Vagus nerve stimulation magnet activation for seizures: a critical review.

Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0-89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15-67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.

Association of MRI T1 relaxation time with neuropsychological test performance in manganese- exposed welders.

This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11±0.05mg/m3. Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times.

Pterocarpans phaseollin and neorautenol isolated from Erythrina addisoniae induce apoptotic cell death accompanied by inhibition of ERK phosphorylation.

The genus Erythrina (Leguminosae), consisting of over 100 different species, is distributed in tropical regions. In traditional medicine, Erythrina species are used to treat cancer, but little is known about the anticancer mechanisms. From the stem bark of Erythrina addisoniae Hutch. & Dalziel, six prenylated pterocarpans were isolated and analysed for pharmacological activity: While calopocarpin, cristacarpin, orientanol c, and isoneorautenol showed only a weak or moderate toxicity in H4IIE hepatoma cells (EC(50)-value> 25 microM), the toxicity of neorautenol and phaseollin was in the low micromolar range (EC(50)-value: 1 and 1.5 microM, respectively). We further focused on these two substances showing that both increased caspase 3/7 activity and nuclear fragmentation as markers for apoptotic cell death. Neorautenol (10 microM, 2h), but not phaseollin induced the formation of DNA strand breaks (comet assay). Both substances showed no effect on NF-kappaB signalling (SEAP assay: basal activity and stimulation with TNF-alpha), on the other hand both pterocarpans (10 microM, 2 h) decreased the activation of the ERK kinase (p44/p42), an mitogen activated protein kinase which is associated with cell proliferation. We conclude that the pterocarpans phaseollin and neorautenol may be responsible for the anticarcinogenic actions of the plant extract reported in the literature. Further analysis of these substances may lead to new pharmacons to be used in cancer therapy.

Fractionation of skin tumor-initiating activity in coal liquids.

Narrow temperature range distillates from biologically active solvent refined coal-I and -II heavy-end coal liquids were fractionated according to chemical class and assayed for initiation of skin carcinogenesis in CD-1 mice. In addition, instrumental chemical analyses were performed on the distillates and their chemical fractions. Results showed that initiation activity in these complex fuel mixtures could be segregated both by boiling point and chemical class. Neutral polycyclic aromatic hydrocarbon fractions were the most active of the chemical classes, with some initiating activity being shown by nitrogen-containing polycyclic aromatic hydrocarbon. Aliphatic and hydroxylated polycyclic aromatic hydrocarbon fractions showed little or no initiating activity. For the two solvent refined coal-II distillates studied, initiating activity was substantially higher in the material boiling above 850 degrees F than in that boiling 800-850 degrees F, although both contained essentially the same concentrations of benzo[a]pyrene. These data indicate that the overall initiating activity of these complex mixtures is highly dependent on interactions of the many chemical carcinogens and that relative concentrations of known carcinogenic polycyclic aromatic hydrocarbons, such as benzo[a]pyrene and dimethylbenz[a]anthracene, are not the sole determinants of initiating activity.

Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.

The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of beta-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg(-1) day(-1) ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (DeltaT(m) value) or toxicity in the mouse-malaria model.

Short-pulse pump-and-probe technique for airborne laser assessment of Photosystem II photochemical characteristics.

The development of a technique for laser measurement of fPhotosystem II (PS II) photochemical characteristics of phytoplankton and terrestrial vegetation from an airborne platform is described. Results of theoretical analysis and experimental study of pump-and-probe measurement of the PS II functional absorption cross-section and photochemical quantum yield are presented. The use of 10 ns probe pulses of PS II sub-saturating intensity provides a significant, up to 150-fold, increase in the fluorescence signal compared to conventional 'weak-probe' protocol. Little effect on the fluorescence yield from the probe-induced closure of PS II reaction centers is expected over the short pulse duration, and thus a relatively intense probe pulse can be used. On the other hand, a correction must be made for the probe-induced carotenoid triplet quenching and singlet-singlet annihilation. A Stern-Volmer model developed for this correction assumes a linear dependence of the quenching rate on the laser pulse fluence, which was experimentally validated. The PS II saturating pump pulse fluence (532 nm excitation) was found to be 10 and 40 mumol quanta m(-2) for phytoplankton samples and leaves of higher plants, respectively. Thirty mus was determined as the optimal delay in the pump-probe pair. Our results indicate that the short-pulse pump-and-probe measurement of PS II photochemical characteristics can be implemented from an airborne platform using existing laser and LIDAR technologies.

