Is the Pathogenic Ergot Fungus a Conditional Defensive Mutualist for Its Host Grass?

PubMed Central

Wäli, Pauliina P.; Wäli, Piippa R.; Saikkonen, Kari; Tuomi, Juha

2013-01-01

It is well recognized, that outcomes of mutualistic plant-microorganism interactions are often context dependent and can range from mutualistic to antagonistic depending on conditions. Instead, seemingly pathogenic associations are generally considered only harmful to plants. The ergot fungus (Claviceps purpurea) is a common seed pathogen of grasses and cereals. Ergot sclerotia contain alkaloids which can cause severe toxicity in mammals when ingested, and thus the fungal infection might provide protection for the host plant against mammalian herbivores. Theoretically, the net effect of ergot infection would positively affect host seed set if the cost is not too high and the defensive effect is strong enough. According to our empirical data, this situation is plausible. First, we found no statistically significant seed loss in wild red fescue (Festuca rubra) inflorescences due to ergot infection, but the seed succession decreased along increasing number of sclerotia. Second, in a food choice experiment, sheep showed avoidance against forage containing ergot. Third, the frequency of ergot-infected inflorescences was higher in sheep pastures than surrounding ungrazed areas, indicating a protective effect against mammalian grazing. We conclude that, although ergot can primarily be categorized as a plant pathogen, ergot infection may sometimes represent indirect beneficial effects for the host plant. Ergot may thus serve as a conditional defensive mutualist for its host grass, and the pathogenic interaction may range from antagonistic to mutualistic depending on the situation. PMID:23874924

Genome mining of ascomycetous fungi reveals their genetic potential for ergot alkaloid production.

PubMed

Gerhards, Nina; Matuschek, Marco; Wallwey, Christiane; Li, Shu-Ming

2015-06-01

Ergot alkaloids are important as mycotoxins or as drugs. Naturally occurring ergot alkaloids as well as their semisynthetic derivatives have been used as pharmaceuticals in modern medicine for decades. We identified 196 putative ergot alkaloid biosynthetic genes belonging to at least 31 putative gene clusters in 31 fungal species by genome mining of the 360 available genome sequences of ascomycetous fungi with known proteins. Detailed analysis showed that these fungi belong to the families Aspergillaceae, Clavicipitaceae, Arthrodermataceae, Helotiaceae and Thermoascaceae. Within the identified families, only a small number of taxa are represented. Literature search revealed a large diversity of ergot alkaloid structures in different fungi of the phylum Ascomycota. However, ergot alkaloid accumulation was only observed in 15 of the sequenced species. Therefore, this study provides genetic basis for further study on ergot alkaloid production in the sequenced strains.

Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed

USDA-ARS?s Scientific Manuscript database

Ergot-induced disease has been known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mit...

Rapid Screening of Ergot Alkaloids in Sclerotia by MALDI-TOF Mass Spectrometry.

PubMed

Sivagnanam, Kumaran; Komatsu, Emy; Patrick, Susan; Rampitsch, Christoph; Perreault, Hélène; Gräfenhan, Tom

2016-07-01

Ergot is a common disease of wheat and other cereal grains that is predominantly caused by Claviceps purpurea in the field, often affecting crop yield in addition to the environment. Infected grain can be contaminated with dark sclerotia, which contain fungal metabolites such as ergot alkaloids. The occurrence of ergot alkaloids in cereal grain is a major health concern for humans and livestock. Effective and rapid screening of these mycotoxins is crucial for producers, processors, and consumers of cereal-based food and feed grain. Established methods of ergot alkaloid screening based on LC-MS or GC-MS require laborious processes. A novel method using matrix-assisted laser desorption ionization (MALDI)-time-of-flight (TOF) MS was developed to identify four ergot alkaloids. Using dihydroxybenzoic acid as the matrix, ergosine, ergocornine, ergocryptine, and ergocristine were readily detected in individual sclerotia of C. purpurea. The accuracy of the identified ergot alkaloids was further confirmed by tandem MS analysis. MALDI-TOF MS is suitable for high-throughput screening of ergot alkaloids because it permits rapid and accurate identification, simple sample preparation, and no derivatization or chromatographic separation.

Cytotoxicity and accumulation of ergot alkaloids in human primary cells.

PubMed

Mulac, Dennis; Humpf, Hans-Ulrich

2011-04-11

Ergot alkaloids are secondary metabolites produced by fungi of the species Claviceps. Toxic effects after consumption of contaminated grains are described since mediaeval times. Of the more than 40 known ergot alkaloids six are found predominantly. These are ergotamine, ergocornine, ergocryptine, ergocristine, ergosine and ergometrine, along with their corresponding isomeric forms (-inine-forms). Toxic effects are known to be induced by an interaction of the ergot alkaloids as neurotransmitters, like dopamine or serotonin. Nevertheless data concerning cytotoxic effects are missing and therefore a screening of the six main ergot alkaloids was performed in human primary cells in order to evaluate the toxic potential. As it is well known that ergot alkaloids isomerize easily the stability was tested in the cell medium. Based on these results factors were calculated to correct the used concentration values to the biologically active lysergic (-ine) form. These factors range from 1.4 for the most stable compound ergometrine to 5.0 for the most unstable ergot alkaloid ergocristine. With these factors, reflecting the instability, several controverse literature data concerning the toxicity could be explained. To evaluate the cytotoxic effects of ergot alkaloids, human cells in primary culture were used. These cells remain unchanged in contrast to cell lines and the data allow a better comparison to the in vivo situation than using immortalized cell lines. To characterize the effects on primary cells, renal proximal tubule epithelial cells (RPTEC) and normal human astrocytes (NHA) were used. The parameters necrosis (LDH-release) and apoptosis (caspase-3-activation, DNA condensation and fragmentation) were distinguished. The results show that depending on the individual structure of the peptide ergot alkaloids the toxic properties change. While ergometrine as a lysergic acid amide did not show any effect, the peptide ergot alkaloids revealed a different toxic potential. Of all tested ergot alkaloids ergocristine was the most cytotoxic compound inducing apoptosis in human kidney cells starting at a concentration of 1μM in RPTEC. Uptake studies underline the cytotoxic properties, with an accumulation of peptide ergot alkaloids and no uptake of ergometrine. The results represent a new description of effects of ergot alkaloids regarding cytotoxicity and accumulation in human primary cells. For the first time apoptosis has been identified besides well described receptor effects. This gives a hint for a more complex mode of action of ergot alkaloids than described in literature so far. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Identification and characterization of the ergochrome gene cluster in the plant pathogenic fungus Claviceps purpurea.

PubMed

Neubauer, Lisa; Dopstadt, Julian; Humpf, Hans-Ulrich; Tudzynski, Paul

2016-01-01

Claviceps purpurea is a phytopathogenic fungus infecting a broad range of grasses including economically important cereal crop plants. The infection cycle ends with the formation of the typical purple-black pigmented sclerotia containing the toxic ergot alkaloids. Besides these ergot alkaloids little is known about the secondary metabolism of the fungus. Red anthraquinone derivatives and yellow xanthone dimers (ergochromes) have been isolated from sclerotia and described as ergot pigments, but the corresponding gene cluster has remained unknown. Fungal pigments gain increasing interest for example as environmentally friendly alternatives to existing dyes. Furthermore, several pigments show biological activities and may have some pharmaceutical value. This study identified the gene cluster responsible for the synthesis of the ergot pigments. Overexpression of the cluster-specific transcription factor led to activation of the gene cluster and to the production of several known ergot pigments. Knock out of the cluster key enzyme, a nonreducing polyketide synthase, clearly showed that this cluster is responsible for the production of red anthraquinones as well as yellow ergochromes. Furthermore, a tentative biosynthetic pathway for the ergot pigments is proposed. By changing the culture conditions, pigment production was activated in axenic culture so that high concentration of phosphate and low concentration of sucrose induced pigment syntheses. This is the first functional analysis of a secondary metabolite gene cluster in the ergot fungus besides that for the classical ergot alkaloids. We demonstrated that this gene cluster is responsible for the typical purple-black color of the ergot sclerotia and showed that the red and yellow ergot pigments are products of the same biosynthetic pathway. Activation of the gene cluster in axenic culture opened up new possibilities for biotechnological applications like the dye production or the development of new pharmaceuticals.

An old yellow enzyme gene controls the branch point between Aspergillus fumigatus and Claviceps purpurea ergot alkaloid pathways.

PubMed

Coyle, Christine M; Cheng, Johnathan Z; O'Connor, Sarah E; Panaccione, Daniel G

2010-06-01

Ergot fungi in the genus Claviceps and several related fungal groups in the family Clavicipitaceae produce toxic ergot alkaloids. These fungi produce a variety of ergot alkaloids, including clavines as well as lysergic acid derivatives. Ergot alkaloids are also produced by the distantly related, opportunistic human pathogen Aspergillus fumigatus. However, this fungus produces festuclavine and fumigaclavines A, B, and C, which collectively differ from clavines of clavicipitaceous fungi in saturation of the last assembled of four rings in the ergoline ring structure. The two lineages are hypothesized to share early steps of the ergot alkaloid pathway before diverging at some point after the synthesis of the tricyclic intermediate chanoclavine-I. Disruption of easA, a gene predicted to encode a flavin-dependent oxidoreductase of the old yellow enzyme class, in A. fumigatus led to accumulation of chanoclavine-I and chanoclavine-I-aldehyde. Complementation of the A. fumigatus easA mutant with a wild-type allele from the same fungus restored the wild-type profile of ergot alkaloids. These data demonstrate that the product of A. fumigatus easA is required for incorporation of chanoclavine-I-aldehyde into more-complex ergot alkaloids, presumably by reducing the double bond conjugated to the aldehyde group, thus facilitating ring closure. Augmentation of the A. fumigatus easA mutant with a homologue of easA from Claviceps purpurea resulted in accumulation of ergot alkaloids typical of clavicipitaceous fungi (agroclavine, setoclavine, and its diastereoisomer isosetoclavine). These data indicate that functional differences in the easA-encoded old yellow enzymes of A. fumigatus and C. purpurea result in divergence of their respective ergot alkaloid pathways.

An Old Yellow Enzyme Gene Controls the Branch Point between Aspergillus fumigatus and Claviceps purpurea Ergot Alkaloid Pathways▿

PubMed Central

Coyle, Christine M.; Cheng, Johnathan Z.; O'Connor, Sarah E.; Panaccione, Daniel G.

2010-01-01

Ergot fungi in the genus Claviceps and several related fungal groups in the family Clavicipitaceae produce toxic ergot alkaloids. These fungi produce a variety of ergot alkaloids, including clavines as well as lysergic acid derivatives. Ergot alkaloids are also produced by the distantly related, opportunistic human pathogen Aspergillus fumigatus. However, this fungus produces festuclavine and fumigaclavines A, B, and C, which collectively differ from clavines of clavicipitaceous fungi in saturation of the last assembled of four rings in the ergoline ring structure. The two lineages are hypothesized to share early steps of the ergot alkaloid pathway before diverging at some point after the synthesis of the tricyclic intermediate chanoclavine-I. Disruption of easA, a gene predicted to encode a flavin-dependent oxidoreductase of the old yellow enzyme class, in A. fumigatus led to accumulation of chanoclavine-I and chanoclavine-I-aldehyde. Complementation of the A. fumigatus easA mutant with a wild-type allele from the same fungus restored the wild-type profile of ergot alkaloids. These data demonstrate that the product of A. fumigatus easA is required for incorporation of chanoclavine-I-aldehyde into more-complex ergot alkaloids, presumably by reducing the double bond conjugated to the aldehyde group, thus facilitating ring closure. Augmentation of the A. fumigatus easA mutant with a homologue of easA from Claviceps purpurea resulted in accumulation of ergot alkaloids typical of clavicipitaceous fungi (agroclavine, setoclavine, and its diastereoisomer isosetoclavine). These data indicate that functional differences in the easA-encoded old yellow enzymes of A. fumigatus and C. purpurea result in divergence of their respective ergot alkaloid pathways. PMID:20435769

Detection of Total Ergot Alkaloids in Cereal Flour and in Bread by a Generic Enzyme Immunoassay Method.

PubMed

Gross, Madeleine; Curtui, Valeriu; Usleber, Ewald

2018-05-01

Four sets of polyclonal antibodies against ergot alkaloids ergometrine, ergotamine, α-ergocryptine, and ergocornine were produced and characterized in a competitive direct or indirect enzyme immunoassay (EIA). Standard curve LODs were 0.03 ng/mL (ergometrine EIA) to 2.0 ng/mL (ergocornine EIA). Three EIAs were highly specific, whereas the ergometrine EIA had a broad specificity pattern and reacted, albeit weakly, with all seven major ergot alkaloids and their epimeric forms. Using the ergometrine EIA, a generic test system was established in which total ergot alkaloids are quantified by a standard curve for a toxin mixture composed of three alkaloids that matched the ergot alkaloid composition in naturally contaminated rye and wheat products. Sample extraction with acetonitrile-phosphate-buffered saline at pH 6.0 without further cleanup was sufficient for EIA analysis. The LODs for total ergot alkaloids were 20 ng/g in rye and wheat flour and 14 ng/g in bread. Recoveries were 85-110% (RSDs of 0.1-11.7%) at a concentration range of 50-1000 ng/g. The total ergot alkaloid EIA was validated by comparison with HPLC-fluorescence detection. Although some under- and overestimation by the total ergot alkaloid EIA was observed, it was suitable for the reliable identification of positive samples at 10-20 ng/g and for the determination of total ergot alkaloids in a concentration range between 100 and 1000 ng/g.

Ergot Alkaloids of the Family Clavicipitaceae.

PubMed

Florea, Simona; Panaccione, Daniel G; Schardl, Christopher L

2017-05-01

Ergot alkaloids are highly diverse in structure, exhibit diverse effects on animals, and are produced by diverse fungi in the phylum Ascomycota, including pathogens and mutualistic symbionts of plants. These mycotoxins are best known from the fungal family Clavicipitaceae and are named for the ergot fungi that, through millennia, have contaminated grains and caused mass poisonings, with effects ranging from dry gangrene to convulsions and death. However, they are also useful sources of pharmaceuticals for a variety of medical purposes. More than a half-century of research has brought us extensive knowledge of ergot-alkaloid biosynthetic pathways from common early steps to several taxon-specific branches. Furthermore, a recent flurry of genome sequencing has revealed the genomic processes underlying ergot-alkaloid diversification. In this review, we discuss the evolution of ergot-alkaloid biosynthesis genes and gene clusters, including roles of gene recruitment, duplication and neofunctionalization, as well as gene loss, in diversifying structures of clavines, lysergic acid amides, and complex ergopeptines. Also reviewed are prospects for manipulating ergot-alkaloid profiles to enhance suitability of endophytes for forage grasses.

