The role of intravenous valproic acid in status epilepticus.

Valproic acid (VA) has been reported to be effective in status epilepticus (SE) when given rectally. More recently, intravenous (IV) VA has been demonstrated to be effective and safe. Pharmacokinetic studies and initial clinical experience with IV valproic acid suggest that it may have a useful role in the management of refractory status epilepticus, but the magnitude of its utility is not possible to quantify or compare with phenytoin and phenobarbital. In simple SE, IV VA provides less additional benefit, since standard therapy usually works well. IV VA may be useful as a substitute for standard simple SE therapy, but this is difficult to justify unless adverse reactions to standard therapy are anticipated. The published pediatric experience with IV VA for SE is scant.

Emergency department presentations of cerebrovascular disease in children.

Five cases of children with cerebrovascular disease presentations to the emergency department (ED) were selected as a series to illustrate the variety of presentation of cerebrovascular disease in children. This series shows that although cerebrovascular disease in children is uncommon, it is likely that cases will occasionally present acutely to an ED. The emergency physician's role in the management of suspected acute strokes in children is that of immediate stabilization, imaging to rule out hemorrhage, other studies to rule out emergent acute disease, and timely consultation for further management. Computed tomography (CT) is useful to detect an acute hemorrhage or old ischemic lesion. Magnetic resonance imaging has superior image resolution over CT, but CT may be more practical initially. Magnetic resonance angiography is a useful part of the stroke workup in children.

2-Iminothiazolidine-4-carboxylic acid produces hippocampal CA1 lesions independent of seizure excitation and glutamate receptor activation.

We previously demonstrated that 2-iminothiazolidine-4-carboxylic acid (2-ICA), formed by cyanide reacting with cysteine, caused glutamate antagonist-sensitive seizures when injected i.c.v. (intracerebroventricular) in mice and produced hippocampal CA1 damage following i.c.v. infusion in rats. In this study, the ability of either 2-ICA, glutamate, proline or NMDA (N-methyl-D-aspartate) injected i.c.v. to produce hippocampal lesions sensitive to glutamate antagonists was compared in mice. Hippocampal CA1 damage was observed 5-days following either a seizure (3.2 mumol) or subseizure (1.0 mumol) dose of 2-ICA. Glutamate (3.2 mumol) or proline (10 mumol) also produced hippocampal damage; glutamate damage was primarily to the CA1 subfield, whereas proline damaged neurons throughout the entire hippocampal formation. NMDA (3.2 nmol) caused seizure activity in all animals with a 50% lethality. No hippocampal damage was observed in surviving mice. Neither MK-801 (dizocilpine maleate) nor CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) pretreatment prevented hippocampal lesions produced by 2-ICA. In contrast, MK-801 significantly reduced the frequency of mice displaying glutamate hippocampal lesions, but failed to block seizures produced by glutamate. MK-801 also protected neurons in the CA2-3 zone and the dentate gyrus, but not in the CA1 region of proline-injected mice. Finally, pretreatment with the mixed metabotropic glutamate receptor (mGluR)1/mGluR2 antagonist-agonist (S)-4-carboxy-3-hydroxyphenylglycine (CHPG) prevented hippocampal damage produced by the mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), but did not protect against 2-ICA hippocampal lesions. These results show that 2-ICA hippocampal CA1 damage is not mediated through ionotropic or metabotropic glutamate receptors. 2-ICA hippocampal damage may represent a neurotoxicity that is distinct from excitotoxic-mediated cell death.

Inhibition of potassium-stimulated dopamine release by the nitric oxide generator isosorbide dinitrate.

In PC12 cells, isosorbide dinitrate (ISDN) and S-nitrosol-acetyl-penicillamine (SNAP), both nitric oxide (NO) generators, attenuated K+ (56 mM)-stimulated release of dopamine. The attenuation was not observed with isosorbide, an ISDN analog lacking NO generating capacity. In this model, A23187 (Ca2+ ionophore), Bay K8644 (Ca2+ slow channel agonist) and veratridine (Na+ channel agonist) stimulated dopamine release. Treatment with ISDN enhanced Bay K8644 and veratridine-evoked dopamine release, while ISDN had no significant effect on the A23187 response. Incubation with 8-bromo-cGMP (membrane permeable cGMP analog) had no effect on basal or stimulated dopamine release in these cells, suggesting NO's response was not mediated by cGMP. In additional studies, K+ (56 mM), Bay K8644 and veratridine elevated cytosolic free calcium levels ([Ca2+]i). ISDN reduced K(+)-stimulated increase in [Ca2+]i, but enhanced the increases of [Ca2+]i induced by Bay K8644 or veratridine. These results suggest NO interacts with K(+)-induced membrane depolarization (possibly by inhibiting membrane conductance to K+) to attenuate Ca2+ influx and Ca(2+)-mediated dopamine secretion stimulated by K+.

