SUBCLINICAL EPILEPTIC SEIZURES—Impairment of Motor Performance and Derivative Difficulties

Modern clinical observations have greatly expanded the conception of the characteristics of the various kinds of epilepsy. By simultaneously recording electroencephalograms and the performance of simple motor tasks, it has been possible to demonstrate the effects of epileptic seizures not detectable by unaided observation and not noted by the patient. The effects of these subclinical seizures have been manifested variously—by a lengthening of the time between stimulus and reaction, by inaccuracies of response to stimuli, or by total cessation of performance.From this study it is suggested that subclinical seizures probably play a role in producing some of the psychiatric conditions associated with the convulsive disorders, as well as primary behavior disturbances and undifferentiated mental deficiency. It is also suggested that such subclinical seizures may possibly contribute to the characteristics of some cases of criminality and antisocial reactions and schizophrenic reactions.     

Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel Facile Synthesis and Potential Anti-Epileptic Activity

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.     

Neuromonitoreo no invasivo en unidades de cuidados intensivos en Colombia

Continuous non-invasive electroencephalographic monitoring is an essential technique for critical care patients as it shows directly and indirectly the patient’s brain activity and makes it possible to relate it with findings in the clinical status. It is highly sensitive, although its specificity is lower, so they can show alterations of the state of consciousness without clarifying the etiology.Continuous electroencephalographic recording in patients with altered levels of consciousness, seizures, and convulsive and non-convulsive status epilepticus has been increasing in recent years as real-time feedback of the cerebral function shows evolution changes and allows for the identification of electric and subclinical epileptic seizures that are highly important since they do not have clinical correlations.These findings in electroencephalographic monitoring also help to modify pharmacological and antiseizure treatments. For practitioners, they are advantageous when making timely decisions that impact the prognosis of the patient.     

Glycine potentiates the action of some anticonvulsant drugs in some seizure models

The anticonvulsant effect of either phenobarbital or dilantin was potentiated by exogenous glycine in DBA/2 audiogenic seizure mice and in 3-mercaptopropionic acid-induced seizures. In seizures caused by pentylenetetrazol, glycine potentiated the anticonvulsant effect of phenobarbital only slightly; in combination with dilantin, which was ineffective by itself, it did not have an effect. Valproic acid, in large doses, prevented 3-mercaptopropionic acid-induced seizures; glycine did not potentiate its effect. Glycine thus potentiates anticonvulsant effects, but only of some drugs and only in some of the seizure models. This suggests that the mechanism of the anticonvulsant effect of glycine is similar to that of some of the anticonvulsant drugs such as dilantin and different from others, and that this mechanism is not effective in all seizure models.     

Allergenic tropomyosins and their cross-reactivities

The ingestion or inhalation of some proteins may lead to adverse immune reactions. Allergens may trigger allergic reactions in genetically predisposed individuals when they are absorbed through the skin or make contact with mucous membranes. An allergic disease often deteriorates the quality of life and may sometimes be life-threatening due to anaphylactic shock. A number of allergens have been characterized from various multicellular organisms to date. It is thought to be reasonable to pay a special attention to the substance which is highly cross-reactive and which causes adverse responses in the molecules that are not sensitized but similar to the sensitized allergen. Tropomyosin has been described as an important food allergen in shrimp, lobster, crab, oysters, squid, and other invertebrates. Allergic reactions to shellfish and mollusks are often cross-reactive, which may be explained by the highly conserved amino acid sequences of tropomyosins among invertebrates, but vertebrate tropomyosins are not known to be allergenic. Several tropomyosins from domestic arthropods have been reported to be allergenic. Recently, it was suggested that an infection of helminthic parasites might lead to sensitization to tropomyosin and elicit allergic reactions to other invertebrates. Much effort has been made to characterize these allergenic tropomyosins from various sources. We will discuss the physicochemical characteristics and the potential application of tropomyosin for the diagnosis and therapeutics of allergic disorders.     

A study on differences between radiation-induced micronuclei and apoptosis of lymphocytes in breast cancer patients after radiotherapy

Cancer patients' responses to radiotherapy vary in severity. It has been suggested that it may be due to differences in intrinsic cellular radiosensitivity. Prediction of tissue reactions to radiotherapy would permit tailoring of dosage to each patient. Towards this goal the micronucleus and apoptosis tests have been proposed as methods for measurement of chromosomal damage in peripheral blood lymphocytes. In this study, gamma-ray sensitivity of cultured lymphocytes of 26 breast cancer patients with early or late reactions was investigated. After irradiation with 4 Gy gamma radiation in G0, the frequency of micronuclei for patients with early reactions was significantly higher (P < 0.05) than for patients with late reactions. In the contrary the frequency of apoptosis for patients with early reactions was significantly lower (P < 0.05) than in the other group. It could be suggested that such a reduced amount of micronuclei in the late effects group is due to the presence of some residual DNA damages which are not completely repaired and lesions show increasing severity when the patients' cells are irradiated again. These induced damages, probably are high enough to stimulate other endpoints like apoptosis instead of micronuclei.     