Ergot Alkaloids of the Family Clavicipitaceae

PubMed Central

Florea, Simona; Panaccione, Daniel G.; Schardl, Christopher L.

2017-01-01

Ergot alkaloids are highly diverse in structure, exhibit diverse effects on animals, and are produced by diverse fungi in the phylum Ascomycota, including pathogens and mutualistic symbionts of plants. These mycotoxins are best known from the fungal family Clavicipitaceae and are named for the ergot fungi that, through millennia, have contaminated grains and caused mass poisonings, with effects ranging from dry gangrene to convulsions and death. However, they are also useful sources of pharmaceuticals for a variety of medical purposes. More than a half-century of research has brought us extensive knowledge of ergot-alkaloid biosynthetic pathways from common early steps to several taxon-specific branches. Furthermore, a recent flurry of genome sequencing has revealed the genomic processes underlying ergot-alkaloid diversification. In this review, we discuss the evolution of ergot-alkaloid biosynthesis genes and gene clusters, including roles of gene recruitment, duplication and neofunctionalization, as well as gene loss, in diversifying structures of clavines, lysergic acid amides, and complex ergopeptines. Also reviewed are prospects for manipulating ergot-alkaloid profiles to enhance suitability of endophytes for forage grasses. PMID:28168931

Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed

NASA Astrophysics Data System (ADS)

Craig, A.; Klotz, James; Duringer, Jennifer

2015-02-01

Ergot-induced disease was known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mitigate migraine headaches and have had indications as anticarcinogens. Although ergot alkaloids have been used for centuries, basic pharmacokinetic data has not been documented for clinical disease. Consequently, a threshold dose and accurate dose-response data have yet to be established. Throughout the past several years, new detection techniques have emerged to detect these alkaloids at the parts per billion which have allowed for new efforts to be made with respect to determining threshold levels and making accurate clinical diagnoses. This perspectives article provides a critical initial step for establishing a uniform interpretation of ergot toxicosis from limited existing data.

Effect of feeding sorghum ergot (Claviceps africana) to sows during mid-lactation on plasma prolactin and litter performance.

PubMed

Kopinski, J S; Blaney, B J; Murray, S-A; Downing, J A

2008-10-01

Diets containing 3% sorghum ergot (16 mg alkaloids/kg, including 14 mg dihydroergosine/kg) were fed to 12 sows from 14 days post-farrowing until weaning 14 days later, and their performance was compared with that of 10 control sows. Ergot-fed sows displayed a smaller weight loss during lactation of 24 kg/head vs. 29 kg/head in control sows (p > 0.05) despite feed consumption being less (61 kg/head total feed intake vs. 73 kg/head by control sows; p < 0.05). Ergot-fed sows had poorer weight gain of litters over the 14-day period (16.6 kg/litter vs. 28.3 kg/litter for controls; p < 0.05) despite an increase in consumption of creep feed by the piglets from the ergot-fed sows (1.9 kg/litter compared with 1.1 kg/litter by the control; p > 0.05). Sow plasma prolactin was reduced with ergot feeding after 7 days to 4.8 microg/l compared with 15.1 microg/l in the control sows (p < 0.01) and then at weaning was 4.9 microg/l compared with 8.0 microg/l (p < 0.01) in the control sows. Two sows fed ergot ceased lactation early, and the above sow feed intakes, body weight losses with litter weight gains and creep consumption indirectly indicate an ergot effect on milk production.

Tall fescue seed extraction and partial purification of ergot alkaloids

USDA-ARS?s Scientific Manuscript database

Many substances in the tall fescue/endophyte association (Schedonorus arundinaceus/Epichloë coenophiala) have biological activity. Of these compounds only the ergot alkaloids are known to have significant mammalian toxicity and the predominant ergot alkaloids are ergovaline and ergovalinine. Because...

Ergot cluster-encoded catalase is required for synthesis of chanoclavine-I in Aspergillus fumigatus.

PubMed

Goetz, Kerry E; Coyle, Christine M; Cheng, Johnathan Z; O'Connor, Sarah E; Panaccione, Daniel G

2011-06-01

Genes required for ergot alkaloid biosynthesis are clustered in the genomes of several fungi. Several conserved ergot cluster genes have been hypothesized, and in some cases demonstrated, to encode early steps of the pathway shared among fungi that ultimately make different ergot alkaloid end products. The deduced amino acid sequence of one of these conserved genes (easC) indicates a catalase as the product, but a role for a catalase in the ergot alkaloid pathway has not been established. We disrupted easC of Aspergillus fumigatus by homologous recombination with a truncated copy of that gene. The resulting mutant (ΔeasC) failed to produce the ergot alkaloids typically observed in A. fumigatus, including chanoclavine-I, festuclavine, and fumigaclavines B, A, and C. The ΔeasC mutant instead accumulated N-methyl-4-dimethylallyltryptophan (N-Me-DMAT), an intermediate recently shown to accumulate in Claviceps purpurea strains mutated at ccsA (called easE in A. fumigatus) (Lorenz et al. Appl Environ Microbiol 76:1822-1830, 2010). A ΔeasE disruption mutant of A. fumigatus also failed to accumulate chanoclavine-I and downstream ergot alkaloids and, instead, accumulated N-Me-DMAT. Feeding chanoclavine-I to the ΔeasC mutant restored ergot alkaloid production. Complementation of either ΔeasC or ΔeasE mutants with the respective wild-type allele also restored ergot alkaloid production. The easC gene was expressed in Escherichia coli, and the protein product displayed in vitro catalase activity with H(2)O(2) but did not act, in isolation, on N-Me-DMAT as substrate. The data indicate that the products of both easC (catalase) and easE (FAD-dependent oxidoreductase) are required for conversion of N-Me-DMAT to chanoclavine-I.

Ergot Alkaloid Biosynthesis in the Maize (Zea mays) Ergot Fungus Claviceps gigantea.

PubMed

Bragg, Paige E; Maust, Matthew D; Panaccione, Daniel G

2017-12-13

Biosynthesis of the dihydrogenated forms of ergot alkaloids is of interest because many of the ergot alkaloids used as pharmaceuticals may be derived from dihydrolysergic acid (DHLA) or its precursor dihydrolysergol. The maize (Zea mays) ergot pathogen Claviceps gigantea has been reported to produce dihydrolysergol, a hydroxylated derivative of the common ergot alkaloid festuclavine. We hypothesized expression of C. gigantea cloA in a festuclavine-accumulating mutant of the fungus Neosartorya fumigata would yield dihydrolysergol because the P450 monooxygenase CloA from other fungi performs similar oxidation reactions. We engineered such a strain, and high performance liquid chromatography and liquid chromatography-mass spectrometry analyses demonstrated the modified strain produced DHLA, the fully oxidized product of dihydrolysergol. Accumulation of high concentrations of DHLA in field-collected C. gigantea sclerotia and discovery of a mutation in the gene lpsA, downstream from DHLA formation, supported our finding that DHLA rather than dihydrolysergol is the end product of the C. gigantea pathway.

Lactam ergot alkaloids (ergopeptams) as predominant alkaloids in sclerotia of Claviceps purpurea from Norwegian wild grasses.

PubMed

Uhlig, Silvio; Petersen, Dirk

2008-07-01

Four major alkaloids in the extracts from sclerotia of Claviceps purpurea, picked from wild grasses, have been identified as lactam (non-cyclol) ergot alkaloids. The structural information was obtained from ion trap MS and NMR spectroscopy. The data for one of the lactam ergot alkaloids were coinciding with ergocristam [N-(lysergyl-valyl)-cyclo(phenylalanyl-prolyl)]. The structural information of two further lactam alkaloids was suggestive of either alpha- or beta-ergocryptam [N-(lysergyl-valyl)-cyclo(leucyl-prolyl) or N-(lysergyl-valyl)-cyclo(isoleucyl-prolyl)] and ergoannam [N-(lysergyl-leucyl)-cyclo(leucyl-prolyl) or N-(lysergyl-isoleucyl)-cyclo(isoleucyl-prolyl)]. The constitution of the fourth lactam ergot alkaloid corresponded to N-(lysergyl-isoleucyl)-cyclo(phenylalanyl-prolyl), a new ergopeptam, which has not been described before. Additionally, the cyclol-analogue of the new ergopeptam was detected in the extracts and has been identified on the basis of its product ion spectrum from fragmentation of [M+H](+). The study described in this paper shows that lactam ergot alkaloids may not only be minor products of ergopeptine biosynthesis, as has been suggested hitherto, but may be major biosynthetic endproducts for some ergot strains. This is also the first report demonstrating the production of an ergot alkaloid that contains isoleucine as the second amino acid, i.e. the N-(lysergyl-isoleucyl)-moiety, by parasitic, naturally growing C. purpurea. This unusual type of ergot alkaloid has so far only been found in saprophytic cultures of C. purpurea.

One hundred million year old ergot: psychotropic compounds in the Cretaceous?

USDA-ARS?s Scientific Manuscript database

A fungal sclerotium similar to sclerotia of the genus Claviceps, commonly known as ergot, was found infecting a grass kernel in Early Cretaceous Myanmar amber. This represents the first fossil record of ergot dating as far back as the Cretaceous period. The fungus, described as Palaeoclaviceps para...

Vasoconstrictive responses of the testicular and caudal arteries in bulls exposed to ergot alkaloids from tall fescue

USDA-ARS?s Scientific Manuscript database

Color Doppler ultasonography was used to evaluate vasoconstrictive responses of the testicular artery in yearling bulls to ergot alkaloids. Ergot alkaloid-induced constriction of the testicular artery could disrupt thermoregulation of the testes and reduce bull fertility. Luminal areas of the test...

Recent investigations of ergot alkaloids incorporated into plant and/or animal systems

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by fungi have a basic chemical structure but different chemical moieties at substituent sites resulting in various forms of alkaloids that are distinguishable from one another. Since the ergoline ring structure found in ergot alkaloids is similar to that of biogenic amines (...

Biology, Genetics, and Management of Ergot (Claviceps spp.) in Rye, Sorghum, and Pearl Millet

PubMed Central

Miedaner, Thomas; Geiger, Hartwig H.

2015-01-01

Ergot is a disease of cereals and grasses caused by fungi in the genus Claviceps. Of particular concern are Claviceps purpurea in temperate regions, C. africana in sorghum (worldwide), and C. fusiformis in pearl millet (Africa, Asia). The fungi infect young, usually unfertilized ovaries, replacing the seeds by dark mycelial masses known as sclerotia. The percentage of sclerotia in marketable grain is strictly regulated in many countries. In winter rye, ergot has been known in Europe since the early Middle Ages. The alkaloids produced by the fungus severely affect the health of humans and warm-blooded animals. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility. Plant traits reducing ergot infection include immediate pollination of receptive stigmas, closed flowering (cleistogamy), and physiological resistance. Genetic, nonpollen-mediated variation in ergot susceptibility could be demonstrated in all three affected cereals. Fungicides have limited efficacy and application is weather dependent. Sorting out the sclerotia from the harvest by photocells is expensive and time consuming. In conclusion, molecular-based hybrid rye breeding could improve pollen fertility by introgressing effective restorer genes thus bringing down the ergot infection level to that of conventional population cultivars. A further reduction might be feasible in the future by selecting more resistant germplasm. PMID:25723323

Biology, genetics, and management of ergot (Claviceps spp.) in rye, sorghum, and pearl millet.

PubMed

Miedaner, Thomas; Geiger, Hartwig H

2015-02-25

Ergot is a disease of cereals and grasses caused by fungi in the genus Claviceps. Of particular concern are Claviceps purpurea in temperate regions, C. africana in sorghum (worldwide), and C. fusiformis in pearl millet (Africa, Asia). The fungi infect young, usually unfertilized ovaries, replacing the seeds by dark mycelial masses known as sclerotia. The percentage of sclerotia in marketable grain is strictly regulated in many countries. In winter rye, ergot has been known in Europe since the early Middle Ages. The alkaloids produced by the fungus severely affect the health of humans and warm-blooded animals. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility. Plant traits reducing ergot infection include immediate pollination of receptive stigmas, closed flowering (cleistogamy), and physiological resistance. Genetic, nonpollen-mediated variation in ergot susceptibility could be demonstrated in all three affected cereals. Fungicides have limited efficacy and application is weather dependent. Sorting out the sclerotia from the harvest by photocells is expensive and time consuming. In conclusion, molecular-based hybrid rye breeding could improve pollen fertility by introgressing effective restorer genes thus bringing down the ergot infection level to that of conventional population cultivars. A further reduction might be feasible in the future by selecting more resistant germplasm.

Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity

PubMed Central

Mulac, Dennis; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

2012-01-01

Scope Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. Methods and results In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-brain barrier in a well established in vitro model system using primary porcine brain endothelial cells. It could clearly be demonstrated that ergot alkaloids are able to cross the blood-brain barrier in high quantities in only a few hours. We could further identify an active transport for ergometrine as a substrate for the BCRP/ABCG2 transporter. Investigations concerning barrier integrity properties have identified ergocristinine as a potent substance to accumulate in these cells ultimately leading to a weakened barrier function. Conclusion For the first time we could show that the so far as biologically inactive described 8-(S) isomers of ergot alkaloids seem to have an influence on barrier integrity underlining the necessity for a risk assessment of ergot alkaloids in food and feed. PMID:22147614

Ergot alkaloid intoxication in perennial ryegrass (Lolium perenne): an emerging animal health concern in Ireland?