Seizures and selective CA-1 hippocampal lesions induced by an excitotoxic cyanide metabolite, 2-iminothiazolidine-4-carboxylic acid.

Excitatory amino acid (EAA)-like and excitotoxic properties of the secondary metabolite of cyanide, 2-iminothiazolidine-4-carboxylic acid, (2-ICA) were evaluated because of its possible role in cyanide-induced neurotoxicity. Intracerebroventricular (i.c.v.) injections of 2-ICA in mice produced wild-running seizures that were qualitatively and quantitatively similar to seizures observed with glutamate. 2-ICA, kainate and proline seizures were prevented by both the NMDA and non-NMDA antagonists, MK-801 and CNQX, respectively. In contrast, NMDA-induced seizures were prevented by MK-801, but not CNQX. When infused i.c.v. in rats over a seven day period, 2-ICA produced extensive and selective loss of CA-1 pyramidal neurons of the hippocampus. In hippocampal slices preloaded with D-[3H]aspartate, 2-ICA superfusion did not evoke release nor significantly augment potassium stimulated release of the radiolabeled transmitter. These findings indicate 2-ICA has excitotoxic properties and its role in cyanide neurotoxicity deserves further study.

Enhancement of NMDA-mediated responses by cyanide.

The effect of cyanide on NMDA-activated ion current and MK801 binding was studied in cultured rat hippocampal neurons. In microfluorometric analysis using fura-2, removal of extracellular Mg2+ resulted in a five-fold increase in NMDA-induced peak of [Ca2+]i. One mM NaCN enhanced the peak NMDA responses in the presence, but not in the absence of extracellular Mg2+. Cyanide enhanced the immediate rise in [Ca2+]i produced by NMDA, followed over a 1-5 min period by a gradual increase of [Ca2+]i. Similar results were obtained in whole-cell patch clamp recordings from hippocampal neurons. One mM KCN enhanced the NMDA-activated current in the presence, but not in the absence of extracellular Mg2+. This effect was independent of cyanide-mediated metabolic inhibition since the recording pipette contained ATP (2 mM). In binding assays NaCN (1 mM) increased the binding affinity of [3H]MK-801 to rat forebrain membranes in the presence of Mg2+, whereas in the absence of Mg2+, NaCN did not influence binding. These results indicate that cyanide enhances NMDA-mediated Ca2+ influx and inward current by interacting with the Mg2+ block of the NMDA receptor. The effect of cyanide can be explained by an initial interaction with the Mg2+ block of the NMDA receptor/ionophore which appears to be energy-independent, followed by a gradual increase in Ca2+ influx resulting from cellular energy reserve depletion.

Plasma membrane hyperpolarization by cyanide in chromaffin cells: role of potassium channels.

Exposure of rat pheochromocytoma (PC12) cells to cyanide produces elevation of cytosolic calcium, impaired Na(+)-H+ exchange, membrane lipid peroxidation and release of neurotransmitters. Since these observations suggested cyanide alters plasma membrane function, the present study examined the effect of NaCN on the membrane potential of undifferentiated PC12 cells in suspension. In PC12 cells loaded with the voltage sensitive fluorescent dye, bis-oxonol, cyanide (2.5-10 mM) elicited an immediate (within seconds), concentration related decrease in fluorescence, indicating hyperpolarization of the plasma membrane. Increasing extracellular K+ concentration to 20 mM blocked the effect of cyanide (5 mM), suggesting cyanide increased K+ efflux. Pretreatment with quinine blocked the cyanide-induced hyperpolarization, whereas glyburide had little effect, showing the hyperpolarization produced by cyanide was due to activation of Ca2+ sensitive K+ channels. Removal of Ca2+ from the media did not influence cyanide-induced hyperpolarization. However, buffering intracellular Ca2+ by loading cells with the Ca2+ chelators, Quin II or BAPTA, abolished the cyanide effect, showing cytosolic Ca2+ is a key factor. These findings suggest that cyanide mobilizes Ca2+ from intracellular stores which leads to hyperpolarization via the activation of Ca2+ sensitive K+ channels.

