Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin.

The decline in the high incidence of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer-type dementia among the Chamorro population of the western Pacific islands of Guam and Rota, coupled with the absence of demonstrable viral and hereditable factors in this disease, suggests the gradual disappearance of an environmental factor selectively associated with this culture. One candidate is seed of the neurotoxic plant Cycas circinalis L., a traditional source of food and medicine which has been used less with the Americanization of the Chamorro people after World War II. Macaques were fed the Cycas amino acid beta-N-methylamino-L-alanine, a low-potency convulsant that has excitotoxic activity in mouse brain, which is attenuated by N-methyl-D-aspartate receptor antagonists. These animals developed corticomoto-neuronal dysfunction, parkinsonian features, and behavioral anomalies, with chromatolytic and degenerative changes of motor neurons in cerebral cortex and spinal cord. In concert with existing epidemiological and animal data, these findings support the hypothesis that cycad exposure plays an important role in the etiology of the Guam disease.

WEB in Partially Thrombosed Intracranial Aneurysms: A Word of Caution.

Despite the proved safety and efficacy of Woven EndoBridge (WEB) flow disruption in conventional intracranial saccular aneurysms, the literature on its use in partially thrombosed intracranial aneurysms is scarce. We report a series of 4 patients in whom partially thrombosed intracranial aneurysms were treated with the WEB. The 2 patients who received additional intraluminal treatment with conventional stents made a good clinical recovery. Meanwhile, those patients who were treated with the WEB alone had fatal rupture of the aneurysm at short- to medium-term follow-up. This small, select case series demonstrates that WEB placement with adjunctive stent placement may be an effective treatment in the management of partially thrombosed intracranial aneurysms, which merits further validation. However, exclusive intrasaccular flow disruption may have an adverse influence on the natural history of this disease.

The neurotoxin, beta-N-methylamino-L-alanine (BMAA) interacts with the strychnine-insensitive glycine modulatory site of the N-methyl-D-aspartate receptor.

Electrophysiological and receptor binding techniques were used to determine whether the neurotoxin beta-N-methylamino-L-alanine (BMAA), a monocarboxylic amino acid, can act at the strychnine-insensitive glycine modulatory site to modify the activity of N-methyl-D-aspartate receptors. DL-BMAA but not L-BMAA reversibly potentiated the amplitude of NMDA-activated currents. Neither DL-BMAA nor L-BMAA were able independently to active currents. The reversal potential and the potential-dependence of the amplitude were not affected by DL-BMAA. The DL-BMAA effect was reversibly antagonized by 7-chlorokynurenic acid. Concentration jump experiments showed that the time course of the "off" response of NMDA-activated currents in the presence of DL-BMAA is faster than in the presence of glycine, suggesting that DL-BMAA dissociates from the receptor more rapidly than glycine. DL-BMAA produced a concentration-dependent displacement of [3H]glycine binding which was additive with that of 7-chlorokynurenic acid. These data indicate that D-BMAA could act as a stereospecific modulator of NMDA receptor function by acting as an agonist at the strychnine-insensitive glycine modulatory site of the NMDA receptor.

Effects of a muscarinic antagonist on various components of female sexual behavior in the rat.

The effects of the muscarinic antagonist scopolamine on lordosis, solicitation, pacing, approach, attractivity, and activity were evaluated in ovariectomized rats brought into sexual receptivity with estrogen and progesterone. Systemic (1 mg/rat) or intraventricular (10 micrograms bilaterally) administration of scopolamine significantly reduced the incidence of lordosis and solicitation behaviors and disrupted typical pacing of sexual contacts with a stimulus male. In addition, females avoided contact with a stimulus male, but not a stimulus female, following intraventricular infusion of scopolamine. The levels of general activity and frequencies of sexual contacts were similar in females treated intraventricularly with scopolamine and vehicle solutions. Consequently, scopolamine disrupted various components of sexual behavior, including lordosis, solicitation, pacing, and approach, without altering female attractivity or general activity.

