Creation and piloting of a new hospital capacity assessment tool in a major urban area.

OBJECTIVES: Crowded hospital emergency departments (EDs) can undermine the ability of a region's safety net to provide safe, timely care. However, data to measure hospital capacity community-wide is generally unavailable. This study aimed to assess hospital crowding, capacity and patient flow in an urban community using the newly developed hospital capacity assessment tool (HCAT). STUDY DESIGN: A survey of the eight acute care hospitals in the District of Columbia (DC) with active EDs. METHODS: Existing emergency care assessment tools were reviewed. Eighteen of the 57 questions on the HCAT were adapted from existing hospital surveys, while the remaining 39 questions were constructed de novo for use in this assessment. Hospitals were provided with paper and electronic versions of the HCAT. RESULTS: All eight DC hospitals completed the HCAT; however, three hospitals were unable to answer many of the questions due to a lack of regular data collection. The HCAT data shows throughput times in DC hospitals that are substantially longer than national averages. CONCLUSIONS: The HCAT is a promising tool for evaluating community-wide emergency care. Findings from the HCAT allowed for the introduction of new ED performance data into the local decision-making process.

Violence in the emergency department.

Violence in the emergency department is a frequently encountered problem that is often not promptly or adequately addressed. This article outlines the epidemiology of violence in the emergency department, including patients at greatest risk for aggressive behavior. The necessary steps to identify and approach these patients and recommended methods for sedation and restraint are discussed.

Riluzole series. Synthesis and in vivo "antiglutamate" activity of 6-substituted-2-benzothiazolamines and 3-substituted-2-imino-benzothiazolines.

Two series of analogues of riluzole, a blocker of excitatory amino acid mediated neurotransmission, have been synthesized: monosubstituted 2-benzothiazolamines and 3-substituted derivatives. Of all the compounds prepared in the first series, only 2-benzothiazolamines bearing alkyl, polyfluoroalkyl, or polyfluoroalkoxy substituents in the 6-position showed potent anticonvulsant activity against administration of glutamic acid in rats. The most active compounds displaying in vivo "antiglutamate" activity were the 6-OCF(3) (riluzole), 6-OCF(2)CF(3), 6-CF(3), and 6-CF(2)CF(3) substituted derivatives with ED(50) values between 2.5 and 3.2 mg/kg i.p. Among the second series of variously substituted benzothiazolines, compounds as active as riluzole or up to 3 times more potent were identified in two series: benzothiazolines bearing a beta-dialkylaminoethyl moiety and compounds with an alkylthioalkyl chain and their corresponding sulfoxides and sulfones. The most potent derivatives were 2-imino-3-(2-methylthio)- and 2-imino-3-(2-methylsulfinyl)-ethyl-6-trifluoromethoxybenzothiazolines (61 and 64, ED(50) = 1.0 and 1.1 mg/kg i.p., respectively). In addition, intraperitoneal administration of some of the best benzothiazolines protected mice from mortality produced by hypobaric hypoxia.

The naphtosultam derivative RP 62203 (fananserin) has high affinity for the dopamine D4 receptor.

The dopamine D4 receptor is a potential target for novel antipsychotic drugs. Most available compounds with affinity for the dopamine D4 receptor also bind to dopamine D2 receptors. This report describe the affinity of the 5-HT2A receptor antagonist RP 62203 (fananserin) for the human dopamine D4 receptor. Fananserin displaces [3H]spiperone binding to recombinant human dopamine D4 receptors with a Ki of 2.93 nM. This compares with an affinity (Ki) of 0.37 nM for the rat 5-HT2A receptor and of 726 mM for the rat dopamine D2 receptor. [3H]Fananserin can be used to label the recombinant dopamine D4 receptor expressed in Chinese hamster ovary cells with a KD of 0.725 nM. Fananserin is, thus, the first compound to be reported that distinguishes between dopamine D4 and D2 receptors.

Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3.