Biopsy-proven isolated sarcoid meningitis. Case report.

Neurosarcoidosis without systemic involvement is rare and difficult to diagnose. The case of a 27-year-old man with a 6-week history of headache, mental status changes, and polyradiculopathy attributable to hypoglycorrheic lymphocytic meningitis is presented. Extensive testing for occult systemic sarcoidosis was negative. The presence of noncaseating granulomatous inflammation was established by open brain biopsy, and the patient improved clinically with oral steroid therapy. In individuals with undiagnosed chronic meningitis, brain biopsy may be necessary to rule out isolated neurosarcoidosis.

N-methyl-D-aspartate receptors mediate cyanide-induced cytotoxicity in hippocampal cultures.

We reported previously that glutamate excitotoxicity may contribute to cyanide-induced neuronal injury. Cyanide stimulates glutamate release which can activate glutamate receptors to initiate excitotoxic processes. This study examines the role of EAA receptor subtypes in mediating cyanide-induced cytotoxicity. Cytotoxicity was assessed in primary rat hippocampal cultures by measuring lactate dehydrogenase (LDH) in the culture media. NaCN (0.1-10 mM) or glutamate (0.01-1 mM) produced concentration-dependent cytotoxicity following 18 hrs of incubation. Glutamate-induced cytotoxicity was partially blocked by the non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the NMDA antagonist, 2-amino-5-phosphonovalerate (APV). Simultaneous exposure of cultures to both CNQX and APV provided complete protection against glutamate cytotoxicity. NaCN-induced cytotoxicity was not blocked by CNQX, but completely blocked by APV and simultaneous exposure to CNQX and APV did not offer added protection. These results indicate that in hippocampal cultures, both non-NMDA and NMDA receptors mediate glutamate excitotoxicity, whereas NaCN-induced cytotoxicity is mediated primarily by activation of the NMDA receptors.

Effects of chronic morphine on biliary tract responses to cholecystokinin-octapeptide in female guinea pigs.

Acute and chronic opiates impairs the emptying of bile from the gallbladder of male guinea pigs. In view of the higher incidence of gallstone attacks in women, the aim of this study was to determine if this impairment would extend to female guinea pigs. Implantation of morphine pellets (400mg) in female guinea pigs did depress CCK-induced emptying of gallbladder bile. Likewise, gallbladder muscle strips isolated from the morphine treated animals showed depressed responses to CCK. The morphine treatment also antagonized CCK-induced cessation of bile flow present in female guinea pigs. In addition, the morphine treatment blocked both CCK-induced phasic contractions of the isolated isolated Sphincter of Oddi and the secondary cessation of bile flow observed following iv CCK. Thus this study demonstrates that opiate antagonism of CCK does extend to the biliary tract of female guinea pigs, and suggests that resultant biliary stasis could facilitate gallstone formation.

Potentiation of cyanide neurotoxicity by blockade of ATP-sensitive potassium channels.

Exposure of primary hippocampal cultures to NaCN (2 mM) or glyburide (5 microM) alone for 3 h did not produce a rise in extracellular lactic dehydrogenase (LDH) activity. Coincubation with NaCN and glyburide produced a significant efflux of LDH from the neurons. Diazoxide or D-2-amino-5-phosphovalerate (APV) partially reversed the release of LDH by the combination of NaCN and glyburide. These observations indicate ATP-sensitive potassium channels (KATP) are activated by nonlethal concentrations of cyanide and their blockade with glyburide unmasks cyanide's toxicity. The cytotoxicity of cyanide appears to result from a combination of processes resulting in altered ion handling and excitotoxicity.

Acute rheumatic fever in Hawaii: 1966 to 1988.

Seventy five children with acute rheumatic fever (ARF) were hospitalized on Oahu from 1984 to 1988. The annual incidence rate was 9.5 (all rates are per 100,000 children per year). The first attack and recurrent attack rates were 7.9 and 1.6. Polyarthritis occurred in 84%, chorea in 7%, and carditis in 32%. Mitral insufficiency was the most common valvular lesion (88%). Hawaiians/part Hawaiians and Samoans had the highest incidence rates (relative risk 3 and 56, respectively). Polynesian children were 84 times more likely to develop carditis. Five hundred thirty nine ARF cases were hospitalized on Oahu, 1966 to 1974 and from 1976 to 1988. The annual incidence rate of ARF on Oahu has remained fairly constant at about 12.4. The incidence rates in all ethnic groups have decreased except in Samoan children.