Airborne test of laser pump-and-probe technique for assessment of phytoplankton photochemical characteristics.

Initial results of the airborne LIDAR measurement of photochemical quantum yield, Phi(Po), and functional absorption cross-section, sigma(PS II), of Photosystem II (PS II) are reported. NASA's AOL3 LIDAR was modified to implement short-pulse pump-and-probe (SP-P&P) LIDAR measurement protocol. The prototype system is capable of measuring a pump-induced increase in probe-stimulated chlorophyll fluorescence, DeltaF/F(sat), along with the acquisition of ;conventional' LIDAR-fluorosensor products from an operational altitude of 150 m. The use of a PS II sub-saturating probe pulse increases the response signal but also results in excessive energy quenching (EEQ) affecting the DeltaF/F(sat) magnitude. The airborne data indicated up to a 3-fold EEQ-caused decline in DeltaF/F(sat), and 2-fold variability in the EEQ rate constant over a spatial scale a few hundred kilometers. Therefore, continuous monitoring of EEQ parameters must be incorporated in the operational SP-P&P protocol to provide data correction for the EEQ effect. Simultaneous airborne LIDAR measurements of Phi(Po) and sigma(PS II) with EEQ correction were shown to be feasible and optimal laser excitation parameters were determined. Strong daytime DeltaF/F(sat) decline under ambient light was found in the near-surface water layer over large aquatic areas. An example of SP-P&P LIDAR measurement of phytoplankton photochemical and fluorescent characteristics in the Chesapeake Bay mouth is presented. Prospects for future SP-P&P development and related problems are discussed.

Laboratory investigation of human deaths from vampire bat rabies in Peru.

In the spring of 1996, multiple cases of an acute febrile illness resulting in several deaths in remote locations in Peru were reported to the Centers for Disease Control and Prevention (CDC). The clinical syndromes for these cases included dysphagia and encephalitis. Because bat bites were a common occurrence in the affected areas, the initial clinical diagnosis was rabies. However, rabies was discounted primarily because of reported patient recovery. Samples of brain tissue from two of the fatal cases were received at CDC for laboratory confirmation of the rabies diagnosis. An extensive array of tests on the formalin-fixed tissues confirmed the presence of both rabies viral antigen and nucleic acid. The virus was shown to be most closely related to a vampire bat rabies isolate. These results indicate the importance of maintaining rabies in the differential diagnosis of acute febrile encephalitis, particularly in areas where exposure to vampire bats may occur.

Medicinal plants in tropical medicine. 1. Medicinal plants against protozoal diseases.

The active principles obtained from some of the traditional medicinal plants which are used worldwide for the treatment of protozoal diseases are reviewed. Among the active molecules considered from recent literature are bisbenzylisoquinoline, protoberberine and indole alkaloids, sesquiterpenes, quassinoids and limonoids. This review indicates that there are many antiprotozoal natural products already known which require further scientific investigation. There is a strong possibility that other antiprotozoal compounds with novel chemical structures and potentially novel modes of action will be discovered in plants.

Determination of anti-giardial activity in vitro by means of soluble formazan production.

A new microplate assay for the determination of activity in vitro against Giardia intestinalis has been developed in which viability is measured by soluble formazan production from a tetrazolium reagent. Metabolic reduction of the latter gives rise to a coloured product which may be determined directly by optical density measurement. Using this method the anti-giardial activities of more than 20 anti-microbial compounds have been assessed. The results obtained with a number of known anti-giardial agents, including metronidazole (50% inhibitory concentration [IC50] = 2.98 microM) and furazolidone (IC50 = 4.14 microM), compare well with previously published data; mepacrine, however, was found to produce a biphasic dose-response curve from which two IC50 values (0.816 and 6.83 microM) were obtained. This method provides a convenient means by which the search for new anti-giardial agents may be facilitated.

Global and regional cerebral blood flow. Noninvasive quantitation in patients with subarachnoid hemorrhage.