Glutamic acid is the major excitatory amino acid of the central nervous system which interacts with two receptor families, the ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) are coupled to G proteins and can be divided into three subgroups based on their sequence homology, signal transduction pathway and pharmacology. In this study, we describe the cloning of the cDNA encoding the human metabotropic glutamate receptor type 3 (HmGluR3). It was obtained by reverse transcription-polymerase chain reaction (RT-PCR) with degenerate oligonucleotides corresponding to highly conserved sequences between rat mGluRs. The receptor shows 879 amino acids with 96% amino acid sequence identity with rat mGluR3. It is strongly expressed in fetal and adult whole brain, especially in caudate nucleus and corpus callosum. The gene was identified by fluorescence in situ hybridization on chromosome 7 band q22. Activation of the human mGluR3, permanently expressed in Baby Hamster Kidney (BHK) cells, by excitatory amino acid inhibits the forskolin-stimulated accumulation of intracellular cAMP. The rank order of potency is L-glutamic acid > or = (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R)-ACPD) >> ibotenic acid > quisqualic acid. (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mM] is without effect on inhibition of forskolin-induced cAMP accumulation by L-glutamic acid.

Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro.

The NMDA antagonist and neuroprotective effects of RPR 104632 (2H-1,2,4-benzothiadiazine-1-dioxide-3-carboxylic acid), a new benzothiadiazine derivative, with affinity for the glycine site of the NMDA receptor-channel complex are described. RPR 104632 antagonized the binding of [3H]5,7-dichlorokynurenic acid to the rat cerebral cortex, with a Ki of 4.9 nM. This effect was stereospecific, since the (-)-isomer was 500-fold more potent than the (+)-isomer. The potent affinity of RPR 104632 for the glycine site was confirmed by the observation that RPR 104632 inhibited [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) binding in the presence of N-methyl-D-aspartate (NMDA) (IC50 = 55 nM), whereas it had no effect on the competitive NMDA site or on the dissociative anaesthetic site. RPR 104632 inhibited the NMDA-evoked increase in guanosine 3',5'-cyclic monophosphate (cGMP) levels of neonatal rat cerebellar slices (IC50 = 890 nM) in a non-competitive manner and markedly reduced NMDA-induced neurotoxicity in rat hippocampal slices and in cortical primary cell cultures. These results suggest that RPR 104632 is a high-affinity specific antagonist of the glycine site coupled to the NMDA receptor channel with potent neuroprotective properties in vitro.

Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea-pig.

1. The NK1 tachykinin receptor agonists, septide, [Sar9,Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10-20 min) when injected intracerebroventricularly (i.c.v.) in the guinea-pig. The most potent in eliciting this hyperactivity was septide (from 0.63 to 5 micrograms), compared to [Sar9,Met(O2)11]SP, which was active at 2.5 and 5 micrograms and [Pro9]SP which induced a non-significant increase even at 10 micrograms. 2. Wet-dog shakes were elicited by septide, [Sar9,Met(O2)11]SP and [Pro9]SP injected by the i.c.v. route in the guinea-pig. [Sar9,Met(O2)11]SP, active from 0.16 to 2.5 micrograms was more potent than septide (active at 1.25 micrograms) and [Pro9]SP (active at 0.63 micrograms) in eliciting such behaviour. To a lesser extent, grooming was also observed after injection of these agonists. 3. The NK2 tachykinin receptor agonist, [Lys5,MeLeu9,Nle10]NKA(4-10), up to the dose of 10 micrograms i.c.v. had no effect in the guinea-pig. It neither modified locomotor activity nor induced a characteristic behavioural response. At higher doses (20 micrograms), some toxic effects were noted. 4. The NK3 tachykinin receptor agonist, senktide, contrasts with the NK1 receptor agonists in that it elicited only wet-dog shakes, at doses ranging from 0.32 to 1.25 micrograms. It neither modified locomotor activity (1 microgram) nor induced grooming (up to 5 micrograms) in the guinea-pig. 5. To our knowledge, these results are the first demonstration that the guinea-pig could be useful to differentiate tachykinin agonists on the basis of their behavioural profile, distinct from those obtained in mice and rats.

Effects of AMPA receptor modulators on the production of arachidonic acid from striatal neurons.