Subcellular distribution of 2?,3?-cyclic nucleotide-3?-phosphodiesterase in cat peripheral nerve.

Subcellular distribution of 2?,3?-cyclic nucleotide-3?-phosphodiesterase (CNPase) in desheathed, saline perfused cat sciatic nerve is reported. CNPase specific activity was enriched in the total particulate (P(2)) fraction and was low in the soluble (S(2)) fraction. "Light-myelin" floating above the 0.60 M sucrose phase had the highest CNPase activity, 2.5-fold over the crude homogenate (CH). By contrast, enzyme activity in "heavy myelin" floating above the 0.85 M sucrose interface was equal to that of the CH and accounted for only 12% of total activity. CNPase activity in the membranes floating above the 0.25 and 0.60 and 0.85 M sucrose phases comprised nearly 70% of the total CNPase activity. The "light myelin" fraction floating above the 0.60 M sucrose accounted for approx. 51% of the total CNPase activity. SDS-PAGE of membranes individually harvested from above the 0.25 and 0.60 and 0.85 M sucrose phases revealed the presence of myelin-specific proteins (P(0), P(1); and P(2)). Electron microscope examination demonstrated the presence of myelin in each membrane fraction. The results of this study show that the majority of CNPase activity is associated with "light myelin" in cat peripheral nerve.

Specific antagonism of excitotoxic action of 'uncommon' amino acids assayed in organotypic mouse cortical cultures.

Beta-N-Methylamino-L-alanine (BMAA) and beta-N-oxalylamino-L-alanine (BOAA) are chemically related excitant amino acids present in the seeds of Cycas circinalis and Lathyrus sativus, respectively. Consumption of these seeds has been linked to Guam amyotrophic lateral sclerosis (BMAA) and lathyrism (BOAA) (a form of primary lateral sclerosis). We report that the acute neuronotoxic actions of these amino acids are blocked selectively by specific glutamate receptor antagonists. Administration of BOAA and BMAA to neonatal mouse cortex explants (EC100 = 28 microM and 1.6 mM, respectively) rapidly induces postsynaptic vacuolation (PSV) and neuronal degeneration characterized by dark/shrunken (D/S) cells. BOAA-mediated neuronotoxic effects are attenuated in a concentration-dependent manner by cis-2,3-piperidine dicarboxylic acid (PDA), an antagonist of quisqualate (QA)-preferring and kainate (KA)-preferring glutamate receptors. PDA maximally protected against BOAA-induced PSV by 84% at 1 mM and D/S cells by 80% at 0.5 mM. BMAA-induced cellular changes were antagonized selectively in a concentration-dependent manner by 2-amino-7-phosphono-heptanoic acid (AP7), an N-methyl-D-aspartate (NMDA) glutamate-receptor antagonist. AP7 maximally protected against BMAA-induced PSV and D/S by 88% at 1.0 and 0.5 mM, respectively. These protective actions were selective and specific since AP7 failed to attenuate BOAA-induced alterations, and PDA was ineffective in ameliorating BMAA-induced changes. Other glutamate receptor antagonists (glutamic diethyl ester and streptomycin) failed to protect the explants from the destructive action of either toxin. Taken collectively, our data indicate that the acute neuronotoxic actions of BOAA and BMAA (or a metabolite) operate through different glutamate receptor species.(ABSTRACT TRUNCATED AT 250 WORDS)

Action of acrylamide on selected enzymes of energy metabolism in denervated cat peripheral nerves.

The effect of acrylamide on selected glycolytic and citric acid cycle enzymes has been studied in denervated cat sciatic nerves in vitro and in vivo. The enzyme activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), neuron specific enolase (NSE), succinate dehydrogenase (SDH), and lactate dehydrogenase (LDH), has been examined in saline-perfused, desheathed and denervated peroneal (P) and tibial (T) nerves from cats treated with acrylamide (15 mg/kg/day, s.c.) or vehicle for 15 days. GAPDH activity in denervated P and T nerve stumps was 2.0- and 2.3-fold higher than normal P and T nerve values. GAPDH activity in Schwann cells in denervated P and T nerves of acrylamide-treated cats was markedly reduced (56% and 61% of untreated denervated nerves, respectively). LDH and SDH activities were unaffected by acrylamide and NSE activity was absent in denervated nerve stumps. Acrylamide (0.5 and 20 mM) inhibited GAPDH activity in denervated nerve homogenates by 67% and 29%, respectively. This study demonstrates that acrylamide inhibits GAPDH in Schwann cells. The significance of GAPDH inhibition by acrylamide in denervated nerves and its relation to distal axonopathy has been discussed.