Since inert gas washout techniques for cerebral blood flow (CBF) measurement are not applicable to asymmetrical pathological states where assumptions about constancy of distribution, volume, and partition coefficients cannot be held to be valid, a new approach to regional and global CBF is described. Regional volume and regional mean transit time are measured independently to give regional volume flow in ml/min. In a pilot study, this noninvasive, quantitative technique has been applied to 37 patients with various clinical responses to subarachnoid hemorrhage. Global CBF and clinical grading were significantly associated. Reduction of regional CBF and spasm of the relevant arterial supply were also significantly associated in these patients.

Epidermal carcinogenesis studies of synthetic fossil fuel materials in mice.

Skin tumor response in mice to solvent fractions of heavy distillate (HD) from a solvent-refined coal (SRC-II) process indicated that the basic tar and neutral tar were the most carcinogenically potent fractions. Assays of another SRC-II coal liquid that had been fractionally distilled indicated that the carcinogenicity of this material for mouse skin is due to that portion boiling above 371 degrees C (700 degrees F), and that the carcinogenic potency of the material increased with boiling point. Samples of the 399-427 degrees C (750-800 degrees F) distillate were nitrosated to destroy primary aromatic amines and were chemically fractionated to assess the carcinogenicity of chemical class fractions of these complex mixtures. Data from these assays indicated that neutral polycyclic aromatic hydrocarbons (PAH) and nitrogen-containing polycyclic aromatic compounds (NPAC) both contribute to the carcinogenicity of this distillate.

Correlation of hyperforin content of Hypericum perforatum (St John's Wort) extracts with their effects on alcohol drinking in C57BL/6J mice: a preliminary study.

Extracts of the herb St John's Wort have been shown to reduce alcohol intake in alcohol-preferring rats, but it is not known which of the constituent(s) are responsible for this effect. In this study, the effect of a crude methanolic extract of Hypericum perforatum (negligible hyperforin content) on alcohol drinking in C57BL/6J alcohol-preferring mice was compared with that of a hyperforin-rich extract (45% hyperforin) prepared by extracting the herb with supercritical carbon dioxide. The dose of the hyperforin-rich extract required to significantly reduce 10% ethanol intake (5 mg/kg) was 125-fold less than that required for the crude extract (625 mg/kg), and was comparable to the dose of fluoxetine (10 mg/kg) required to produce a similar effect. None of these agents significantly affected water intake. These results suggest that the effects of H. perforatum extracts on alcohol drinking behaviour are due to the hyperforin content of the herb rather than to other, more polar constituents. Hyperforin is an unstable compound and this study also highlights the effect of different methods of extract preparation on hyperforin content.

Chemical basis for photomutagenicity in synthetic fuels and correlation with carcinogenicity.

Photomutagens (chemicals that enhance the mutagenicity of non-ionizing radiation) have been detected in experimental coal- and oil shale-derived synthetic fuel samples using Salmonella typhimurium strain TA98 and fluorescent light. In this study, photomutagenic activity was measured among distillation and chemical class fractions from a blend of direct coal liquefaction process materials. Photomutagenicity increased with increasing boiling point and was concentrated in fractions enriched in neutral polycyclic aromatic compounds (neutral PACs). The photomutagenic activities of the materials tested correlate well with the previously reported tumorigenic activities of the same samples on mouse skin, but correlate poorly with the previously reported mutagenic activities of the same samples in the Salmonella/mammalian-microsome test (using strain TA98), in which neutral PAC-enriched fractions were not active. These data suggest that relatively high boiling neutral PACs are important chemical photomutagens in synthetic fuels and suggest the potential use of the photomutation assay as an improved, relatively simple, inexpensive and short-term bioassay for detecting carcinogens as mutagens in complex mixtures such as synthetic fuels.

Can ethnopharmacology contribute to the development of antimalarial agents?