The abilities of different compounds acting at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors to modulate the overflow of [3H]arachidonic acid from rat striatal neurons were examined. The combination of AMPA (0.1 mM) and carbachol (1mM) stimulated [3H]arachidonic acid production, this effect could be dose-dependently enhanced by the newly discovered allosteric modulator of AMPA receptors: cyclothiazide. Competitive (6-cyano-7-nitroquinoxaline-2,3-dione [CNQX] and 6-(1-imidazolyl)-7-nitroquinazoline-2,3-dione [YM 900]) and non-competitive antagonists, like 1-(amino)-phenyl)-4-methyl -7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), antagonized the responses induced by either AMPA + carbachol or AMPA + carbachol + cyclothiazide. In order to appreciate the respective part of AMPA-versus kainate-preferring receptors experiments were performed with kainic acid (0.1 mM) and the more specific kainate agonist domoic acid (0.1 mM). Kainic acid behaves like AMPA, but the response induced by the combination domoic acid + carbachol could not be potentiated by cyclothiazide. On the contrary, concanavalin A potentiated the responses evoked by kainic acid or domoic acid (in combination with carbachol) but did not enhance the AMPA-evoked response. It could be concluded that both AMPA- and kainate-preferring receptors are present in cultured rat striatal neurons and that these two types of receptors were involved together with muscarinic receptors in the overflow of [3H]arachidonic acid.

Effects of complete and partial lesions of the dopaminergic mesotelencephalic system on skilled forelimb use in the rat.

This study compares certain behavioural consequences of partial and complete unilateral lesions of the dopaminergic mesotelencephalic system. We investigated skilled forelimb use, rotations induced by apomorphine and amphetamine, and dopaminergic metabolism of the nigrostriatal system of rats that had received a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. The rats classified Apo(+), that rotated after the administration of apomorphine, had a complete lesion of the nigrostriatal system, whereas those classified Apo(-), that did not rotate after the administration of apomorphine, had a partial lesion of the nigrostriatal system. In the Apo(+) rats, 99.8% of the dopamine in the striatum was depleted, as was 85% of that in the substantia nigra. For the Apo(-) rats, 72% of the dopamine in the striatum was depleted as was 56% of that in the substantia nigra. When investigated with the staircase test, the animals with the most severe dopamine depletions were those most impaired in the paw reaching task. Complete and partial unilateral depletions of the dopaminergic mesotelencephalic system impaired the hierarchic phases of paw reaching differently. A complete dopamine depletion, but not a partial one, decreased the number of attempts made with the contralateral paw, and induced a bias towards the ipsilateral paw. A partial dopamine lesion impaired the sensorimotor co-ordination of both paws, whereas the complete dopamine lesion had a greater effect on the contralateral paw than on the ipsilateral paw. The mild paw reaching impairments observed in animals with moderate depletions of dopamine are proposed as a model of the early symptoms of Parkinson's disease that may be useful for the development of protective or restorative therapies.

Effects of non-NMDA receptor modulators on [3H] dopamine release from rat mesencephalic cells in primary culture.

The effects of AMPA and kainate on [3H]dopamine release from fetal (embryonic day 15) rat mesencephalic neurons in primary culture were enhanced markedly in a dose-dependent fashion by cyclothiazide, a recently described inhibitor of AMPA receptor desensitization. The EC50 value for cyclothiazide was 2.2 +/- 0.8 microM. The release of [3H]dopamine induced by both AMPA (or kainic acid) and the combination of AMPA (or kainic acid) with cyclothiazide was antagonized by specific antagonists like 6-cyano-7-nitroquinoxaline-2,3-dione or the noncompetitive benzodiazepine GYKI 52466. Unlike cyclothiazide, the lectin concanavalin A did not stimulate [3H]dopamine release. These results established the involvement of AMPA-preferring receptors on [3H]dopamine release from rat mesencephalic neurons in primary culture and provided further evidence for the existence of regulatory allosteric sites on AMPA receptor subunits.

The human galanin receptor: ligand-binding and functional characteristics in the Bowes melanoma cell line.