PubMed

Canty, Mary J; Fogarty, Ursula; Sheridan, Michael K; Ensley, Steve M; Schrunk, Dwayne E; More, Simon J

2014-01-01

Four primary mycotoxicosis have been reported in livestock caused by fungal infections of grasses or cereals by members of the Clavicipitaceae family. Ergotism (generally associated with grasses, rye, triticale and other grains) and fescue toxicosis (associated with tall fescue grass, Festuca arundinacea) are both caused by ergot alkaloids, and referred to as 'ergot alkaloid intoxication'. Ryegrass staggers (associated with perennial ryegrass Lolium perenne) is due to intoxication with an indole-diperpene, Lolitrem B, and metabolites. Fescue-associated oedema, recently described in Australia, may be associated with a pyrrolizidine alkaloid, N-acetyl norloline. Ergotism, caused by the fungus Claviceps purpurea, is visible and infects the outside of the plant seed. Fescue toxicosis and ryegrass staggers are caused by Neotyphodium coenophalium and N. lolii, respectively. Fescue-associated oedema has been associated with tall fescue varieties infected with a specific strain of N. coenophialum (AR542, Max P or Max Q). The name Neotyphodium refers to asexual derivatives of Epichloë spp., which have collectively been termed the epichloë fungi. These fungi exist symbiotically within the grass and are invisible to the naked eye. The primary toxicological effect of ergot alkaloid involves vasoconstriction and/or hypoprolactinaemia. Ingestion of ergot alkaloid by livestock can cause a range of effects, including poor weight gain, reduced fertility, hyperthermia, convulsions, gangrene of the extremities, and death. To date there are no published reports, either internationally or nationally, reporting ergot alkaloid intoxication specifically associated with perennial ryegrass endophytes. However, unpublished reports from the Irish Equine Centre have identified a potential emerging problem of ergot alkaloid intoxication with respect to equines and bovines, on primarily perennial ryegrass-based diets. Ergovaline has been isolated in varying concentrations in the herbage of a small number of equine and bovine farms where poor animal health and performance had been reported. Additionally, in some circumstances changes to the diet, where animals were fed primarily herbage, were sufficient to reverse adverse effects. Pending additional information, these results suggest that Irish farm advisors and veterinarians should be aware of the potential adverse role on animal health and performance of ergot alkaloids from perennial ryegrass infected with endophytic fungi.

Ergot alkaloid intoxication in perennial ryegrass (Lolium perenne): an emerging animal health concern in Ireland?

PubMed Central

2014-01-01

Four primary mycotoxicosis have been reported in livestock caused by fungal infections of grasses or cereals by members of the Clavicipitaceae family. Ergotism (generally associated with grasses, rye, triticale and other grains) and fescue toxicosis (associated with tall fescue grass, Festuca arundinacea) are both caused by ergot alkaloids, and referred to as ‘ergot alkaloid intoxication’. Ryegrass staggers (associated with perennial ryegrass Lolium perenne) is due to intoxication with an indole-diperpene, Lolitrem B, and metabolites. Fescue-associated oedema, recently described in Australia, may be associated with a pyrrolizidine alkaloid, N-acetyl norloline. Ergotism, caused by the fungus Claviceps purpurea, is visible and infects the outside of the plant seed. Fescue toxicosis and ryegrass staggers are caused by Neotyphodium coenophalium and N. lolii, respectively. Fescue-associated oedema has been associated with tall fescue varieties infected with a specific strain of N. coenophialum (AR542, Max P or Max Q). The name Neotyphodium refers to asexual derivatives of Epichloë spp., which have collectively been termed the epichloë fungi. These fungi exist symbiotically within the grass and are invisible to the naked eye. The primary toxicological effect of ergot alkaloid involves vasoconstriction and/or hypoprolactinaemia. Ingestion of ergot alkaloid by livestock can cause a range of effects, including poor weight gain, reduced fertility, hyperthermia, convulsions, gangrene of the extremities, and death. To date there are no published reports, either internationally or nationally, reporting ergot alkaloid intoxication specifically associated with perennial ryegrass endophytes. However, unpublished reports from the Irish Equine Centre have identified a potential emerging problem of ergot alkaloid intoxication with respect to equines and bovines, on primarily perennial ryegrass-based diets. Ergovaline has been isolated in varying concentrations in the herbage of a small number of equine and bovine farms where poor animal health and performance had been reported. Additionally, in some circumstances changes to the diet, where animals were fed primarily herbage, were sufficient to reverse adverse effects. Pending additional information, these results suggest that Irish farm advisors and veterinarians should be aware of the potential adverse role on animal health and performance of ergot alkaloids from perennial ryegrass infected with endophytic fungi. PMID:25295161

Sorghum ergot (Claviceps africana) associated with agalactia and feed refusal in pigs and dairy cattle.

PubMed

Blaney, B J; McKenzie, R A; Walters, J R; Taylor, L F; Bewg, W S; Ryley, M J; Maryam, R

2000-02-01

To establish the aetiology and define the main clinical features of a syndrome characterised by severe feed refusal, death of piglets and reduced milk production in pigs and dairy cattle. Clinical, pathological, toxicological and epidemiological examination of clinical cases in 10 piggeries and 4 dairies, located between 50 and 150 km south-west of Rockhampton. All cases were associated with the feeding of sorghum grain infected with sorghum ergot (Claviceps africana). There was mild to severe feed refusal when the sorghum was first offered. Sows fed ergot before farrowing had shrunken udders, produced no colostrum, and displayed signs of oestrus. All of their piglets died, apparently from starvation: necropsy of a few piglets showed that they were born alive and walked, but had ingested no milk. Sows fed the grain after farrowing had severe reductions in milk production despite aggressive sucking by piglets, leading to very poor growth of piglets. There were no signs of infectious disease. Ergot in sorghum samples ranged from 1 to 31% ergot sclerotes by weight. Total alkaloid concentrations in mixed feeds ranged from 5 to 40 mg/kg, with dihydroergosine accounting for approximately 90%. At the same time, in the same districts, there were reports of feed refusal and reduced milk production from 4 dairy farms. Grain samples from these farms contained up to 17% C africana ergot sclerotia. Agalactia and feed refusal are classical signs of poisoning by rye ergot (C purpurea), but this is the first time that sorghum ergot has been associated with a similar syndrome.

Effect of ergot alkaloids associated with fescue toxicosis on hepatic cytochrome P450 and antioxidant proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Settivari, Raja S.; Evans, Tim J.; Rucker, Ed

Intake of ergot alkaloids found in endophyte-infected tall fescue grass is associated with decreased feed intake and reduction in body weight gain. The liver is one of the target organs of fescue toxicosis with upregulation of genes involved in xenobiotic metabolism and downregulation of genes associated with antioxidant pathways. It was hypothesized that short-term exposure of rats to ergot alkaloids would change hepatic cytochrome P450 (CYP) and antioxidant expression, as well as reduce antioxidant enzyme activity and hepatocellular proliferation rates. Hepatic gene expression of various CYPs, selected nuclear receptors associated with the CYP induction, and antioxidant enzymes were measured usingmore » real-time PCR. Hepatic expression of CYP, antioxidant and proliferating cell nuclear antigen (PCNA) proteins were measured using Western blots. The CYP3A1 protein expression was evaluated using primary rat hepatocellular cultures treated with ergovaline, one of the major ergot alkaloids produced by fescue endophyte, in order to assess the direct role of ergot alkaloids in CYP induction. The enzyme activities of selected antioxidants were assayed spectrophotometrically. While hepatic CYP and nuclear receptor expression were increased in ergot alkaloid-exposed rats, the expression and activity of antioxidant enzymes were reduced. This could potentially lead to increased oxidative stress, which might be responsible for the decrease in hepatocellular proliferation after ergot alkaloid exposure. This study demonstrated that even short-term exposure to ergot alkaloids can potentially induce hepatic oxidative stress which can contribute to the pathogenesis of fescue toxicosis.« less

Semiquantitative determination of ergot alkaloids in seed, straw, and digesta samples using a competitive enzyme-linked immunosorbent assay.

PubMed

Schnitzius, J M; Hill, N S; Thompson, C S; Craig, A M

2001-05-01

Ergot alkaloids present in endophyte-infected (E+) tall fescue cause fescue toxicosis and other toxic effects in livestock that consume infected plant tissue, leading to significant financial losses in livestock production each year. The predominant method currently in use for quantifying ergot alkaloid content in plant tissue is through high-performance liquid chromatography (HPLC), which quantifies the amount of ergovaline, one of many ergot alkaloids in E+ plant tissue. The enzyme-linked immunosorbent assay (ELISA) method used in this study detects quantities of nonspecific ergot alkaloids and therefore accounts for greater amounts of the total ergot alkaloid content in E+ tissue than does HPLC. The ELISA can also be used to more expediently analyze a larger number of forage samples without sophisticated and costly analytical equipment and therefore could be more desirable in a diagnostic setting. The purpose of this study was to evaluate the between-day and within-run variability of the ELISA and to determine the binding efficiency of 6 ergot alkaloids to the 15F3.E5 antibody used in the competitive ELISA to ascertain its feasibility as a quick analysis tool for ergot alkaloids. Straw samples had an average coefficient of variation (CV) for concentration of 10.2% within runs and 18.4% between runs, and the seed samples had an average CV for concentration of 13.3% within runs and 24.5% between runs. The grass tissue-based lysergic acid standard curve calculated from the ELISA had an average r2 of 0.99, with a CV of 2.1%. Ergocryptine, ergocristine, ergocornine, and ergotamine tartrate did not bind strongly to the 15F3.E5 antibody because of the presence of large side groups on these molecules, which block their binding to the antibody, whereas ergonovine and ergonovine maleate were bound much more efficiently because of their structural similarity to lysergic acid. Clarified rumen fluid was tested as an additional matrix for use in the ergot alkaloid competitive ELISA to determine whether future livestock metabolism experiments on the postingestion fate of ergot alkaloids in ruminants could utilize this assay as a quick screening tool for the presence of nonspecific ergot alkaloids in rumen fluid. HPLC and ELISA procedures were compared for their ability in determining ergot alkaloid toxicity based on the repeatability of the procedures and on the specific compounds they measure. The ratio of ELISA concentration to HPLC concentration (ergovaline) varied from 2.00 to 2.81 in seed samples and from 0.62 to 8.66 in straw samples, showing no consistent pattern between the 2 methods. Based on the lack of data at present for the identity of the toxin causing endophyte toxicosis and the lack of agreement between the ergovaline HPLC and ELISA analyses for ergot alkaloids, each method is equally valid as an indicator of toxicityand is the best means for determining the quantity of the specific toxin(s) they measure.

Screening and optimization of some inorganic salts for the production of ergot alkaloids from Penicillium species using surface culture fermentation process.

PubMed

Shahid, Memuna Ghafoor; Nadeem, Muhammad; Baig, Shahjehan; Cheema, Tanzeem Akbar; Atta, Saira; Ghafoor, Gul Zareen

2016-03-01

The present study deals with the production of ergot alkaloids from Penicillium commune and Penicillium citrinum, using surface culture fermentation process. Impact of various inorganic salts was tested on the production of ergot alkaloids during the optimization studies of fermentation medium such as impact of various concentration levels of succinic acid, ammonium chloride, MgSO4, FeSO4, ZnSO4, pH and the effect of various incubation time periods was also determined on the production of ergot alkaloids from Penicillium commune and Penicillium citrinum. Highest yield of ergot alkaloids was obtained when Penicillium commune and Penicillium citrinum that were grown on optimum levels of ingredients such as 2 g succinic acid, 1.5 and 2 g NH4Cl, 1.5 g MgSO4, 1 g FeSO4, 1 and 1.5 g ZnSO4 after 21 days of incubation time period using pH 5 at 25(°)C incubation temperature in the fermentation medium. Ergot alkaloids were determined using Spectrophotometry and Thin Layer Chromatography (TLC) techniques.

Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids.

PubMed

Hulvová, Helena; Galuszka, Petr; Frébortová, Jitka; Frébort, Ivo

2013-01-01

Ergot alkaloids produced by the fungus Claviceps parasitizing on cereals, include three major groups: clavine alkaloids, d-lysergic acid and its derivatives and ergopeptines. These alkaloids are important substances for the pharmatech industry, where they are used for production of anti-migraine drugs, uterotonics, prolactin inhibitors, anti-Parkinson agents, etc. Production of ergot alkaloids is based either on traditional field cultivation of ergot-infected rye or on submerged cultures of the fungus in industrial fermentation plants. In 2010, the total production of these alkaloids in the world was about 20,000 kg, of which field cultivation contributed about 50%. This review covers the recent advances in understanding of the genetics and regulation of biosynthesis of ergot alkaloids, focusing on possible applications of the new knowledge to improve the production yield. Copyright © 2012 Elsevier Inc. All rights reserved.

QTL analysis of ergot resistance in sorghum.

PubMed

Parh, D K; Jordan, D R; Aitken, E A B; Mace, E S; Jun-ai, P; McIntyre, C L; Godwin, I D

2008-08-01

Sorghum ergot, caused predominantly by Claviceps africana Frederickson, Mantle, de Milliano, is a significant threat to the sorghum industry worldwide. The objectives of this study were firstly, to identify molecular markers linked to ergot resistance and to two pollen traits, pollen quantity (PQ) and pollen viability (PV), and secondly, to assess the relationship between the two pollen traits and ergot resistance in sorghum. A genetic linkage map of sorghum RIL population R931945-2-2 x IS 8525 (resistance source) was constructed using 303 markers including 36 SSR, 117 AFLP , 148 DArT and two morphological trait loci. Composite interval mapping identified nine, five, and four QTL linked to molecular markers for percentage ergot infection (PCERGOT), PQ and PV, respectively, at a LOD >2.0. Co-location/linkage of QTL were identified on four chromosomes while other QTL for the three traits mapped independently, indicating that both pollen and non pollen-based mechanisms of ergot resistance were operating in this sorghum population. Of the nine QTL identified for PCERGOT, five were identified using the overall data set while four were specific to the group data sets defined by temperature and humidity. QTL identified on SBI-02 and SBI-06 were further validated in additional populations. This is the first report of QTL associated with ergot resistance in sorghum. The markers reported herein could be used for marker-assisted selection for this important disease of sorghum.

Spatial patterns of ergot and quantification of sclerotia in perennial ryegrass seed fields

USDA-ARS?s Scientific Manuscript database

Ergot, caused by Claviceps purpurea, is a major disease of perennial ryegrass grass grown for seed in eastern Oregon. The objective of this research was to quantify and describe the spatial patterns of ergot severity in each of three 50 ha commercial fields of perennial ryegrass grown for seed in 20...

Analysis and modification of ergot alkaloid profiles in fungi.