The resistance of Plasmodium falciparum, the cause of tertian malaria, to synthetic antimalarials, together with the resistance of the vector mosquitoes to insecticides, has resulted in a resurgence in the use of quinine and a search for new antimalarial agents. In recent years, artemisinin, isolated from Artemisia annua which is used in Chinese traditional medicine for the treatment of malaria, has proved to be effective in the treatment of cerebral malaria due to chloroquine-resistant strains of P. falciparum. The development of in vitro tests utilising P. falciparum obtained from malaria patients means that it is possible to use bioassay guided fractionation of active extracts in order to isolate active principles. A number of laboratories throughout the world are currently investigating plants used in traditional medicine for their active constituents. Some of their results will be described and in particular two aspects of our investigations with species of Simaroubaceae and Menispermaceae will be discussed. There is every possibility that such approaches which use leads from Ethnopharmacology will result in the development of new antimalarial agents. It is vitally important to those populations relying on traditional medicines for the treatment of malaria that the safety and efficacy of such medicines be established, their active principles determined and that reproducible dosage forms be prepared and made available for use.

Antiplasmodial activities of some Ghanaian plants traditionally used for fever/malaria treatment and of some alkaloids isolated from Pleiocarpa mutica; in vivo antimalarial activity of pleiocarpine.

Fourteen Ghanaian plants used in folk medicine to treat fever/malaria were screened for activity against Plasmodium falciparum (strain K1) and were tested for general toxicity to the brine shrimp. Extracts from three of the plants, Pleiocarpa mutica, Cleistopholis patens and Uvaria chamae were found to have significant antiplasmodial activity. The extract of U. chamae was toxic to brine shrimps. These findings lend support to the use of these plants in traditional medicine. Possible toxicity due to U. chamae is a cause for concern. Five known alkaloids, pleiocarpine (1), kopsinine (2), pleiocarpamine (3), eburnamine (4) and pleiomutinine (5) were isolated from the roots of P. mutica. This is the first report of the occurrence of (4) in P. mutica. Compound (5) was the most active against P. falciparum (IC50 = 5 microM). Although (1) was inactive against malaria parasites in vitro, it was moderately active against P. berghei in mice (25 mg kg(-1) daily for 4 days reduced parasitaemia by 28.5% compared to untreated controls).

Plants as sources of antimalarial drugs, Part 6: Activities of Simarouba amara fruits.

Extracts prepared from Simarouba amara fruits collected in Panama have been found to be active against Plasmodium falciparum in vitro and against Plasmodium berghei in mice. Four active quassinoids have been identified as ailanthinone, 2'-acetylglaucarubinone, glaucarubinone and holacanthone.

Parasitological and microbiological evaluation of Mixe Indian medicinal plants (Mexico).

Medicinal plants are an important health resource in many regions of the Americas and are of particular importance to many Indian communities. Based on a recent ethnobotanical study in Mexico, we investigated the activity of 29 plant extracts against Entamoeba histolytica, three bacteria (Bacillus subtilis, Escherichia coli, and Micrococcus luteus) and two fungi (Cladosporium cucumerinum and Penicillium oxalicum). After separation of these extracts between CH2Cl2 and H2O the resulting phases were also evaluated.

Alstonia species: are they effective in malaria treatment?

A review of the literature on Alstonia species indicates that evidence in support of their effectiveness in the treatment of malaria is controversial. The antiprotozoal activity of the major alkaloid present in Alstonia species, echitamine, was assessed in vitro against Plasmodium falciparum and Giardia intestinalis. Echitamine displayed little antiplasmodial activity, but two quinoline alkaloids from A. coriacea (corialstonine and corialstonidine) were found to have some activity against P. falciparum although this was approximately 10 times less than that of quinine. None of the three Alstonia alkaloids was active against G. intestinalis. These results are discussed in the context of previously published data.

[Molecular modelling of usambarensine, tubulosine and emetine, cytotoxic amebicide alkaloids]. / Modélisation moléculaire de l'usambarensine, de la tubulosine et de l'émétine, alcaloïdes cytotoxiques et antiamibiens.

The analyses of the different possible conformations of usambarensine, tubulosine and emetine, which possess interesting cytotoxic and amoebicide properties showed us that they cannot take the planar conformation proposed to explain the activity of this type of molecules on protein synthesis. Nevertheless, a common (non planar) conformation exists where the angles between the two plans containing the aromatic rings are nearly the same for the three compounds. This fact could confirm the hypothesis of a common receptor which would be slightly different in amoebae because of its higher sensitivity to usambarensine.