Blockade of N-methyl-D-aspartate receptors prevents cyanide-induced neuronal injury in primary hippocampal cultures.

Cyanide-induced alterations of cytosolic calcium levels and cytotoxicity were examined in primary cultures of rat hippocampus. Cytosolic free Ca2+ ([Ca2+]i) levels were measured in hippocampal neurons using the fluorescent probe, fura 2. A concentration-dependent rise in [Ca2+]i occurred rapidly following exposure of cells to 0.5-10 mM NaCN. In normal medium (1.3 mM Ca2+), 2 mM NaCN produced an increase in [Ca2+]i (172 +/- 27% of control), 45 sec following exposure. Ca2+ elevation produced by NaCN was blocked by removal of Ca2+ from the external medium or by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonovalerate (APV). The cytotoxicity of cyanide, assessed by measuring the efflux of lactate dehydrogenase, was blocked by APV. These results indicate that in hippocampal neurons, cytosolic Ca2+ accumulation induced by cyanide originates from the extracellular compartment and the NMDA receptor ionophore is a significant route for Ca2+ entry. It is proposed that excitotoxic mechanisms may contribute to altered neuronal homeostasis and injury associated with cyanide.

Effects of chronic morphine on biliary tract responses to cholecystokinin-octapeptide in male guinea pigs.

Opioid peptides share the spasmogenic action of acutely administered morphine on the sphincter of Oddi. In this study, gallbladder function was assessed following chronic opioid administration. Implantation of morphine pellets (400 mg) in male guinea pigs depressed cholecystokinin-octapeptide(CCK)-induced emptying of gallbladder bile (monitored via a duodenal cannula). Gallbladder muscle strips, isolated from the morphine treated animals, showed depressed contractile responses to CCK. This antagonism was non-specific and indirectly mediated, as ACh contractions were also depressed, whereas CCK-induced contractions of gallbladder strips from untreated animals were unaffected by direct exposure to morphine (3 x 10(-6)M). The depression of CCK stimulation of bile flow by chronic morphine administration in male guinea pigs suggests that chronic exposure to opioids can impede gallbladder emptying.

Cyanide induces Ca(2+)-dependent and -independent release of glutamate from mouse brain slices.

The effect of cyanide-induced histotoxic hypoxia on endogenous glutamate release from mouse cortical, cerebellar and hippocampal slices was studied. Incubation of slices with cyanide over a 30 min period resulted in extracellular accumulation of glutamate which was decreased in the absence of Ca2+ in the incubation media. When glutamate release was continuously monitored by fluorometry, cyanide initiated a rapid release of glutamate. This initial release was found to be independent of extracellular calcium. Depolarizing concentrations of potassium chloride produced a predominantly Ca(2+)-dependent release. It is concluded that cyanide exposure induced a rapid release of endogenous glutamate mediated by both Ca(2+)-dependent and Ca(2+)-independent mechanisms.

Assessment of the role of alpha-methylepinine in the neurotoxicity of MDMA.

To assess the potential involvement of metabolism of 3,4-methylenedioxymethamphetamine (MDMA) to the catechol alpha-methylepinine in producing serotonergic neurotoxicity, we attempted to correlate aspects of this reaction with the neurotoxicity profile of MDMA. In contrast to the stereoselectivity of S-(+)-MDMA in causing persistent declines in rat brain 5-hydroxyindole levels, no stereochemical component to the metabolic reaction was apparent. Rat liver microsomes generated a significantly greater amount of alpha-methylepinine than did mouse microsomes, but similar amounts of metabolite were produced by brain microsomes from the two species. Formation of alpha-methylepinine by hepatic, but not brain, microsomes was inhibited by SKF 525A and induced by phenobarbital, possibly indicating a tissue specificity in cytochrome P-450-dependent metabolism of MDMA. To directly assess whether alpha-methylepine is a likely mediator of MDMA neurotoxicity, the compound was administered intracerebroventricularly. No persistent declines in biogenic amines or their metabolites were observed one week following treatment. These data suggest that alpha-methylepinine alone is not responsible for the neurotoxic effects of MDMA.

Rapid sequence anesthesia induction for emergency intubation.