PubMed

Panaccione, Daniel G; Ryan, Katy L; Schardl, Christopher L; Florea, Simona

2012-01-01

The ergot alkaloids are a family of secondary metabolites produced by a phylogenetically discontinuous group of fungi. Various members of the family are important in agriculture, where they accumulate in grain crops or forage grasses and adversely affect humans or animals who consume them. Other ergot alkaloids have been used clinically to treat a variety of diseases. Because of their significance in agriculture and medicine, the ability to detect and quantify these alkaloids from a variety of substrates is important. The primary analytical approach for these purposes has been high performance liquid chromatography. The ability to manipulate ergot alkaloid production in fungi, by transformation-mediated approaches, has been useful for studies on the biosynthesis of these alkaloids and may have practical application in agriculture and medicine. Such modifications have been informed by comparative genomic approaches, which have provided information on the gene clusters associated with ergot alkaloid biosynthesis. Copyright © 2012 Elsevier Inc. All rights reserved.

[Isolation of the ergot (Claviceps purpurea (Fr.) Tul., strain VKM-F-366D), producing the lactamic alkaloid ergocornam].

PubMed

Komarova, E L; Shain, S S; Sheĭchenko, V I

2002-01-01

A new ergot strain VKM-F-3662D producing lactamic alkaloid ergocornam with concomitant alkaloids valinamide and ergometrine was isolated during selective works with sclerotium MS-462, which was obtained from ergocryptine ergot strain VKM-F-2642D. The structure of these alkaloids was determined by 1H and 13C NMR.

Ergotism related to a single dose of ergotamine tartrate in an AIDS patient treated with ritonavir

PubMed Central

Blanche, P; Rigolet, A; Gombert, B; Ginsburg, C; Salmon, D; Sicard, D

1999-01-01

We report a rare case of ergotism related to a single dose of ergotamine tartrate in a man with AIDS being treated with ritonavir. He was treated with a prostacyclin analogue and made a complete recovery.


Keywords: ergotism; ergotamine tartrate; AIDS; ritonavir; adverse drug reaction; HIV infection PMID:10616689

Genetics, Genomics and Evolution of Ergot Alkaloid Diversity

PubMed Central

Young, Carolyn A.; Schardl, Christopher L.; Panaccione, Daniel G.; Florea, Simona; Takach, Johanna E.; Charlton, Nikki D.; Moore, Neil; Webb, Jennifer S.; Jaromczyk, Jolanta

2015-01-01

The ergot alkaloid biosynthesis system has become an excellent model to study evolutionary diversification of specialized (secondary) metabolites. This is a very diverse class of alkaloids with various neurotropic activities, produced by fungi in several orders of the phylum Ascomycota, including plant pathogens and protective plant symbionts in the family Clavicipitaceae. Results of comparative genomics and phylogenomic analyses reveal multiple examples of three evolutionary processes that have generated ergot-alkaloid diversity: gene gains, gene losses, and gene sequence changes that have led to altered substrates or product specificities of the enzymes that they encode (neofunctionalization). The chromosome ends appear to be particularly effective engines for gene gains, losses and rearrangements, but not necessarily for neofunctionalization. Changes in gene expression could lead to accumulation of various pathway intermediates and affect levels of different ergot alkaloids. Genetic alterations associated with interspecific hybrids of Epichloë species suggest that such variation is also selectively favored. The huge structural diversity of ergot alkaloids probably represents adaptations to a wide variety of ecological situations by affecting the biological spectra and mechanisms of defense against herbivores, as evidenced by the diverse pharmacological effects of ergot alkaloids used in medicine. PMID:25875294

Effect of acute exposure to ergot alkaloids on short-chain fatty acid absorption and barrier function of isolated bovine ruminal epithelium

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids present in endophyte-infected tall fescue are the causative agents for fescue toxicosis in cattle. Ergot alkaloids have been shown to cause a reduction in blood flow to the rumen epithelium as well as a decrease in short-chain fatty acid (SCFA) absorption from the washed rumen of ste...

The history of ergot of rye (Claviceps purpurea) II: 1900-1940.

PubMed

Lee, M R

2009-12-01

Ergot, in 1900, was a 'chemical mess'. Henry Wellcome, the pharmaceutical manufacturer, invited Henry Hallett Dale, a physiologist, to join his research department and solve this problem. Dale, in turn, recruited an outstanding group of scientists, including George Barger, Arthur Ewins and Harold Dudley, who would make distinguished contributions not only to the chemistry of ergot but also to the identification of acetylcholine, histamine and tyramine and to studies on their physiological effects. Initially Barger and Dale isolated the compound ergotoxine, but this proved to be a false lead; it was later shown to be a mixture of three different ergot alkaloids. The major success of the Wellcome group was the discovery and isolation of ergometrine, which would prove to be life-saving in postpartum haemorrhage. In 1917 Arthur Stoll and his colleagues started work on ergot at Sandoz Pharmaceuticals in Basel. A series of important results emerged over the next 30 years, including the isolation of ergotamine in 1918, an effective treatment for migraine with aura.

Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories.

PubMed

Steiner, Ulrike; Leistner, Eckhard

2018-03-02

Naturally occurring and semisynthetic ergot alkaloids play a role in health care or as recreational drugs in Western and indigenous Mexican societies. Evidence is summarized that ergot alkaloids present in Central American Convolvulaceae like Turbina corymbosa, Ipomoea violacea , and Ipomoea asarifolia are colonized by different species of a newly described clavicipitaceous fungal genus named Periglandula . The fungi are associated with peltate glandular trichomes on the adaxial leaf surface of its host plants. The Periglandula fungi are not yet culturable in vitro but were demonstrated to have the capacity to synthesize ergot alkaloids. The alkaloids do not remain in the fungal mycelium but are translocated via the glandular trichomes into their plant host. Both fungi and host benefit from a symbiotic lifestyle. In evolutionary terms the alkaloid biosynthetic gene cluster in the Periglandula/Ipomoea symbiosis is likely to have a conserved (basic) structure while biosynthetic ergot gene clusters within the genera Claviceps and Epichloe were under ecological selection for alkaloid diversification. Georg Thieme Verlag KG Stuttgart · New York.

The ergot alkaloid gene cluster: functional analyses and evolutionary aspects.

PubMed

Lorenz, Nicole; Haarmann, Thomas; Pazoutová, Sylvie; Jung, Manfred; Tudzynski, Paul

2009-01-01

Ergot alkaloids and their derivatives have been traditionally used as therapeutic agents in migraine, blood pressure regulation and help in childbirth and abortion. Their production in submerse culture is a long established biotechnological process. Ergot alkaloids are produced mainly by members of the genus Claviceps, with Claviceps purpurea as best investigated species concerning the biochemistry of ergot alkaloid synthesis (EAS). Genes encoding enzymes involved in EAS have been shown to be clustered; functional analyses of EAS cluster genes have allowed to assign specific functions to several gene products. Various Claviceps species differ with respect to their host specificity and their alkaloid content; comparison of the ergot alkaloid clusters in these species (and of clavine alkaloid clusters in other genera) yields interesting insights into the evolution of cluster structure. This review focuses on recently published and also yet unpublished data on the structure and evolution of the EAS gene cluster and on the function and regulation of cluster genes. These analyses have also significant biotechnological implications: the characterization of non-ribosomal peptide synthetases (NRPS) involved in the synthesis of the peptide moiety of ergopeptines opened interesting perspectives for the synthesis of ergot alkaloids; on the other hand, defined mutants could be generated producing interesting intermediates or only single peptide alkaloids (instead of the alkaloid mixtures usually produced by industrial strains).

Post-genome research on the biosynthesis of ergot alkaloids.

PubMed

Li, Shu-Ming; Unsöld, Inge A

2006-10-01

Genome sequencing provides new opportunities and challenges for identifying genes for the biosynthesis of secondary metabolites. A putative biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine type, was identified in the genome sequence of ASPERGILLUS FUMIGATUS by a bioinformatic approach. This cluster spans 22 kb of genomic DNA and comprises at least 11 open reading frames (ORFs). Seven of them are orthologous to genes from the biosynthetic gene cluster of ergot alkaloids in CLAVICEPS PURPUREA. Experimental evidence of the identified cluster was provided by heterologous expression and biochemical characterization of two ORFs, FgaPT1 and FgaPT2, in the cluster of A. FUMIGATUS, which show remarkable similarities to dimethylallyltryptophan synthase from C. PURPUREA and function as prenyltransferases. FgaPT2 converts L-tryptophan to dimethylallyltryptophan and thereby catalyzes the first step of ergot alkaloid biosynthesis, whilst FgaPT1 catalyzes the last step of the fumigaclavine C biosynthesis, i. e., the prenylation of fumigaclavine A at C-2 position of the indole nucleus. In addition to information obtained from the gene cluster of ergot alkaloids from C. PURPUREA, the identification of the biosynthetic gene cluster of fumigaclavine C in A. FUMIGATUS opens an alternative way to study the biosynthesis of ergot alkaloids in fungi.

Localization of ergot alkaloids in sclerotia of Claviceps purpurea by matrix-assisted laser desorption/ionization mass spectrometry imaging.

PubMed

Dopstadt, Julian; Vens-Cappell, Simeon; Neubauer, Lisa; Tudzynski, Paul; Cramer, Benedikt; Dreisewerd, Klaus; Humpf, Hans-Ulrich

2017-02-01

The fungus Claviceps purpurea produces highly toxic ergot alkaloids and accumulates these in the hardened bodies of fungal mycelium. These so-called sclerotia, or ergot bodies, replace the crop seed of infected plants, which can include numerous important food- and feedstuff such as rye and wheat. While several studies have explored details of the infection process and development of ergot bodies, little information is available on the spatial distribution of the mycotoxins in the sclerotia. Here we used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) at a lateral resolution of 35 μm to visualize the distribution of two representative alkaloids, ergocristine and ergometrine, produced by Ecc93 and Gal 310 variants of C. purpurea, respectively, after infection of rye. To improve cryosectioning of this fragile biological material tissue with complex texture, we developed a practical embedding protocol based on cellulose polymers. The MALDI-MS images recorded from the so produced intact tissues sections revealed that ergometrine exhibited a relatively homogeneous distribution throughout the ergot body, whereas ergocristine was found to be enriched in the proximal region. This finding can be correlated to the morphological development of sclerotia as ergot alkaloids are only produced in the sphacelial stage. The ability to localize toxins and other secondary metabolites in intact sections of crop-infecting fungi with high lateral resolution renders MALDI-MSI a powerful tool for investigating biosynthetic pathways and for obtaining a deeper understanding of the parasite-host interaction. Graphical abstract Workflow for identification and spatial localization of ergot alkaloids in infected rye grains.

Online detection and quantification of ergot bodies in cereals using near infrared hyperspectral imaging.

PubMed

Vermeulen, Ph; Pierna, J A Fernández; Egmond, H P van; Dardenne, P; Baeten, V

2012-01-01

The occurrence of ergot bodies (sclerotia of Claviceps purpurea) in cereals presents a high toxicity risk for animals and humans due to the alkaloid content. To reduce this risk, the European Commission fixed an ergot concentration limit of 0.1% in all feedstuffs containing unground cereals, and a limit of 0.05% in 'intervention' cereals destined for humans. This study sought to develop a procedure based on near infrared hyperspectral imaging and multivariate image analysis to detect and quantify ergot contamination in cereals. Hyperspectral images were collected using an NIR hyperspectral line scan combined with a conveyor belt. All images consisted of lines of 320 pixels that were acquired at 209 wavelength channels (1100-2400 nm). To test the procedure, several wheat samples with different levels of ergot contamination were prepared. The results showed a correlation higher than 0.99 between the predicted values obtained using chemometric tools such as partial least squares discriminant analysis or support vector machine and the reference values. For a wheat sample with a level of ergot contamination as low as 0.01 %, it was possible to identify groups of pixels detected as ergot to conclude that the sample was contaminated. In addition, no false positives were obtained with non-contaminated samples. The limit of detection was found to be 145 mg/kg and the limit of quantification 341 mg/kg. The reproducibility tests of the measurements performed over several weeks showed that the results were always within the limits allowed. Additional studies were done to optimise the parameters in terms of number of samples analysed per unit of time or conveyor belt speed. It was shown that ergot can be detected using a speed of 1-100 mm/s and that a sample of 250 g can be analysed in 1 min.

Identification of cellular and molecular factors determining the response of cancer cells to six ergot alkaloids.

PubMed

Mrusek, Marco; Seo, Ean-Jeong; Greten, Henry Johannes; Simon, Michael; Efferth, Thomas

2015-02-01

Ergot alkaloids are psychoactive and vasoconstricting agents of the fungus Claviceps purpurea causing poisoning such as ergotism in medieval times (St. Anthony's Fire). This class of substances also inhibits tumor growth in vitro and in vivo, though the underlying mechanisms are unclear as yet. We investigated six ergot alkaloids (agroclavine, ergosterol, ergocornin E, ergotamine, dihydroergocristine, and 1-propylagroclavine tartrate) for their cytotoxicity towards tumor cell lines of the National Cancer Institute, USA. 1-Propylagroclavine tartrate (1-PAT) revealed the strongest cytotoxicity. Out of 76 clinically established anticancer drugs, cross-resistance was found between the ergot alkaloids and 6/7 anti-hormonal drugs (=85.7 %) and 5/15 DNA-alkylating drugs (=33.3 %). The IC50 values for the six alkaloids were not correlated to well-known determinants of drug resistance, such as proliferative activity (as measured by cell doubling times, PCNA expression, and cell cycle distribution), the multidrug resistance-mediating P-glycoprotein/MDR1 and expression or mutations of oncogenes and tumor suppressor genes (EGFR, RAS, TP53). While resistance of control drugs (daunorubicin, cisplatin, erlotinib) correlated with these classical resistance mechanisms, ergot alkaloids did not. Furthermore, COMPARE and hierarchical cluster analyses were performed of mRNA microarray data to identify genes correlating with sensitivity or resistance to 1-PAT. Twenty-three genes were found with different biological functions (signal transducers, RNA metabolism, ribosome constituents, cell cycle and apoptosis regulators etc.). The expression of only 3/66 neuroreceptor genes correlated with the IC50 values for 1-PAT, suggesting that the psychoactive effects of ergot alkaloids may not play a major role for the cytotoxic activity against cancer cells. In conclusion, the cytotoxicity of ergot alkaloids is not involved in classical mechanisms of drug resistance opening the possibility to bypass resistance and to treat otherwise drug-resistant and refractory tumors. The modes of action are multifactorial, which is a typical feature of many natural compounds.