Expression of functional metabotropic and ionotropic glutamate receptors in baculovirus-infected insect cells.

An ionotropic glutamate receptor of the kainate subtype (GluR6) and a G-protein coupled metabotropic glutamate receptor (mGluR1 alpha) were expressed and studied in two insect cell lines: sf9 cells from Spodoptera frugiperda and MG1 cells from Trichoplusia ni. Application of kainate to GluR6-infected MG1 cells produced kainate-activated currents. Glutamate activation of mGluR1 alpha in MG1- and sf9-infected cells caused rapid, transient increases in intracellular calcium levels. This effect was more pronounced in MG1 cells compared to sf9 cells. These results indicate that functional glutamate receptors can be expressed in the baculovirus system, and that MG1 cells may have several advantages over the widely used sf9 cells for studying the functional properties of receptors and channels.

Substance use disorders. Difficulties in diagnoses.

Patients attempt, consciously or unconsciously, to minimize or disguise their substance use, in part to preserve shreds of self-respect, avoid guilt and shame, and avoid the real or imagined criticism of others. It is ironic that substance users not only use the substance to gain access to pleasant events or escape or avoid unpleasant events, but also to deny, minimize, or disguise that very use for the same reasons.

Children's and adults' predictive saccades to square-wave targets.

Predictive saccades to square-wave targets were investigated in school age children and adults at target frequencies of 0.25, 0.5, 0.75, 1.0 and 1.25 Hz. Both children and adults showed predictive tracking that was greatest at the middle of the frequency range, but children's saccade latencies were greater than those of adults at frequencies of 0.5 Hz and above. The variability of saccade latencies for children and adults were comparable. These results were interpreted as indicating that both children's and adults' oculomotor systems include a prediction operator and respond to predictable stimuli in qualitatively similar, although quantitatively different, ways.

Changes in high affinity sodium independent gamma-aminobutyric acid binding in cerebral cortex and hippocampus of the rat following electroshock.

Electroshock induced seizures in the rat enhanced high affinity specific Na+ independent binding of 3H-gamma aminobutyric acid (GABA) to frozen, Triton X-100 treated cerebral synaptic membranes 30 minutes after exposures to electroshock, although no change in 3H GABA binding was observed in similarly treated preparations from hippocampus. Scatchard analysis of the binding isotherms from cortical membranes indicated that the increase in 3H GABA binding at 30 minutes was due to a rapid increase (39%) in the number of available GABA receptor binding sites (Bmax) rather than an alteration in receptor affinity (KD). The number of binding sites returned to control values within 1 hour and remained so throughout the duration of this study.

Induction of metallothionein in the rat brain by copper implantation but not by cobalt implantation.

Following gel-filtration of cytosol prepared from copper-implanted rat brain there was a pronounced copper-containing, cadmium-binding peak with a relative elution volume similar to that of hepatic metallothionein (MT). No such peak was apparent in cytosol derived from cobalt- or glass-implanted brains. Spectral analysis of a purified protein from copper-implanted brain reveal a UV absorption spectrum characteristic of MT.

Biological variation of cardiac markers: analytical and clinical considerations.

The analytical, within-subject and between-subject components of variation were estimated for serum total creatine kinase (TCK) activity, CK-MB (creatine kinase-MB) activity, CK-MB mass, ratios of CK-MB activity and CK-MB mass to TCK activity and myoglobin concentration in a cohort of 16 apparently healthy subjects over 5 days. Analytical goals based on biological variation showed that, for all quantities except CK-MB mass, methodological improvement is warranted. All cardiac markers showed marked individuality which casts doubt on the utility of conventional population-based reference values as interpretative criteria. The critical differences required for significance of changes in serial results differ markedly from marker to marker and the data allow generation of objective criteria for monitoring individuals.