The human galanin receptor has been characterized pharmacologically from the Bowes melanoma cell line. Using porcine [125I]galanin as the radioligand, a single population of non-interacting high-affinity binding sites (KD = 0.05 +/- 0.01 nM; Bmax = 135 +/- 7 fmol/mg protein) was demonstrated. Human galanin peptide competitively inhibited the specific binding of [125I]galanin (IC50 = 0.35 +/- 0.13 nM) and decreased the forskolin-stimulated cAMP production (EC50 = 0.46 +/- 0.05 nM) with a maximal inhibition of 63 +/- 2% at 10(-7) M. Rat and porcine galanin peptides and the chimeric peptides M15, M35, M32, M40 and C7 also dose-dependently inhibited the forskolin-stimulated cAMP production, while the fragment porcine galanin-(3-29) and [D-Trp2]galanin were found to be inactive. The specific binding of [125I]galanin was decreased in a dose-dependent manner by GTP and the cAMP response was inhibited by the pertussis toxin, suggesting the activation of a G-protein dependent process. The Bowes cell line thus appears to be a relevant tool for the study of human galanin receptor.

CCK-A and CCK-B receptors enhance olfactory recognition via distinct neuronal pathways.

We have previously reported that CCK-A receptor agonists and CCK-B receptor antagonists both enhance memory in an olfactory recognition test. Here, we report that the memory-enhancing effect of the CCK-B receptor antagonist L-365,260 (1 mg/kg i.p.), but not that of the CCK-A receptor agonist caerulein (0.03 mg/kg i.p.), was dramatically decreased following a bilateral transection of the perforant path, a principal source of input to the hippocampal formation. We further confirmed that a significant memory deficit occurred subsequent to this deafferentation of the hippocampus in untreated animals. In contrast, the effect of caerulein, but not that of L-365,260, was abolished following a bilateral subdiaphragmatic vagotomy. These results demonstrate that the hippocampal system plays a role in olfactory recognition and indicate that distinct neuronal pathways underlie the memory-enhancing effects of CCK-A and CCK-B drugs observed in the olfactory recognition test. The former effects (CCK-A) appear to involve a peripheral relay to the brain via the vagus nerve, whereas the latter (CCK-B) are directly central and involve, at least in part, the hippocampal system.

CCK-A and CCK-B selective receptor agonists and antagonists modulate olfactory recognition in male rats.

Modulation of learning and memory is one of the physiological roles that the neuropeptide cholecystokinin (CCK-8) may play. We have used a behavioural model of olfactory recognition among rats to test this hypothesis and to explore the relationship between CCK-A and CCK-B receptors and memory retention. Adult male rats form a transient memory of a juvenile congenere as indicated by a reduction in the duration of investigatory behaviour upon re-exposure 30 min after an initial exposure, but not when re-exposure is delayed until 120 min afterwards. In the present study, rats were treated after the first contact with various compounds; inhibition and facilitation of olfactory recognition were evaluated as the persistence in investigation 30 min and the decrease in investigation 120 min after pharmacological manipulations, respectively. Systemic injection of CCK-8, of a selective CCK-A agonist, or of non-peptide CCK-B antagonists (CI-988 and LY-262691) enhanced olfactory recognition. In contrast, the CCK-B selective agonist BC 264 and the tetrapeptide CCK-4 both disrupted it. Taken together with previous evidence of the detrimental effect of the nonpeptide. CCK-A antagonist devazepide on olfactory recognition, these results confirm and extend the hypothesis that there is a balance between CCK-A-mediated facilitative effects and CCK-B-mediated inhibitory effects on memory retention.

Differential ability of tachykinin NK-1 and NK-2 agonists to produce scratching and grooming behaviours in mice.

Potent and selective NK-1 and NK-2 agonists as well as compounds with lower selectivity and affinity for NK-1 binding sites were compared in their ability to produce scratching and grooming behaviours when injected intracerebroventricularly in mice. Septide, an agonist with a low affinity for NK-1 binding sites, [Sar9, Met(O2)11]SP and to a lesser extent [Pro9]SP, two potent and selective NK-1 agonists were the most effective drugs in stimulating these behaviours. Only high doses of [Apa9,10]SP and [Lys5, Tyr7, Pro8]NKA(4-10), two agonists with low affinity for NK-1 binding sites, produced scratching and grooming responses. Similarly, only high doses of [Lys5, MeLeu9, NLe10]NKA(4-10), a potent NK-2 agonist, produced grooming behaviour. When coinjected with the endopeptidase enzyme inhibitor phosphoramidon, the effects of [Apa9,10]SP, [Lys5, Tyr7, Pro8]NKA(4-10) and [Pro9]SP were markedly enhanced. Analyses of the potency of the different agents to displace 3H-SP binding in mouse subcortical structures revealed that the affinities of the agonists for NK-1 receptors are similar to those previously reported in rat brain. The efficacy of the agonists at producing behavioural responses was not equivalent to their potency to bind to central NK-1 receptors. These findings therefore suggest that a stimulation of NK-1 but also non classical NK-1 receptors are involved in the induction of scratching and grooming behaviours.

Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats.

Nitric oxide (NO) is a messenger molecule that is produced in the brain from the metabolism of L-arginine to L-citrulline. Growing evidence suggests a physiological role for NO in long-term potentiation (LTP). Since LTP is a form of synaptic plasticity thought to be involved in learning and memory, we have tested whether inhibition of endogenous NO production affects memory capacities of rats. We found that the NO synthase [L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39] inhibitor N omega-nitro-L-arginine, at doses blocking LTP in hippocampal slices, impairs spatial learning in a radial arm maze and olfactory memory in a social recognition test. In contrast, N omega-nitro-L-arginine left shock-avoidance learning unaffected. These results indicate that NO is involved in some but not all forms of memory and further support the existence of a causal link between LTP and spatial learning.

A non-peptide NK1-receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically.

1. The non-peptide neurokinin NK1-receptor antagonist, RP 67580 (3aR, 7aR), a perhydroisoindolone derivative, powerfully reduced plasma extravasation in rat hind paw skin induced by local application of xylene (ID50 = 0.03 mg kg-1, i.v.) or capsaicin (ID50 = 0.06 mg kg-1, i.v.), or by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,Pro9]SP(6-11)) (ID50 = 0.04-0.05 mg kg-1, i.v.). RP 67580 (1 mg kg-1, i.v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 82 +/- 5%). These effects were found to be stereospecific, the enantiomer, RP 68651 (3aS, 7aS), being inactive at 1 mg kg-1, i.v. 2. In rats neonatally treated with capsaicin (50 mg kg-1, s.c.), plasma extravasation induced by SP was significantly increased (by 43 +/- 7%). RP 67580 (1 mg kg-1, i.v.) completely inhibited the SP-induced plasma extravasation in capsaicin neonatally treated-animals, as it did in control animals. This result suggests that RP 67580 acts at the postsynaptic level for the inhibition of plasma extravasation. 3. Opioid receptor agonists, mu-(morphine) and kappa-(PD-117302) at 10 mg kg-1, s.c., in contrast to NK1-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective against plasma extravasation induced by electrical nerve stimulation (74 +/- 4% and 48 +/- 9% inhibition at 10 mg kg-1, s.c. of morphine and PD-117302, respectively, compared to 90 +/- 3% inhibition obtained with RP 67580, 3 mg kg-1, s.c.). These results indicate the presynaptic action of opioid receptor agonists, in contrast to the postsynaptic action of NK1-receptor antagonists for the inhibition of plasma extravasation.4. Ligature of the saphenous nerve distal to the point of electrical stimulation, local application of lignocaine to the saphenous nerve, neonatal capsaicin pretreatment, and colchicine at very low doses(120 microg kg-1 day-1 given for 3 days) were found to prevent plasma extravasation elicited by electrical nerve stimulation.5. The foregoing results demonstrate that the non-peptide NK1-receptor antagonist, RP67580, is a potent inhibitor of plasma extravasation induced in skin by NK1-receptor agonists, by local application of chemical irritants (capsaicin or xylene) or by electrical nerve stimulation. Moreover, opioid receptor agonists and colchicine inhibit plasma extravasation induced by electrical nerve stimulation but not that elicited by exogenous SP. Therefore, it is possible to inhibit neurogenic inflammation either at the presynaptic level with opioid receptor agonists and colchicine, or at the postsynaptic level withNK1-receptor antagonists, and that the new non-peptide NK1-receptor antagonists may have a great potential for alleviation of inflammation in various pathological syndromes in man.

New indole derivatives as potent and selective serotonin uptake inhibitors.

A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.