Ergot: from witchcraft to biotechnology.

PubMed

Haarmann, Thomas; Rolke, Yvonne; Giesbert, Sabine; Tudzynski, Paul

2009-07-01

The ergot diseases of grasses, caused by members of the genus Claviceps, have had a severe impact on human history and agriculture, causing devastating epidemics. However, ergot alkaloids, the toxic components of Claviceps sclerotia, have been used intensively (and misused) as pharmaceutical drugs, and efficient biotechnological processes have been developed for their in vitro production. Molecular genetics has provided detailed insight into the genetic basis of ergot alkaloid biosynthesis and opened up perspectives for the design of new alkaloids and the improvement of production strains; it has also revealed the refined infection strategy of this biotrophic pathogen, opening up the way for better control. Nevertheless, Claviceps remains an important pathogen worldwide, and a source for potential new drugs for central nervous system diseases.

Drug dependence associated with triptans and ergot derivatives: a case/non-case study.

PubMed

Beau-Salinas, Frédérique; Jonville-Béra, Annie Pierre; Cissoko, Haware; Bensouda-Grimaldi, Lamiae; Autret-Leca, Elisabeth

2010-04-01

The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database. Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%. Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine. These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Ergotism in Norway. Part 1: The symptoms and their interpretation from the late Iron Age to the seventeenth century.

PubMed

Alm, Torbjørn; Elvevåg, Brita

2013-03-01

Ergotism is a horrendous disease with grotesque symptoms caused by ingesting specific ergot alkaloids. Mass poisoning episodes are attributable to consumption of grain - usually rye - infected with the fungus Claviceps purpurea. By focusing on possible cases of ergotism, we re-examine Norwegian history from the sagas through to the end of the seventeenth century. Our review - not intended to be exhaustive, or ex post facto to assign medical or psychiatric labels - draws attention to the very real possibility that many remarkable medical cases may have been the result of the ingestion of highly poisonous and psychoactive food substances. Where possible we highlight explanations given at the time - often rooted in religion or demonology - to explain the disease.

Evidence that enforced sunlight exposure can cause hyperthermia in cattle ingesting low levels of ergot of rye (Claviceps purpurea), when air temperature and humidity conditions are only moderate.

PubMed

Bourke, C A

2003-09-01

To determine the rectal temperature response of cattle, following the oral administration of ergot of rye (Claviceps purpurea), under pen conditions of enforced sunlight compared with those of enforced shade. Hereford cross steers were divided into two groups of 18. One group was dosed once, on a Monday morning, with finely ground rye grass ergots at a rate of 180 mg/kg body weight and held in the sun for 7 h each day until Friday afternoon. The other group was not dosed but was similarly held in the sun during the same period. Their rectal temperatures were measured early morning and mid afternoon, from Monday to Friday inclusive. The process was repeated for each group, but this time they were held in the shade. The four treatment options were run concurrently by conducting the experiments over 6 weeks and using 3 animals in each treatment group, each week. The thermic response over all weeks, of the ergot treated, sunlight exposed cattle, was deemed greater than for the other groups, based on the following four parameters. The increase in rectal temperature between early morning and mid afternoon, the size of the mid afternoon rectal temperature rise, the difference between the maximum mid afternoon rectal temperature recorded by an animal in the sun compared with that recorded by the same animal in the shade, and finally the number of animals in a treatment group that recorded rectal temperatures > 40.00 degrees C. The difference in the daily increase in body temperature between the ergot treated, sun exposed cattle and the ergot treated, shaded cattle, was greater than that observed between the sun exposed and shade restricted control cattle. Nine of 18 ergot treated and sun exposed cattle developed hyperthermia; no cattle in the other three groups did. Some sunlight exposed cattle, dosed with a low amount of ergot of rye, can experience a body temperature elevation above the normal range, even under mild ambient temperature and humidity conditions. Sunlight exposure causes an increase in body temperature in normal cattle that is probably attributable to solar radiant heat. Ergot ingestion causes an increase in body temperature in shaded cattle that is probably attributable to ambient temperature and humidity effects. This response can be increased by sun exposure and this increase is attributable to solar radiant heat effects and possibly also solar radiation. A response to radiant heat is consistent with the known physiological effects of ingested ergot alkaloids, but a response to solar radiation is not.

Ergot and Its Alkaloids

PubMed Central

Schiff, Paul L.

2006-01-01

This manuscript reviews the history and pharmacognosy of ergot, and describes the isolation/preparation, chemistry, pharmacodynamics, and pharmacotherapeutics of the major ergot alkaloids and their derivatives. A brief discussion of the hallucinogenic properties of lysergic acid diethylamide is also featured. An abbreviated form of the material found in this paper is presented in a 4-hour didactic format to third-professional year PharmD students as part of their study of vascular migraine headaches, Parkinson's disease, and naturally occurring hallucinogens/hallucinogen derivatives in the modular course offering Neurology/Psychiatry. PMID:17149427

Analysis of Ergot Alkaloids

PubMed Central

Crews, Colin

2015-01-01

The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures for ergot alkaloid analysis comprise liquid chromatography with tandem mass spectrometry (LC-MS/MS) and liquid chromatography with fluorescence detection (LC-FLD). Other methods based on immunoassays are under development and variations of these and minor techniques are available for specific purposes. PMID:26046699

21 CFR 310.531 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of...

Code of Federal Regulations, 2013 CFR

2013-04-01

... subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben... aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract...

21 CFR 310.531 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of...

Code of Federal Regulations, 2011 CFR

2011-04-01

... subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben... aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract...

21 CFR 310.531 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of...

Code of Federal Regulations, 2010 CFR

2010-04-01

... subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben... aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract...

21 CFR 310.531 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of...

Code of Federal Regulations, 2012 CFR

2012-04-01

... subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben... aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract...

21 CFR 310.531 - Drug products containing active ingredients offered over-the-counter (OTC) for the treatment of...

Code of Federal Regulations, 2014 CFR

2014-04-01

... subnitrate, calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, ichthammol, isobutamben... aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, cholesterol, ergot fluid extract...

Ergot alkaloids in Norwegian wild grasses: a mass spectrometric approach.

PubMed

Uhlig, Silvio; Vikøren, Turid; Ivanova, Lada; Handeland, Kjell

2007-01-01

Ergot alkaloids are mycotoxins which are produced among fungi in the family Clavicipitaceae. Poisoning with ergot alkaloids is an important veterinary problem in animal husbandry and has recently also been recognised in wild animals. While the poisoning syndrome observed in domestic animals such as cattle, horses and sheep is usually caused by endophyte-infected grass, the recently observed ergotism among Norwegian cervids is probably due to infection of wild grasses with Claviceps. Mass spectrometry is today the method of choice for the rapid qualitative and quantitative determination of many natural compounds. This study uses tandem quadrupole mass spectrometry as well as ion trap mass spectrometry in connection with electrospray(+) ionisation for the quantification, screening and fragmentation of ergot alkaloids in extracts from Claviceps sclerotia that had been picked from wild grasses from several locations in Norway. Ergotamine, ergovaline, ergonovine and ergocryptine were available as standards and were quantified in the extracts, while ergocrystine, ergocornine, ergonine/ergosine, lysergic acid and lysergol were identified on the basis of their molecular weights and semi-quantified. Ergocrystine dominated the alkaloid spectrum of most extracts. Levels of the quantified alkaloids were in the range 0.2-9300 microg/g. Several unknown ergot alkaloids were found in the extracts. MS(n) experiments identified some as simple lysergic acid amide derivatives, while othes are probably related to ergocrystine and ergocryptine by dehydration, dehydrogenation and/or amino acid substitution at R(1) of the peptide moiety.

Improving field production of ergot alkaloids by application of gametocide on rye host plants.

PubMed

Hanosová, Helena; Koprna, Radoslav; Valík, Josef; Knoppová, Lucie; Frébort, Ivo; Dzurová, Lenka; Galuszka, Petr

2015-12-25

Ergot alkaloids are widely used in the pharmaceutical industry in drug preparations for treating migraines and Parkinson's disease, inducing uterine contraction, and other purposes. Phytopathogenic fungi of the genus Claviceps (e.g. C. purpurea) comprise a major biological source of ergot alkaloids. Worldwide industrial production of these alkaloids derives almost equally from two biotechnological procedures: submerged culture of the fungus in fermenters and field parasitic production in dormant fungal organs known as sclerotia (also termed ergot). Ergot yields from field cultivation are greatly affected by weather and also can be much reduced by pollen contamination from imperfectly male-sterile rye, as only unfertilized ovaries can be infected by C. purpurea spores. Two substances with gametocidal effect - maleic hydrazide and 2-chloroethylphosphonic acid - were tested during three consecutive seasons in small field experiments for the ability to induce or amplify the male sterility of rye as well as the impacts on germination of C. purpurea spores and general vitality of rye host plants. Maleic hydrazide was proven to be a highly effective gametocide on both a fertile rye variety and a variety with imperfectly induced cytoplasmic male sterility. It showed negligible effect on germination of C. purpurea spores. Both accurate dosaging of the active gametocidal compound and timing of the application just 2-3 weeks before onset of anthesis proved crucial to achieving high ergot yield with minimum grain impurities. Copyright © 2015 Elsevier B.V. All rights reserved.

Activities and Effects of Ergot Alkaloids on Livestock Physiology and Production

PubMed Central

Klotz, James L.

2015-01-01

Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity to such stressors. This ultimately results in large financial losses in the form of production losses to livestock producers around the world. This review will focus on the underlying physiological mechanisms that are affected by ergot alkaloids that lead to decreases in livestock production. PMID:26226000

Biosynthetic pathways of ergot alkaloids.

PubMed

Gerhards, Nina; Neubauer, Lisa; Tudzynski, Paul; Li, Shu-Ming

2014-12-10

Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes.

Biosynthetic Pathways of Ergot Alkaloids

PubMed Central

Gerhards, Nina; Neubauer, Lisa; Tudzynski, Paul; Li, Shu-Ming

2014-01-01

Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes. PMID:25513893

Exposure to Ergot Alkaloids During Gestation Reduces Fetal Growth in Sheep

NASA Astrophysics Data System (ADS)

Duckett, Susan; Pratt, Scott; Andrae, John

2014-08-01

Tall fescue [Lolium arundinaceum (Schreb.) Darbysh; Schedonorus phoenix (Scop.) Holub] is the primary cool season perennial grass in the eastern U.S. Most tall fescue contains an endophyte (Neotyphodium coenophialum), which produces ergot alkaloids that cause vasoconstriction and could restrict blood flow to the fetus in pregnant animals. The objective of this study was to examine fetal growth during maternal exposure to ergot alkaloids during gestation. Pregnant ewes (n = 16) were randomly assigned to one of two dietary treatments: 1) endophyte-infected (Neotyphodium coenophialum) tall fescue seed (E+; 0.8 ug of ergovaline /g diet DM) and 2) endophyte-free tall fescue seed (E-; 0.0 ug of ergovaline/g diet DM). Birth weight of lambs was reduced by 37% for E+ compared to E-. Organ and muscle weights were also lighter for E+ than E-. Exposure to ergot alkaloids in utero reduces fetal growth and muscle development.

Lysergic acid amide as chemical marker for the total ergot alkaloids in rye flour - Determination by high-performance thin-layer chromatography-fluorescence detection.

PubMed

Oellig, Claudia

2017-07-21

Ergot alkaloids are generally determined by high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FLD) or mass selective detection, analyzing the individual compounds. However, fast and easy screening methods for the determination of the total ergot alkaloid content are more suitable, since for monitoring only the sum of the alkaloids is relevant. The herein presented screening uses lysergic acid amide (LSA) as chemical marker, formed from ergopeptine alkaloids, and ergometrine for the determination of the total ergot alkaloids in rye with high-performance thin-layer chromatography-fluorescence detection (HPTLC-FLD). An ammonium acetate buffered extraction step was followed by liquid-liquid partition for clean-up before the ergopeptine alkaloids were selectively transformed to LSA and analyzed by HPTLC-FLD on silica gel with isopropyl acetate/methanol/water/25% ammonium hydroxide solution (80:10:3.8:1.1, v/v/v/v) as the mobile phase. The enhanced native fluorescence of LSA and unaffected ergometrine was used for quantitation without any interfering matrix. Limits of detection and quantitation were 8 and 26μg LSA/kg rye, which enables the determination of the total ergot alkaloids far below the applied quality criterion limit for rye. Close to 100% recoveries for different rye flours at relevant spiking levels were obtained. Thus, reliable results were guaranteed, and the fast and efficient screening for the total ergot alkaloids in rye offers a rapid alternative to the HPLC analysis of the individual compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional analysis of the gene controlling hydroxylation of festuclavine in the ergot alkaloid pathway of Neosartorya fumigata

PubMed Central

Bilovol, Yulia; Panaccione, Daniel G.

2016-01-01

Bioactive ergot alkaloids produced by several species of fungi are important molecules in agriculture and medicine. Much of the ergot alkaloid pathway has been elucidated, but a few steps, including the gene controlling hydroxylation of festuclavine to fumigaclavine B, remain unsolved. Festuclavine is a key intermediate in the fumigaclavine branch of the ergot alkaloid pathway of the opportunistic pathogen Neosartorya fumigata and also in the dihydrolysergic acid-based ergot alkaloid pathway of certain Claviceps species. Based on several lines of evidence, the N. fumigata gene easM is a logical candidate to encode the festuclavine-hydroxylating enzyme. To test this hypothesis we disrupted easM function by replacing part of its coding sequences with a hygromycin resistance gene and transforming N. fumigata with this construct. High pressure liquid chromatography analysis demonstrated that easM deletion mutants were blocked in the ergot alkaloid pathway at festuclavine, and downstream products were eliminated. An additional alkaloid, proposed to be a prenylated form of festuclavine on the basis of mass spectral data, also accumulated to higher concentrations in the easM knockout. Complementation with the wild-type allele of easM gene restored the ability of the fungus to produce downstream compounds. These results indicate that easM encodes an enzyme required for fumigaclavine B synthesis likely by hydroxylating festuclavine. The festuclavine-accumulating strain of N. fumigata may facilitate future investigations of the biosynthesis of dihydrolysergic acid derivatives, which are derived from festuclavine and are the basis for several important drugs. PMID:26972831

Functional analysis of the gene controlling hydroxylation of festuclavine in the ergot alkaloid pathway of Neosartorya fumigata.

