the maintenance of memory or its retrieval.

Discriminative stimulus properties of muscarinic agonists.

In a two-lever, food-reinforced drug-discrimination paradigm separate groups of rats were trained to discriminate either arecoline, pilocarpine or oxotremorine from saline. The discriminative cues of all three agonists were potently blocked by scopolamine, but only by 30-60 fold higher doses of methylscopolamine. The three agonists all suppressed overall response rate. These rate-suppressant effects were not blocked by scopolamine in doses which blocked the discriminative cues. In generalization tests, arecoline elicited selection of the drug-appropriate lever in all groups of trained animals. Pilocarpine was discriminated as drug by all pilocarpine-trained animals and by a majority of oxotremorine-trained animals, but was not significantly discriminated by the arecoline-trained group. Oxotremorine was discriminated by all oxotremorine-trained animals but only by some pilocarpine-trained animals, and was not significantly discriminated by the arecoline-trained group. Morphine, haloperidol, chlordiazepoxide, pentobarbital and nicotine were not generalized to any of the training drugs. The discriminative stimuli produced by the training drugs are therefore specific and exhibit properties indicative of an origin at central muscarinic receptors but may not be identical.

The pharmacology of SDZ EAA 494, a competitive NMDA antagonist.

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.

Management of dialysis-associated steal syndrome complicating upper extremity arteriovenous fistulas: use of intraoperative digital photoplethysmography.

Dialysis-associated steal syndrome (DASS) occurring after creation of arteriovenous fistulas often necessitates ligation of the fistula. From June 1987 to June 1990, a total of 542 upper extremity arteriovenous fistulas were constructed: radiocephalic fistulas in 182 patients, 325 forearm loop grafts and 32 upper arm loop grafts. We managed 27 patients with DASS including two patients who were referred from other hospitals. DASS developed in two patients (1%) with radiocephalic fistulas and in 23 patients (6.4%) with arteriovenous grafts. Of the 27 patients, the fistula was ligated in nine because of tissue loss, severity of symptoms, or absence of improvement in digital pressure with the fistula occluded. Intraoperative digital photoplethysmography was used to guide the amount of graft narrowing in 16 patients. The goal was to obtain a digital blood pressure of 50 mm Hg or digital to brachial ratio of more than 0.6. Ten of the 16 patients had satisfactory graft function for more than 6 months, and all patients had improvement or resolution of the steal syndrome. We conclude that DASS is an uncommon complication of upper extremity arteriovenous shunts and narrowing of the fistula and that using intraoperative digital photoplethysmography as a guide is a useful method for relieving the steal syndrome and salvaging the shunt.