Does phenobarbital protect against trimethyltin-induced neuropathology of limbic structures?

Because of the similarity in the pattern of limbic sites damaged by both compounds, it has been suggested that trimethyltin (TMT) may be an excitotoxin like kainic acid (KA). KA produces seizures which eventually result in neuronal damage similar to that found in epilepsy. Anticonvulsants reduce both the seizures and pathology associated with KA. Because TMT may also produce seizures, we undertook to determine whether or not some of the TMT-induced limbic neuropathology could result from seizure activity. To do this, a single dose of TMT chloride (either 7.5 or 15 mg/kg) was given per os to rats, and then phenobarbital (30 mg/kg) was administered subcutaneously in repeated doses. Treatment with phenobarbital did not prevent pathologic changes in the hippocampus, dentate gyrus, and pyriform or prepyriform cortex. Since phenobarbital did not protect against TMT-induced neuronal damage, as it has been reported by others to protect against KA-induced damage, the present findings suggest that these two toxicants probably produce hippocampal pathology via different mechanisms and that the TMT-induced pathologic changes do not require sustained electrical seizure activity.     

A Computational Study of Stimulus Driven Epileptic Seizure Abatement

Active brain stimulation to abate epileptic seizures has shown mixed success. In spike-wave (SW) seizures, where the seizure and background state were proposed to coexist, single-pulse stimulations have been suggested to be able to terminate the seizure prematurely. However, several factors can impact success in such a bistable setting. The factors contributing to this have not been fully investigated on a theoretical and mechanistic basis. Our aim is to elucidate mechanisms that influence the success of single-pulse stimulation in noise-induced SW seizures. In this work, we study a neural population model of SW seizures that allows the reconstruction of the basin of attraction of the background activity as a four dimensional geometric object. For the deterministic (noise-free) case, we show how the success of response to stimuli depends on the amplitude and phase of the SW cycle, in addition to the direction of the stimulus in state space. In the case of spontaneous noise-induced seizures, the basin becomes probabilistic introducing some degree of uncertainty to the stimulation outcome while maintaining qualitative features of the noise-free case. Additionally, due to the different time scales involved in SW generation, there is substantial variation between SW cycles, implying that there may not be a fixed set of optimal stimulation parameters for SW seizures. In contrast, the model suggests an adaptive approach to find optimal stimulation parameters patient-specifically, based on real-time estimation of the position in state space. We discuss how the modelling work can be exploited to rationally design a successful stimulation protocol for the abatement of SW seizures using real-time SW detection.     

Reproduction of the electrophysiologic correlates of a conditioned defense reflex following electroconvulsive activity]

Acute and chronic experiments on cats have shown the possibility of obtaining in one session conditioned EEG-responses and vegetative changes as well as conditioned motor reactions time-locked to the moment of the unconditioned pain stimulation omitted during testing. Electro-convulsive stimulation directly after elaboration prevents the appearance of conditioned motor reactions, while conditioned EEG and vegetative changes are retained after electric seizures. A conclusion has been drawn that the emotional component of conditioned reactions is not subjected to the amnestic effect of electro-convulsive action.     

mGlu5 receptor deletion does not confer seizure protection to mice

Metabotropic glutamate mGlu5 receptors have been implicated in the regulation of seizures and have been suggested as a target against which discovery of novel anticonvulsants may be possible. However, the experimental literature is not consistent in reporting anticonvulsant efficacy of mGlu5 receptor antagonists. Additional assessment of this target was approached in the present study by comparing convulsions in wild-type (WT) and mGlu5 receptor null (knockout or KO) mice. Chemically induced seizures induced by a variety of mechanisms including pentylenetetrazole, N-methyl-d-aspartic acid (NMDA), cocaine, kainic acid, aminophylline, 4-aminopyridine, strychnine, and nicotine did not differentially increase clonic, clonic/tonic, or lethality in WT vs. mGlu5 receptor KO mice. The mGlu5 receptor antagonist 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) did not significantly prevent seizures induced by NMDA; in contrast, the uncompetitive NMDA receptor antagonist, dizocilpine, significantly prevented NMDA-induced seizures and lethality in both WT and KO mice. The present findings do not support the idea that mGlu5 receptors play as important a role in seizure control as previously speculated.     