PubMed

Bilovol, Yulia; Panaccione, Daniel G

2016-11-01

Bioactive ergot alkaloids produced by several species of fungi are important molecules in agriculture and medicine. Much of the ergot alkaloid pathway has been elucidated, but a few steps, including the gene controlling hydroxylation of festuclavine to fumigaclavine B, remain unsolved. Festuclavine is a key intermediate in the fumigaclavine branch of the ergot alkaloid pathway of the opportunistic pathogen Neosartorya fumigata and also in the dihydrolysergic acid-based ergot alkaloid pathway of certain Claviceps species. Based on several lines of evidence, the N. fumigata gene easM is a logical candidate to encode the festuclavine-hydroxylating enzyme. To test this hypothesis we disrupted easM function by replacing part of its coding sequences with a hygromycin resistance gene and transforming N. fumigata with this construct. High-pressure liquid chromatography analysis demonstrated that easM deletion mutants were blocked in the ergot alkaloid pathway at festuclavine, and downstream products were eliminated. An additional alkaloid, proposed to be a prenylated form of festuclavine on the basis of mass spectral data, also accumulated to higher concentrations in the easM knockout. Complementation with the wild-type allele of easM gene restored the ability of the fungus to produce downstream compounds. These results indicate that easM encodes an enzyme required for fumigaclavine B synthesis likely by hydroxylating festuclavine. The festuclavine-accumulating strain of N. fumigata may facilitate future investigations of the biosynthesis of dihydrolysergic acid derivatives, which are derived from festuclavine and are the basis for several important drugs.

Clavine Alkaloids Gene Clusters of Penicillium and Related Fungi: Evolutionary Combination of Prenyltransferases, Monooxygenases and Dioxygenases

PubMed Central

Martín, Juan F.; Liras, Paloma

2017-01-01

The clavine alkaloids produced by the fungi of the Aspergillaceae and Arthrodermatacea families differ from the ergot alkaloids produced by Claviceps and Neotyphodium. The clavine alkaloids lack the extensive peptide chain modifications that occur in lysergic acid derived ergot alkaloids. Both clavine and ergot alkaloids arise from the condensation of tryptophan and dimethylallylpyrophosphate by the action of the dimethylallyltryptophan synthase. The first five steps of the biosynthetic pathway that convert tryptophan and dimethylallyl-pyrophosphate (DMA-PP) in chanoclavine-1-aldehyde are common to both clavine and ergot alkaloids. The biosynthesis of ergot alkaloids has been extensively studied and is not considered in this article. We focus this review on recent advances in the gene clusters for clavine alkaloids in the species of Penicillium, Aspergillus (Neosartorya), Arthroderma and Trychophyton and the enzymes encoded by them. The final products of the clavine alkaloids pathways derive from the tetracyclic ergoline ring, which is modified by late enzymes, including a reverse type prenyltransferase, P450 monooxygenases and acetyltransferases. In Aspergillus japonicus, a α-ketoglutarate and Fe2+-dependent dioxygenase is involved in the cyclization of a festuclavine-like unknown type intermediate into cycloclavine. Related dioxygenases occur in the biosynthetic gene clusters of ergot alkaloids in Claviceps purpurea and also in the clavine clusters in Penicillium species. The final products of the clavine alkaloid pathway in these fungi differ from each other depending on the late biosynthetic enzymes involved. An important difference between clavine and ergot alkaloid pathways is that clavine producers lack the enzyme CloA, a P450 monooxygenase, involved in one of the steps of the conversion of chanoclavine-1-aldehyde into lysergic acid. Bioinformatic analysis of the sequenced genomes of the Aspergillaceae and Arthrodermataceae fungi showed the presence of clavine gene clusters in Arthroderma species, Penicillium roqueforti, Penicillium commune, Penicillium camemberti, Penicillium expansum, Penicillium steckii and Penicillium griseofulvum. Analysis of the gene clusters in several clavine alkaloid producers indicates that there are gene gains, gene losses and gene rearrangements. These findings may be explained by a divergent evolution of the gene clusters of ergot and clavine alkaloids from a common ancestral progenitor six genes cluster although horizontal gene transfer of some specific genes may have occurred more recently. PMID:29186777

Endophyte-associated ergot alkaloids

USDA-ARS?s Scientific Manuscript database

Fescue toxicosis is a very costly (greater than $600 million/annually) for the cattle, horse and small ruminant industries. The tall fescue forage responsible for this intoxication is infected with an endophytic fungus (Neotyphodium coenophialum) that produces ergot alkaloids, which are toxic to th...

D-lysergic acid-activating enzyme from the ergot fungus Claviceps purpurea.

PubMed Central

Keller, U; Zocher, R; Krengel, U; Kleinkauf, H

1984-01-01

A D-lysergic acid-activating enzyme from the ergot fungus Claviceps purpurea was purified about 145-fold. The enzyme was able to catalyse both the D-lysergic acid-dependent ATP-pyrophosphate exchange and the formation of ATP from D-lysergic acid adenylate and pyrophosphate. Both reactions were also catalysed to a decreased but significant extent with respect to dihydrolysergic acid. The molecular mass of the enzyme was estimated to lie between 135 and 140 kDa. The involvement of the enzyme in the biosynthesis of ergot peptide alkaloids is discussed. Images Fig. 4. PMID:6326747

Diversification of Ergot Alkaloids in Natural and Modified Fungi

PubMed Central

Robinson, Sarah L.; Panaccione, Daniel G.

2015-01-01

Several fungi in two different families––the Clavicipitaceae and the Trichocomaceae––produce different profiles of ergot alkaloids, many of which are important in agriculture and medicine. All ergot alkaloid producers share early steps before their pathways diverge to produce different end products. EasA, an oxidoreductase of the old yellow enzyme class, has alternate activities in different fungi resulting in branching of the pathway. Enzymes beyond the branch point differ among lineages. In the Clavicipitaceae, diversity is generated by the presence or absence and activities of lysergyl peptide synthetases, which interact to make lysergic acid amides and ergopeptines. The range of ergopeptines in a fungus may be controlled by the presence of multiple peptide synthetases as well as by the specificity of individual peptide synthetase domains. In the Trichocomaceae, diversity is generated by the presence or absence of the prenyl transferase encoded by easL (also called fgaPT1). Moreover, relaxed specificity of EasL appears to contribute to ergot alkaloid diversification. The profile of ergot alkaloids observed within a fungus also is affected by a delayed flux of intermediates through the pathway, which results in an accumulation of intermediates or early pathway byproducts to concentrations comparable to that of the pathway end product. PMID:25609183

Ergot Alkaloids Produced by Endophytic Fungi of the Genus Epichloë

PubMed Central

Guerre, Philippe

2015-01-01

The development of fungal endophytes of the genus Epichloë in grasses results in the production of different groups of alkaloids, whose mechanism and biological spectrum of toxicity can differ considerably. Ergot alkaloids, when present in endophyte-infected tall fescue, are responsible for “fescue toxicosis” in livestock, whereas indole-diterpene alkaloids, when present in endophyte-infected ryegrass, are responsible for “ryegrass staggers”. In contrast, peramine and loline alkaloids are deterrent and/or toxic to insects. Other toxic effects in livestock associated with the consumption of endophyte-infected grass that contain ergot alkaloids include the “sleepy grass” and “drunken horse grass” diseases. Although ergovaline is the main ergopeptine alkaloid produced in endophyte-infected tall fescue and is recognized as responsible for fescue toxicosis, a number of questions still exist concerning the profile of alkaloid production in tall fescue and the worldwide distribution of tall fescue toxicosis. The purpose of this review is to present ergot alkaloids produced in endophyte-infected grass, the factors of variation of their level in plants, and the diseases observed in the mammalian species as relate to the profiles of alkaloid production. In the final section, interactions between ergot alkaloids and drug-metabolizing enzymes are presented as mechanisms that could contribute to toxicity. PMID:25756954

Electrospray[+] tandem quadrupole mass spectrometry in the elucidation of ergot alkaloids chromatographed by HPLC: screening of grass or forage samples for novel toxic compounds.

PubMed

Lehner, Andreas F; Craig, Morrie; Fannin, Neil; Bush, Lowell; Tobin, Tom

2005-11-01

Ergot alkaloids are mycotoxins generated by grass and grain pathogens such as Claviceps, for example. Ergot alkaloid-poisoning syndromes, such as tall fescue toxicosis from endophyte-infected tall fescue grass, are important veterinary problems for cattle, horses, sheep, pigs and chickens, with consequent impact on food, meat and dairy industries. Damage to livestock is of the order of a billion dollars a year in the United States alone. HPLC with UV and fluorescence detection are the predominant means of ergot alkaloid determination, with focus on quantitation of the marker compound ergovaline, although ELISA methods are undergoing investigation. These techniques are excellent for rapid detection, but of poor specificity in defining new or poorly characterized ergot alkaloids and related compounds. This paper demonstrates the facility of using electrospray(+) mass spectrometry with multiple reaction monitoring (MRM) detection during chromatographic examination of ergot alkaloid standards of lysergic acid, lysergol, ergonovine, ergovaline, ergotamine, ergocornine, ergocryptine and ergocrystine by HPLC. Ergoline-8 position epimers could be separated on the gradient HPLC system for ergocornine, ergocrystine and ergonovine and appeared as shoulders for ergotamine and ergovaline; epimers generally showed different patterns of relative intensity for specific MRM transitions. There was reasonable correspondence between retention of standards on the 2-mm ESI(+)MS phenyl-hexyl-based reverse phase column and those on the 4-mm C18-based column. Since up to 10% of clinical cases involving toxin exposure display unidentified chromatographic peaks, 11 samples of feed components associated with such cases were studied with developed MRM methods to attempt elucidation of crucial components if possible. Ergotamine appeared in all, ergovaline appeared in five and ergocornine appeared in six; ergonovine, ergocryptine, ergocrystine and lysergol also appeared in several. In addition, molecular weights of compounds newly revealed by mass spectrometry suggested ergosine, ergostine and ergoptine in four samples, for which standards were not available. Dehydrated products of ergotamine, ergocrystine and ergocornine were discovered, along with dihydrogenated ergocrystine and ergocryptine in seven of the samples, and the issue was raised as to whether dehydration was strictly an instrument-derived artifact. Finally, five of the samples, along with fescue seed standard, evidenced one or more of 14 new ergot alkaloids ranging in size from 381 to 611 molecular weight and with key mass spectral characteristics of ergot alkaloids, specifically the pair of peaks m/z 223 and 208, corresponding to the ergoline ring system and its demethylated variant, respectively. It is anticipated that findings such as these will provide impetus to future development of analytical methodology for these heretofore relatively rare ergot alkaloid species. Copyright 2005 John Wiley & Sons, Ltd

Mitigation of ergot vasoconstriction by clover isoflavones in goats (Capra hircus)

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by a fungal endophyte (Epichloë coenophiala; formerly Neotyphodium coenphialum) that infects tall fescue (Lolium arundinaceum) can induce persistent constriction of the vasculature in ruminants, hindering their capability to thermo-regulate core body temperature. There is e...

Effect of Ergot Alkaloids on Bovine Foregut Vasculature

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids induce vasoconstriction of bovine foregut vasculature. Ergovaline induced the greatest response in ruminal artery while ergovaline and ergotamine induced the greatest response in ruminal vein. Lysergic acid did not stimulate a contractile response in either the ruminal artery or vein...

A Simple Tall Fescue Seed Extraction and Partial Purification of Ergovaline

USDA-ARS?s Scientific Manuscript database

There are several substances present in the tall fescue/endophyte association (Lolium arundinaceum /Neotyphodium coenophialum) that have biological activity. These include the pyrrolizidine and ergot alkaloids plus peramine. Of these compounds only the ergot alkaloids have significant mammalian to...

Ergovaline recovery from digested tall fescue seedheads

USDA-ARS?s Scientific Manuscript database

Seed heads typically contain high concentrations of ergot alkaloids, which makes them a highly toxic source of ergot alkaloids. Unfortunately, cattle selectively graze tall fescue seedheads. Seedheads were collected from pastures grazed by Angus-cross steers from early-May until mid-June. Pasture...

Bioaccumulation of Ergovaline in Bovine Lateral Saphenous Veins in Vitro

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids have been associated with vasoconstriction in grazing livestock afflicted with the fescue toxicosis syndrome. Previous in vitro investigations studying how ergot alkaloids cause the observed vasoconstriction have shown that ergovaline has a very distinct receptor affinity and sustain...

Evidence for an ergot alkaloid gene cluster in Claviceps purpurea.

PubMed

Tudzynski, P; Hölter, K; Correia, T; Arntz, C; Grammel, N; Keller, U

1999-02-01

A gene (cpd1) coding for the dimethylallyltryptophan synthase (DMATS) that catalyzes the first specific step in the biosynthesis of ergot alkaloids, was cloned from a strain of Claviceps purpurea that produces alkaloids in axenic culture. The derived gene product (CPD1) shows only 70% similarity to the corresponding gene previously isolated from Claviceps strain ATCC 26245, which is likely to be an isolate of C. fusiformis. Therefore, the related cpd1 most probably represents the first C. purpurea gene coding for an enzymatic step of the alkaloid biosynthetic pathway to be cloned. Analysis of the 3'-flanking region of cpd1 revealed a second, closely linked ergot alkaloid biosynthetic gene named cpps1, which codes for a 356-kDa polypeptide showing significant similarity to fungal modular peptide synthetases. The protein contains three amino acid-activating modules, and in the second module a sequence is found which matches that of an internal peptide (17 amino acids in length) obtained from a tryptic digest of lysergyl peptide synthetase 1 (LPS1) of C. purpurea, thus confirming that cpps1 encodes LPS1. LPS1 activates the three amino acids of the peptide portion of ergot peptide alkaloids during D-lysergyl peptide assembly. Chromosome walking revealed the presence of additional genes upstream of cpd1 which are probably also involved in ergot alkaloid biosynthesis: cpox1 probably codes for an FAD-dependent oxidoreductase (which could represent the chanoclavine cyclase), and a second putative oxidoreductase gene, cpox2, is closely linked to it in inverse orientation. RT-PCR experiments confirm that all four genes are expressed under conditions of peptide alkaloid biosynthesis. These results strongly suggest that at least some genes of ergot alkaloid biosynthesis in C. purpurea are clustered, opening the way for a detailed molecular genetic analysis of the pathway.