Emergency intubations are done for a variety of reasons in the emergency department (ED). In some patients, a rapid, controlled induction of anesthesia is useful to facilitate intubation and to reduce the complications of intubation. This is referred to a rapid sequence induction (RSI) in the anesthesia literature. Atropine, thiopental, fentanyl, diazepam, ketamine, vecuronium, succinylcholine, other drugs and their applications for RSI are described. The purpose of this article is to describe the use of RSI in the airway management of ED patients. Nineteen pediatric patients requiring emergency intubation were intubated using RSI with vecuronium and thiopental. Actual intubation difficulty using RSI was significantly less than the anticipated intubation difficulty without RSI. There were no complications caused by intubation or RSI that had a significant impact on patient outcome. We feel that a sedative in combination with vecuronium represents the most optimal means of achieving RSI in the ED setting. Although the induction of general anesthesia is best done by anesthesiologists, emergency physicians are often the most experienced physicians immediately available to manage an airway in a critical emergency. An objective protocol such as that described will make it easier for emergency physicians to perform this procedure when needed.

Interaction of trimethyltin with hippocampal glutamate.

Trimethyltin (TMT) produces selective hippocampal lesions similar to that caused by convulsants which interact with the brain excitatory amino acid transmission. The hippocampal glutamate system was studied because of its possible contribution to neuronal damage produced by TMT. At 24 hr following administration of TMT (3 mg/kg; ip) to mice, hippocampal glutamate levels were decreased, although no changes in levels were observed at 1 hr, 6 hr or 15 hr. In partially depolarized hippocampal slices, TMT (10 microM), produced a release of endogenous glutamate. Continuous monitoring by fluorometry found glutamate release to occur immediately following addition of TMT to partially depolarized slices; this release was dependent on extracellular calcium. These results indicate TMT can activate the endogenous excitotransmitter system, which may contribute to the neuronal damage associated with TMT exposure.

MDMA transiently alters biogenic amines and metabolites in mouse brain and heart.

(+-)-3,4-Methylenedioxymethamphetamine (MDMA) (10, 20, and 40 mg/kg) was administered to male CF-1 mice which were sacrificed 3, 6, or 24 hours posttreatment for analysis of brain and cardiac biogenic amines and metabolites. In contrast to reported effects of MDMA in the rat, the highest dose of MDMA transiently elevated mouse brain 5-hydroxytryptamine (5-HT) 3 hours following drug treatment. Levels of dopamine were not significantly affected. 5-Hydroxyindoleacetic acid and dihydroxyphenylacetic acid were significantly lowered by MDMA at the two early time points. The highest dose of MDMA produced a transient depletion of norepinephrine in mouse brain and heart tissue. Only the effects of MDMA on cardiac norepinephrine were prevented by pretreatment of animals with desipramine. A regimen consisting of four daily doses of 40 mg/kg MDMA only produced significant declines in 5-HIAA, dopamine and homovanillic acid levels one week following the last dose. These data confirm previous reports that mice are resistant to the neurotoxic effects of MDMA suggesting that a species variation in response to MDMA exists.

Induction of interleukin-1 and tumor necrosis factor by 12-O-tetradecanoylphorbol-13-acetate in phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice.

12-O-tetradecanoylphorbol-13-acetate (TPA), the most potent skin tumor promoter known, evokes significant inflammatory responses in mouse skin after topical application. Infiltrating inflammatory cells have been hypothesized to contribute to genetic damage in epidermal cells through the generation of reactive oxygen intermediates (ROIs), thus facilitating the development of tumors. Interleukin-1 (IL-1) and tumor necrosis factor (TNF), small mol. wt cytokines produced by macrophages (MPs), are known to have important roles in the inflammatory process. Lipopolysaccharide (LPS)-triggered release of IL-1 and TNF was determined in culture supernatants of splenic MPs from phorbol ester-sensitive (SENCAR) and resistant (B6C3F1) mice following topical application of 8 micrograms of TPA twice in one week. The findings reported herein indicated that topical application of TPA primed splenic MPs from both SENCAR and B6C3F1 mice in a quantitatively similar manner for the production of IL-1 and TNF; in addition, the release of IL-1 and TNF by splenic MPs from control (naive or acetone-dosed) SENCAR and B6C3F1 mice in response to LPS-triggering in vitro was not significantly different. Therefore, the production and release of these cytokines by activated MPs does not correlate with the reported strain-dependent susceptibilities to TPA-induced inflammation and/or tumor promotion.