LETM1, a gene deleted in Wolf-Hirschhorn syndrome, encodes an evolutionarily conserved mitochondrial protein

The leucine zipper-, EF-hand-containing transmembrane protein 1 (LETM1) has recently been cloned in an attempt to identify genes deleted in Wolf-Hirschhorn syndrome (WHS), a microdeletion syndrome characterized by severe growth and mental retardation, hypotonia, seizures, and typical facial dysmorphic features. LETM1 is deleted in almost all patients with the full phenotype and has recently been suggested as an excellent candidate gene for the seizures in WHS patients. We have shown that LETM1 is evolutionarily conserved throughout the eukaryotic kingdom and exhibits homology to MDM38, a putative yeast protein involved in mitochondrial morphology. Using LETM1-EGFP fusion constructs and an anti-rat LetM1 polyclonal antibody we have demonstrated that LETM1 is located in the mitochondria. The present study presents information about a possible function for LETM1 and suggests that at least some (neuromuscular) features of WHS may be caused by mitochondrial dysfunction.     

Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies

Bilateral lesions of the pontine tegmentum involving the superior cerebellar peduncles and the nucleus reticularis pontis oralis have been shown to attenuate the tonic components of maximal seizures induced by electroshock, sound stimulation (audiogenic), or pentylenetetrazol, although having no effect on clonus in three separate seizure models. The pontine tegmental lesion also abolishes the clonus of minimal audiogenic seizures that have a motor pattern different from that of other clonic models, and are believed to originate in the brain stem. The preponderant suppression of tonus by the pontine tegmental lesion as well as the inhibition of clonus in audiogenic seizures is strikingly similar to the effects of phenytoin in these same seizure models. The findings presented are consistent with the hypothesis that the pontine reticular formation (RF) plays a key role in the generation and/or expression of tonic convulsions. Additional findings are presented that suggest that serotonin may attenuate the tonic components of maximal electroshock seizures by an action on the brain stem. Thus, it seems likely that pontine tegmental lesions as well as antiepileptic drugs and neurotransmitters with preferential effects on tonic seizures act on a common neural substrate that appears to include the brain-stem RF.     

Evidence for diabetes-induced alterations in the sulfation of heparin sulfate intestinal epithelial cells

Two compounds with high affinity for the "peripheral type" benzodiazepine binding sites, PK 11195 (an isoquinoline derivative) and RO5-4864 (a benzodiazepine derivative) can modify the sensitivity of DBA/2J mice to audiogenic seizures. RO5-4864 (1-15 mg/kg) facilitates in a dose-dependent manner the audiogenic seizures and PK 11195 (2-5 mg/kg) antagonizes the RO5-4864 effects. At these doses PK 11195 alone does not modify the sensitivity to audiogenic seizures, but at doses between 20-80 mg/kg it protects DBA/2J mice against audiogenic seizures. By contrast PK 11195 is inactive against the facilitation of audiogenic seizures by ethyl-beta-carboline-3-carboxylate (a brain benzodiazepine receptor inverse agonist) and against the seizure elicited in absence of noise stimuli by RO5-4864 at doses between 20-40 mg/kg. These results suggest that facilitation by RO5-4864 of the audiogenic seizures and its antagonism by PK 11195 are mediated by the peripheral type benzodiazepine binding sites and agree with the thermodynamic analysis of the binding data which suggested that RO5-4864 might be an agonist and PK 11195 an antagonist. The good correlation between pharmacological effects and the occupancy degree of the binding sites as measured by the displacement of the "in vivo" [3H]-PK 11195 binding give an additional support to binding sites mediated effects.     

How FMN binds to anabaena apoflavodoxin: a hydrophobic encounter at an open binding site

Molecular recognition begins when two molecules approach and establish interactions of certain strength. The mechanisms of molecular recognition reactions between biological molecules are not well known, and few systems have been analyzed in detail. We investigate here the reaction between an apoprotein and its physiological cofactor (apoflavodoxin and flavin mononucleotide) that binds reversibly to form a non-covalent complex (flavodoxin) involved in electron transfer reactions. We have analyzed the fast binding reactions between the FMN cofactor (and shorter analogs) and wild type (and nine mutant apoflavodoxins where residues interacting with FMN in the final complex have been replaced). The x-ray structures of two such mutants are reported that show the mutations are well tolerated by the protein. From the calculated microscopic binding rate constants we have performed a Phi analysis of the transition state of complex formation that indicates that the binding starts by interaction of the isoalloxazine-fused rings in FMN with residues of its hydrophobic binding site. In contrast, the phosphate in FMN, known to contribute most to the affinity of the final holoflavodoxin complex, is not bound in the transition state complex. Both the effects of ionic strength and of phosphate concentration on the wild type complex rate constant agree with this scenario. As suggested previously by nmr data, it seems that the isoalloxazine-binding site may be substantially open in solution. Interestingly, although FMN is a charged molecule, electrostatic interactions seem not to play a role in directing the binding, unlike what has been reported for other biological complexes. The binding can thus be best described as a hydrophobic encounter at an open binding site.     