Automation of protein assays with a microcomputer interfaced to a spectrophotometer.

We have developed a system for semi-automatic protein quantitation assays based on an inexpensive, general-purpose microcomputer. A commercial curve fitting program was modified for direct data input from the spectrophotometer via an analog to digital converter. The software provides specific prompts for protein assays resulting in a rapid and user friendly, semi-automated system. A listing of the protein assay results are printed, or stored to a magnetic disk, along with a graphic representation of the standard curve.

Differing effects of low and high bulk maternal dietary supplements during pregnancy.

The study attempted to determine if the bulk of dietary supplements given to pregnant women after midgestation affects fetal growth. 127 Zulu women were randomly assigned to four groups, two of which received daily food supplements designed to raise their energy, protein and vitamin intakes to levels recommended by the U.S. Food and Nutrition Board. One of these supplements had a high bulk, the other a low bulk. The third supplement contained only zinc and the fourth a placebo. Women in all four groups had a similar weight gain and length of gestation. Birth weights were from 6.5 to 9.5% greater with the low bulk than with the other supplements.

Physical proximity as a possible facilitator in post-detoxification treatment-seeking among chemically dependent veterans.

The transition into rehabilitative treatment following detoxification is a critical event for most chemically dependent individuals. A host of factors may enhance or impede this transition, yet little or no research has been done to shed light on this issue. This paper presents the results of the fortuitous changing of one variable which appeared to increase the likelihood of a successful transition, namely, the degree of physical proximity of the detox program and the rehab program. Results indicated a significantly greater proportion of patients successfully making the transition from detox to rehab when the programs were very close proximally than when they were less close. The role of possible patient-to-patient modeling effects was discussed.

Self-efficacy in alcoholics: clinical validation of the Situational Confidence Questionnaire.

Recent theory and empirical data suggest that self efficacy plays an important role in resistance to relapse for substance abusers. This study investigated the validity of the Situational Confidence Questionnaire (SCQ), a new instrument designed to measure self-efficacy expectations in purported high-risk drinking situations. The SCQ was administered to 46 short-term sober (STS) and 25 long-term sober (LTS) alcoholics. STS subjects were newly admitted alcohol treatment patients and LTS subjects had been abstinent for at least one year. Results indicated significantly higher self efficacy for LTS subjects than for STS subjects on total score and on 7 of the 8 subscales (p less than .001). Stepwise discriminant analysis yielded a linear combination of three subscales to account for 49% of the total variance; 92% of the LTS and 65% of the STS subjects were correctly identified by the classification function. These results extended earlier work with the SCQ using newly sober subjects and, in addition, provide encouraging validity data for the SCQ.

Risk of physical abuse to children of spouse abusing parents.

The purpose of this study is to estimate the gender-specific probability of a violent spouse also physically abusing his or her child within a representative sample. The study is based on a sample of 3,363 American parents interviewed for the 1985 National Family Violence Survey. The study shows that marital violence is a statistically significant predictor of physical child abuse. The greater the amount of violence against a spouse, the greater the probability of physical child abuse by the physically aggressive spouse. This relationship is stronger for husbands than for wives. The probability of child abuse by a violent husband increases from 5% with one act of marital violence to near certainty with 50 or more acts of marital violence. The predicted probability of child abuse by a violent wife increases from 5% with one act of marital violence to 30% with 50 or more acts of marital violence. Implications for divorce custody proceedings are discussed.

Statistical analysis of cell directions in applied current experiments.

A program has been developed to analyze cell directions sampled during the course of experiments in which uniform electrical currents are passed over cells grown in tissue culture. The program can test data sets for statistically significant orientation, i.e. clustering about a certain mean angle, and can also perform a pairs test between two data sets to determine whether there is a significant difference in orientation between them.