Validation and transferability study of a method based on near-infrared hyperspectral imaging for the detection and quantification of ergot bodies in cereals.

PubMed

Vermeulen, Ph; Fernández Pierna, J A; van Egmond, H P; Zegers, J; Dardenne, P; Baeten, V

2013-09-01

In recent years, near-infrared (NIR) hyperspectral imaging has proved its suitability for quality and safety control in the cereal sector by allowing spectroscopic images to be collected at single-kernel level, which is of great interest to cereal control laboratories. Contaminants in cereals include, inter alia, impurities such as straw, grains from other crops, and insects, as well as undesirable substances such as ergot (sclerotium of Claviceps purpurea). For the cereal sector, the presence of ergot creates a high toxicity risk for animals and humans because of its alkaloid content. A study was undertaken, in which a complete procedure for detecting ergot bodies in cereals was developed, based on their NIR spectral characteristics. These were used to build relevant decision rules based on chemometric tools and on the morphological information obtained from the NIR images. The study sought to transfer this procedure from a pilot online NIR hyperspectral imaging system at laboratory level to a NIR hyperspectral imaging system at industrial level and to validate the latter. All the analyses performed showed that the results obtained using both NIR hyperspectral imaging cameras were quite stable and repeatable. In addition, a correlation higher than 0.94 was obtained between the predicted values obtained by NIR hyperspectral imaging and those supplied by the stereo-microscopic method which is the reference method. The validation of the transferred protocol on blind samples showed that the method could identify and quantify ergot contamination, demonstrating the transferability of the method. These results were obtained on samples with an ergot concentration of 0.02% which is less than the EC limit for cereals (intervention grains) destined for humans fixed at 0.05%.

The ergot alkaloid gene cluster in Claviceps purpurea: extension of the cluster sequence and intra species evolution.

PubMed

Haarmann, Thomas; Machado, Caroline; Lübbe, Yvonne; Correia, Telmo; Schardl, Christopher L; Panaccione, Daniel G; Tudzynski, Paul

2005-06-01

The genomic region of Claviceps purpurea strain P1 containing the ergot alkaloid gene cluster [Tudzynski, P., Hölter, K., Correia, T., Arntz, C., Grammel, N., Keller, U., 1999. Evidence for an ergot alkaloid gene cluster in Claviceps purpurea. Mol. Gen. Genet. 261, 133-141] was explored by chromosome walking, and additional genes probably involved in the ergot alkaloid biosynthesis have been identified. The putative cluster sequence (extending over 68.5kb) contains 4 different nonribosomal peptide synthetase (NRPS) genes and several putative oxidases. Northern analysis showed that most of the genes were co-regulated (repressed by high phosphate), and identified probable flanking genes by lack of co-regulation. Comparison of the cluster sequences of strain P1, an ergotamine producer, with that of strain ECC93, an ergocristine producer, showed high conservation of most of the cluster genes, but significant variation in the NRPS modules, strongly suggesting that evolution of these chemical races of C. purpurea is determined by evolution of NRPS module specificity.

Relationships among Ergot Alkaloids, Cytochrome P450 Activity, and Beef Steer Growth

NASA Astrophysics Data System (ADS)

Rosenkrans, Charles; Ezell, Nicholas

2015-03-01

Determining a grazing animal’s susceptibility to ergot alkaloids has been a research topic for decades. Our objective was to determine if the Promega™ P450-Glo assay could be used to indirectly detect ergot alkaloids or their metabolites in urine of steers. The first experiment validated the effects of ergot alkaloids [0, 20, and 40 μM of ergotamine (ET), dihydroergotamine (DHET), and ergonovine (EN)] on human CYP3A4 using the P450-Glo assay (Promega™ V9800). With this assay, luminescence is directly proportional to CYP450 activity. Relative inhibition of in vitro cytochrome P450 activity was affected (P < 0.001) by an interaction between alkaloids and concentration. That interaction resulted in no concentration effect of EN, but within ET and DHET 20 and 40 µM concentrations inhibited CYP450 activity when compared with controls. In experiment 2, urine was collected from Angus-sired crossbred steers (n = 39; 216 ± 2.6 d of age; 203 ± 1.7 kg) after grazing tall fescue pastures for 105 d. Non-diluted urine was added to the Promega™ P450-Glo assay, and observed inhibition (3.7 % ± 2.7 of control). Urine content of total ergot alkaloids (331.1 ng/mg of creatinine ± 325.7) was determined using enzyme linked immunosorbent assay. Urine inhibition of CYP450 activity and total alkaloids were correlated (r = -0.31; P < 0.05). Steers were genotyped at CYP450 single nucleotide polymorphism, C994G. Steer genotype affected (P < 0.03) inhibition of CYP450 activity by urine; heterozygous steers had the least amount of CYP450 inhibition suggesting that genotyping cattle may be a method of identifying animals that are susceptible to ergot alkaloids. Although, additional research is needed, we demonstrate that the Promega™ P450-Glo assay is sensitive to ergot alkaloids and urine from steers grazing tall fescue. With some refinement the P450-Glo assay has potential as a tool for screening cattle for their exposure to fescue toxins.

Physiological responses to known intake of ergot alkaloids by steers at environmental temperatures within or greater than their thermoneutral zone

NASA Astrophysics Data System (ADS)

Eisemann, Joan; Huntington, Gerald; Williamson, Megan; Hanna, Michelle; Poore, Matthew

2014-11-01

Two studies separated effects of dietary ergot alkaloids from effects of feed intake or ambient temperature on respiration rate (RR), heart rate (HR), surface temperature (ST), rectal temperature (RT), blood pressure (BP), serum hormone, and plasma metabolite concentrations in beef steers. The balanced, single reversal design for each experiment used 8 beef steers fed tall fescue seed (2.5 g/kg body weight, (BW)) with (E+) or without (E-) ergot alkaloids as part of a 60:40 switchgrass hay: supplement diet. Periods were 35 d with 21 d of preliminary phase and 14 d of feeding fescue seed once daily. Measures of dependent variables were collected on d 20, 25, 29 and 35 of each period at 0730 (before feeding), 1230 and 1530. In Expt 1 steers weighed 286 kg, gained 0.61 kg BW/d, E+ supplied 2.72 mg ergot alkaloids including 1.60 mg ergovaline per steer daily, and mean minimum and maximum daily ambient temperatures were 23.6 and 32.3°C. In Expt 2 steers weighed 348 kg, gained 1.03 kg BW/d, E+ supplied 3.06 mg ergot alkaloids including 2.00 mg ergovaline daily, and mean minimum and maximum daily ambient temperatures were 11.9 and 17.4°C. Dry matter intake was not affected by fescue seed treatment (P < 0.20) in either experiment. In both experiments, E+ reduced HR (P < 0.01) and increased insulin (P = 0.07). Systolic BP minus diastolic BP decreased (P< 0.05) for E+ in both experiments, due to increased diastolic BP in Expt 1 (P < 0.03) and decreased systolic BP in Expt 2 (P < 0.07). In Expt 1, above the thermoneutral zone, E+ increased (P< 0.05) RR, RT and left side ST in comparison to E-, but in Expt 2, within the thermoneutral zone, E+ and E- did not differ (P < 0.18). Ergot alkaloids from fescue seed affect the cardiovascular system of steers separately from effects of feed intake or environmental temperature. Ergot alkaloids interact with ambient temperatures above the steers’ thermoneutral zone to exacerbate the symptoms of hyperthermic stress.

Witchcraft or mycotoxin? The Salem witch trials.

PubMed

Woolf, A

2000-01-01

The Salem witchcraft trials of 1692 have been studied by many historians looking for the complex social, political, and psychological determinants behind the community-wide hysteria that led to a travesty of justice and the deaths of 20 innocent Puritans. Recently, ergot poisoning has been put forth by some as a previously unsuspected cause of the bizarre behaviors of the young adolescent girls who accused the townsfolk of witchcraft. In this essay the circumstances behind the ergot poisoning theory for this historical event are described. When the evidence is weighed carefully both pro and con, it seems unlikely that ergotism explains much of what went on in colonial Salem.

Effects of toxicosis on bull growth, semen characteristics and breeding soundness evaluation

USDA-ARS?s Scientific Manuscript database

Tall fescue (Lolium arundinaceum) possesses heat, drought, and pest resistance conferred to the plant by its mutualistic relationship with the ergot alkaloid producing fungal endophyte, Neotyphodium coenophialum. The objective of this study was to evaluate the impact of ergot alkaloid consumption on...

Ergot alkaloids reduce rumen epithelial blood flow and volatile fatty acid absorption

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids have been shown to induce vasoconstriction of both peripheral and ruminal vessels. Constriction of ruminal vessels could lead to a reduction in epithelial blood flow thereby reducing nutrient absorption. The objectives of this experiment were to determine if steers receiving endophyt...

Physiologic effects of ergot alkaloids: What happens when excretion does not equal absorption?

USDA-ARS?s Scientific Manuscript database

Increased persistence of tall fescue (Lolium arundinaceum) infested with an endophytic fungus Epichloë coenophiala (formerly Neotyphodium coenophialum) in forage-based agriculture has led to increased effort in understanding the negative effects caused by consumption of ergot alkaloids by animals co...

Activities and effects of ergot alkaloids on livestock physiology and production

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids can have a broad impact on many different physiological mechanisms that can alter the homeostasis of livestock exposed to these toxins through consumption of infested feedstuffs. This altered homeostasis causes an increased sensitivity in livestock to perturbations in the ambient env...

Vasoconstrictive responses by the carotid and auricular arteries in goats to ergot alkaloid exposure

USDA-ARS?s Scientific Manuscript database

A fungal endophyte (Neotyphodium coenophialum) infects most plants of ‘Kentucky 31’ tall fescue (Lolium arundinaceum) and produces ergot alkaloids that cause persistent constriction of the vascular system in grazing livestock. Consequently, animals undergoing this toxicosis cannot regulate core body...

Physiologic effects of ergot alkaloids: What happens when excretion does not equal consumption?

USDA-ARS?s Scientific Manuscript database

Increased persistence of tall fescue (Lolium arundinaceum) infested with an endophytic fungus Epichloë coenophiala (formerly Neotyphodium coenophialum) in forage-based agriculture has led to increased effort in understanding the negative effects caused by consumption of ergot alkaloids by animals co...

Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

USDA-ARS?s Scientific Manuscript database

Ergovaline is an ergot alkaloid found in some endophyte-infected ryegrasses and has been implicated in the expression of ergotism-like symptoms of grazing livestock, as well as in the protection of the plant against invertebrate predation and abiotic stresses. These selection pressures have resulted...

Development and validation of a LC-MS method for quantitation of ergot alkaloids in lateral saphenous vein tissue

USDA-ARS?s Scientific Manuscript database

A liquid chromatography-mass spectrometry (LC/MS) method for simultaneous quantitation of seven ergot alkaloids (lysergic acid, ergonovine, ergovaline, ergocornine, ergotamine, ergocryptine and ergocrystine) in vascular tissue was developed and validated. Reverse-phase chromatography, coupled to an...

Comparison of electrospray ionization and atmospheric pressure photoionization liquid chromatography mass spectrometry methods for analysis of ergot alkaloids from endophyte-infected sleepygrass (Achnatherum robustum).

PubMed

Jarmusch, Alan K; Musso, Ashleigh M; Shymanovich, Tatsiana; Jarmusch, Scott A; Weavil, Miranda J; Lovin, Mary E; Ehrmann, Brandie M; Saari, Susanna; Nichols, David E; Faeth, Stanley H; Cech, Nadja B

2016-01-05

Ergot alkaloids are mycotoxins with an array of biological effects. With this study, we investigated for the first time the application of atmospheric pressure photoionization (APPI) as an ionization method for LC-MS analysis of ergot alkaloids, and compared its performance to that of the more established technique of electrospray ionization (ESI). Samples of the grass Achnatherum robustum infected with the ergot producing Epichloë fungus were extracted using cold methanol and subjected to reserved-phase HPLC-ESI-MS and HPLC-APPI-MS analysis. The ergot alkaloids ergonovine and lysergic acid amide were detected in these samples, and quantified via external calibration. Validation parameters were recorded in accordance with ICH guidelines. A triple quadrupole MS operated in multiple reaction monitoring yielded the lowest detection limits. The performance of APPI and ESI methods was comparable. Both methods were subject to very little matrix interference, with percent recoveries ranging from 82% to 100%. As determined with HPLC-APPI-MS quantification, lysergic acid amide and ergonovine were extracted from an A. robustum sample infected with the Epichloë fungus at concentrations of 1.143±0.051 ppm and 0.2822±0.0071 ppm, respectively. There was no statistically significant difference between these concentrations and those determined using ESI for the same samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Genetic variation for resistance to ergot (Claviceps purpurea [Fr.] Tul.) among full-sib families of five populations of winter rye (Secale cereale L.).

PubMed

Mirdita, V; Dhillon, B S; Geiger, H H; Miedaner, T

2008-12-01

Ergot (Claviceps purpurea [Fr.] Tul.) is a serious disease of rye (Secale cereale L.) and it adversely affects the quality of grain. The present investigation was undertaken to study genotypic variability among full-sib families (FSF) of five open-pollinated (OP) winter rye populations of highly diverse origin, namely Dankovskie Selekcyine (Poland), Charkovskaja (Ukraine), NEM4 (Russia), Halo and Carokurz, both from Germany. About 50 FSF were developed at random in each population, and the FSF of each population were evaluated in separate but adjacent experiments conducted in four environments under artificial inoculation. A mixture of conidia of C. purpurea isolates was sprayed thrice during the flowering period. The materials were manually harvested at yellow-ripe stage. Resistance trait recorded was disease severity, i.e. percent ergot sclerotia in grain by weight. Mean ergot severity ranged from 2.29 to 4.08% for the five populations across environments. Significant genotypic variation (P < 0.01) due to FSF and FSF x environment interaction was observed within each population. Genotypic variation within all populations was higher than that among five populations. All populations showed high estimates of heritability (0.72-0.89). The study indicated that the evaluated OP populations are rich reservoirs of genetic variation that should also be used in hybrid breeding. Recurrent selection to further improve ergot resistance should be successful.