Effect of alternating G loads on the activities of a human operator wearing a protective helmet

Specific types of operator activity make it necessary to wear a helmet protecting the head against various physical factors. Wearing a heavy helmet for a long time may affect the quality of operator activity when the operator is exposed to alternating G loads. Studies have been performed using a dynamic model of a vehicle subjected to considerable alternating G loads. Crash test dummies have been used to test a system protecting the cervical region of the spinal column. The effects of accelerations, vibrations, and the time of wearing helmets with different weights on the functional state and operator performance have been studied. Data on the effects of helmet weight on some physiological, psychological, and biomechanical reactions of human operators are reported. Some relationships have been found that have practical implications for the functional improvement of the operator component of vehicle operation.     

锰毒及植物耐性机理研究进展

综述了近些年国内外关于锰毒及植物耐锰机理的研究成果,并指出了存在的问题和发展前景。锰毒是酸性土壤上限制作物产量的重要因子,国内外针对锰毒及植物耐受机制进行了相关研究,但进展较为缓慢。锰对植物的毒害效应体现在不同的细胞组织及生理生化水平上,不同植物耐受锰的机理也存在差异性,但大都集中在有机酸的螯合解毒、内部积累、外部排斥及氧化等方面。某些锰胁迫所诱导的基因也被筛选出来,并且部分生物学功能得以鉴定。此外,锰与其他营养元素间的协同或拮抗作用也得以阐述,伴随锰超富积植物-商陆在中国的发现,对锰毒及植物耐性机理的深入研究和探讨,将会对植物修复技术的开展产生理论和实践意义。     

The effect of taurine on kindled seizures in the rat

Recently, it has been reported that taurine, an amino acid with anticonvulsant properties, does not suppress experimental seizures generated by the "kindling" technique. This finding seems somewhat paradoxical since taurine antagonizes other sorts of experimental convulsion and since kindled seizures are easily suppressed by other anticonvulsant drugs. Further tests were therefore conducted during which taurine's anticonvulsant effects were assessed: (1) when kindling stimulation was dropped to near-threshold levels; (2) when cortical as well as limbic kindled foci were stimulated; (3) when developing as well as fully kindled seizures were involved; and (4) when taurine was introduced directly into the ventricles of the brain. Even in these tests which were specifically designed to favour the appearance of anticonvulsant effects, no taurine antagonism of kindled seizures was found.     

The Age-related Gliosis and Accompanying Deficit in Spatial Learning are Unaffected by Dimebon

A non-selective antihistamine, dimebon, has recently emerged as a potential treatment for Alzheimer’s disease and Huntington’s disease. Dimebon exerts several effects in addition to its anti-histaminergic effect, and of particular interest is its ability to enhance cognitive function in several models. The mechanism underlying this is unknown though it has been suggested that it may be associated with its anti-cholinergic action. Dimebon has also been reported to be neuroprotective, perhaps as a result of its ability to stabilize mitochondria. We considered that these effects might impact on the well-described age-related impairment in spatial learning and therefore examined the effect of repeated administration of dimebon on performance of young and aged animals in the Morris water maze. Whereas a clear age-related deficit was observed, dimebon failed to exert any effect on performance. Similarly, dimebon exerted no effect on the age-related increase in hippocampal expression of several markers of microglial and astroglial activation. We conclude that, despite its cognitive enhancing effects in some models, dimebon failed to modulate the deficit in spatial learning in aged rats and the evidence suggests that the drug does not possess anti-inflammatory properties.     

Unusual origins of isotope effects in enzyme-catalysed reactions

High hydrostatic pressure is a neglected tool for probing the origins of isotope effects. In chemical reactions, normal primary deuterium isotope effects (DIEs) arising solely from differences in zero point energies are unaffected by pressure; but some anomalous isotope effects in which hydrogen tunnelling is suspected are partially suppressed. In some enzymatic reactions, high pressure completely suppresses the DIE. We have now measured the effects of high pressure on the parallel 13C heavy atom isotope effect of yeast alcohol dehydrogenase and found that it is also suppressed by high pressure and, similarly, suppressed in its entirety. Moreover, the volume changes associated with the suppression of both deuterium and heavy atom isotope effects are virtually identical. The equivalent decrease in activation volumes for hydride transfer, when one mass unit is added to the carbon end of a scissile C-H bond as when one mass unit is added to the hydrogen end, suggests a common origin. Given that carbon is highly unlikely to undergo tunnelling, it follows that hydrogen is not doing so either. The origin of these isotope effects must lie elsewhere. We offer protein domain motions as a possibility.