Contractile response of bovine lateral saphenous vein to ergotamine tartrate exposed to different concentrations of molecularly imprinted polymers

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids, in their active isomeric form, affect animal health and performance and adsorbents are used to mitigate toxicities by reducing bioavailability. Adsorbents with high specificity (molecularly imprinted: MIP and non-imprinted: NIP polymers) adsorb ergot alkaloids in vitro, but require ...

Interaction of isoflavones and endophyte-infected tall fescue seed extract on vasoactivity of bovine mesenteric vasculature

USDA-ARS?s Scientific Manuscript database

It was hypothesized that isoflavones may attenuate ergot alkaloid-induced vasoconstriction and possibly alleviate diminished contractility of vasculature after exposure to ergot alkaloids. The objective of this study was to determine if prior incubation of bovine mesenteric vasculature with the isof...

Effect of grazing seedhead-suppressed tall fescue pasture on the vasoactivity of serotonin receptors

USDA-ARS?s Scientific Manuscript database

Previous research has demonstrated that exposure to ergot alkaloids reduces vasoactivity of serotonin (5HT) receptors. Chemical suppression of tall fescue seedhead production is a tool to reduce the level of exposure to ergot alkaloids by a grazing animal. Therefore, the objective was to evaluate co...

Effects of ergot alkaloid exposure on serotonin receptor mRNA in the smooth muscle of the bovine gastrointestinal tract

USDA-ARS?s Scientific Manuscript database

Various serotonin (5HT) receptor subtypes have been located in the gastrointestinal tract and some are associated with gut motility. Cattle exposed to ergot alkaloids through consumption of contaminated feedstuffs have demonstrated signs (e.g. - increased rumen DM content and total content) that sug...

Ergot alkaloids decrease rumen epithelial blood flow

USDA-ARS?s Scientific Manuscript database

Two experiments were conducted to determine if ergot alkaloids affect blood flow to the absorptive surface of the rumen of steers. Steers (n=8 total) were pair-fed alfalfa cubes at 1.5× NEM and received ground endophyte-infected tall fescue seed (E+) or endophyte-free tall fescue seed (E-) via rumen...

From the Lab Bench: Season Changes in Ergot Alkaloid Concentrations of Toxic Tall Fescue

USDA-ARS?s Scientific Manuscript database

A column was written to discuss seasonal trends in ergot alkaloids produced by the fungal endophyte that infects most plants of tall fescue. Tall fescue is the predominant grass utilized for forage in the U.S. transition zone between the temperature northeast and subtropical southeast; however, erg...

Ergopeptines bromocriptine and ergovaline and the dopamine type-2 receptor inhibitor domperidone inhibit bovine equilibrative nucleoside transporter 1-like activity

USDA-ARS?s Scientific Manuscript database

Forages infected with Neotyphodium coenophialum produce ergot alkaloids that alter the systemic physiology of cattle such that reproduction, lactation, and growth are decreased. Ergopeptines are one predominant class of ergot alkaloids. However, aside from their interactions with biogenic amine rece...

Screening of Balansia epichloe-infected grass species for in situ ergot alkaloids using laser ablation electrospray ionization-mass spectrometry

USDA-ARS?s Scientific Manuscript database

The Balansia are clavicipitaceous symbiotic species associated with various species of tropical grasses. Laboratory culture procedures established that the Balansia species are often conspecific with grasses in tall fescue pastures that produced ergot alkaloids. However, any effects of hosts on the...

Immunochemical Analysis of Paxilline and Ergot Alkaloid Mycotoxins in Grass Seeds and Plants.

PubMed

Bauer, Julia I; Gross, Madeleine; Cramer, Benedikt; Humpf, Hans-Ulrich; Hamscher, Gerd; Usleber, Ewald

2018-01-10

Limited availability of toxin standards for lolitrem B and ergovaline impedes routine control of grasses for endophyte toxins. This study aimed at assessing the applicability of an enzyme immunoassay (EIA) for the indole-diterpene mycotoxin paxilline, in combination with a generic EIA for ergot alkaloids, as alternative parameters for screening purposes. Analysis of grass seeds and model pastures of four different grass species showed that both EIAs yielded highly positive results for paxilline and ergot alkaloids in perennial ryegrass seeds. Furthermore, evidence for natural occurrence of paxilline in grass in Germany was obtained. High performance liquid chromatography-tandem mass spectrometry analysis qualitatively confirmed the paxilline EIA results but showed that paxilline analogues 1'-O-acetylpaxilline and 13-desoxypaxilline were the predominant compounds in seeds and grass. In the absence of easily accessible reference standards for specific analysis of some major endophyte toxins, analysis of paxilline and ergot alkaloids by EIA may be suitable substitute parameters. The major advantage of this approach is its ease of use and speed, providing an analytical tool which could enhance routine screening for endophyte toxins in pasture.

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

PubMed Central

Chan, John D.; Agbedanu, Prince N.; Grab, Thomas; Zamanian, Mostafa; Dosa, Peter I.; Day, Timothy A.; Marchant, Jonathan S.

2015-01-01

Abstract Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. PMID:26367744

The identification of QTL controlling ergot sclerotia size in hexaploid wheat implicates a role for the Rht dwarfing alleles.

PubMed

Gordon, Anna; Basler, Ryan; Bansept-Basler, Pauline; Fanstone, Vicky; Harinarayan, Lakshmi; Grant, Paul K; Birchmore, Richard; Bayles, Rosemary A; Boyd, Lesley A; O'Sullivan, Donal M

2015-12-01

Four QTL conferring resistance to ergot were identified in the UK winter wheat varieties 'Robigus' and 'Solstice'. Two QTL co-located with semi-dwarfing alleles at the Rht loci Rht - 1B and Rht - 1D implicating a role of these DELLA proteins in infection success of Claviceps purpurea. The fungal pathogen Claviceps purpurea infects ovaries of a broad range of temperate grasses and cereals, including hexaploid wheat, causing a disease commonly known as ergot. Sclerotia produced in place of seed carry a cocktail of harmful alkaloid compounds that result in a range of symptoms in humans and animals, causing ergotism. Following a field assessment of C. purpurea infection in winter wheat, two varieties 'Robigus' and 'Solstice' were selected which consistently produced the largest differential effect on ergot sclerotia weights. They were crossed to produce a doubled haploid mapping population, and a marker map, consisting of 714 genetic loci and a total length of 2895 cM was produced. Four ergot reducing QTL were identified using both sclerotia weight and size as phenotypic parameters; QCp.niab.2A and QCp.niab.4B being detected in the wheat variety 'Robigus', and QCp.niab.6A and QCp.niab.4D in the variety 'Solstice'. The ergot resistance QTL QCp.niab.4B and QCp.niab.4D peaks mapped to the same markers as the known reduced height (Rht) loci on chromosomes 4B and 4D, Rht-B1 and Rht-D1, respectively. In both cases, the reduction in sclerotia weight and size was associated with the semi-dwarfing alleles, Rht-B1b from 'Robigus' and Rht-D1b from 'Solstice'. Two-dimensional, two-QTL scans identified significant additive interactions between QTL QCp.niab.4B and QCp.niab.4D, and between QCp.niab.2A and QCp.niab.4B when looking at sclerotia size, but not between QCp.niab.2A and QCp.niab.4D. The two plant height QTL, QPh.niab.4B and QPh.niab.4D, which mapped to the same locations as QCp.niab.4B and QCp.niab.4D, also displayed significant genetic interactions.

Claviceps cyperi, a new cause of severe ergotism in dairy cattle consuming maize silage and teff hay contaminated with ergotised Cyperus esculentus (nut sedge) on the Highveld of South Africa.

PubMed

Naudè, T W; Botha, C J; Vorster, J H; Roux, C; Van der Linde, E J; Van der Walt, S I; Rottinghaus, G E; Van Jaarsveld, L; Lawrence, A N

2005-03-01

During December/January 1996/97 typical summer syndrome (hyperthermia and a 30% drop in milk yield) occurred in succession in two Holstein dairy herds (n=240 and n=150 milking cows, respectively) on the South African Highveld. These farms are situated in the midst of the prime maize and dairy farming areas of South Africa where this condition had never been diagnosed before. The individual components of the concentrate on both farms were negative for ergot alkaloids. Endophytic fungi and/or ergot infestation of teff and other grasses fed to the cows were then suspected of being involved, but neither endophytes nor ergot alkaloids could be implicated from these sources. By measuring the serum prolactin levels of groups of sheep (n=5) fed the first farm's total mixed ration (TMR) or its three individual fibre components for a period of 11 days, the source of the ergot alkaloids was identified. A statistically significant decrease in the level of this hormone occurred only in the group on maize silage (which constituted 28% on dry matter base of the TMR). The involvement of the maize silage was further chemically confirmed by the high levels of total ergot alkaloids, predominantly ergocryptine, found by LC-MS in the silage as well as in the TMR (115-975 ppb and 65-300 ppb, respectively). The ergot alkaloid content (mainly ergocryptine) of the maize silage on the second affected farm was 875 ppb. Withdrawal of contaminated silage resulted in gradual recovery of stock on both farms. Nut sedge (Cyperus esculentus and Cyperus rotundus of the family Cyperaceae) has a world-wide distribution and is a common weed in annual crops, and can be parasitized by Claviceps cyperi. Careful examination of the maize silage from both farms revealed that it was heavily contaminated with nut sedge and that it contained minute sclerotia, identified as those of Claviceps cyperi, originating from the latter. Nut sedge was abundant on both farms and it is believed that late seasonal rain had resulted in mature, heavily ergotised nut sedge being cut with the silage. Claviceps cyperi sclerotia, collected on the affected fields in the following autumn contained 3600-4000 ppm ergocryptine. That the dominant alkaloid produced by this particular fungus was indeed ergocryptine, was confirmed by negative ion chemical ionization MS/MS. In one further outbreak in another Holstein herd, teff hay contaminated with ergotised nut sedge and containing 1200 ppb alkaloids, was incriminated as the cause of the condition. This is the first report of bovine ergotism not associated with the Poaceae infected with Claviceps purpureum or endophytes but with the family Cyperaceae and this particular fungal phytopathogen.

Development of a methodology to measure the effect of ergot alkaloids on forestomach motility using real-time wireless telemetry

USDA-ARS?s Scientific Manuscript database

The objectives of these experiments were to characterize rumen motility patterns of cattle fed once daily using a real-time wireless telemetry system, determine when to measure rumen motility with this system, and determine the effect of ruminal dosing of ergot alkaloids on rumen motility. Ruminally...

Case Study: Recovery from ergot alkaloid-induced vasoconstriction for steers conditioned to grazing seedhead suppressed and unsuppressed pastures of toxic endophyte-infected tall fescue

USDA-ARS?s Scientific Manuscript database

Chemical seedhead suppression of toxic endophyte-infected (E+) tall fescue can enhance steer performance and mitigate the adverse effects of ergot alkaloids on cattle physiology; however, it is not known if seedhead suppression can mitigate alkaloid-induced vasoconstriction and improve post-graze pe...

The history of ergot of rye (Claviceps purpurea) III: 1940-80.

PubMed

Lee, M R

2010-03-01

The period 1940-80 in the history of ergot was dominated by two investigators, Arthur Stoll and Albert Hofmann. There was great excitement when their group isolated from ergot preparations the powerful psychotropic agent lysergic acid diethylamide (LSD). It was thought that this substance would help to find the cause of schizophrenia and other psychotic disorders, but it would prove to be a great disappointment and Hofmann would say later, in private, that he regretted having spent so much time on the compound. By contrast, bromocriptine, derived from ergocriptine, would prove a pivotal substance in our knowledge of dopamine receptors in the central nervous system. It is widely used for the suppression of lactation, the treatment of prolactinomas and the management of Parkinson's disease.

Quantitative molecular diagnostic assays of grain washes for Claviceps purpurea are correlated with visual determinations of ergot contamination.

PubMed

Comte, Alexia; Gräfenhan, Tom; Links, Matthew G; Hemmingsen, Sean M; Dumonceaux, Tim J

2017-01-01

We examined the epiphytic microbiome of cereal grain using the universal barcode chaperonin-60 (cpn60). Microbial community profiling of seed washes containing DNA extracts prepared from field-grown cereal grain detected sequences from a fungus identified only to Class Sordariomycetes. To identify the fungal sequence and to improve the reference database, we determined cpn60 sequences from field-collected and reference strains of the ergot fungus, Claviceps purpurea. These data allowed us to identify this fungal sequence as deriving from C. purpurea, and suggested that C. purpurea DNA is readily detectable on agricultural commodities, including those for which ergot was not identified as a grading factor. To get a sense of the prevalence and level of C. purpurea DNA in cereal grains, we developed a quantitative PCR assay based on the fungal internal transcribed spacer (ITS) and applied it to 137 samples from the 2014 crop year. The amount of Claviceps DNA quantified correlated strongly with the proportion of ergot sclerotia identified in each grain lot, although there was evidence that non-target organisms were responsible for some false positives with the ITS-based assay. We therefore developed a cpn60-targeted loop-mediated isothermal amplification assay and applied it to the same grain wash samples. The time to positive displayed a significant, inverse correlation to ergot levels determined by visual ratings. These results indicate that both laboratory-based and field-adaptable molecular diagnostic assays can be used to detect and quantify pathogen load in bulk commodities using cereal grain washes.

Quantitative molecular diagnostic assays of grain washes for Claviceps purpurea are correlated with visual determinations of ergot contamination

PubMed Central

Comte, Alexia; Gräfenhan, Tom; Links, Matthew G.; Hemmingsen, Sean M.

2017-01-01

We examined the epiphytic microbiome of cereal grain using the universal barcode chaperonin-60 (cpn60). Microbial community profiling of seed washes containing DNA extracts prepared from field-grown cereal grain detected sequences from a fungus identified only to Class Sordariomycetes. To identify the fungal sequence and to improve the reference database, we determined cpn60 sequences from field-collected and reference strains of the ergot fungus, Claviceps purpurea. These data allowed us to identify this fungal sequence as deriving from C. purpurea, and suggested that C. purpurea DNA is readily detectable on agricultural commodities, including those for which ergot was not identified as a grading factor. To get a sense of the prevalence and level of C. purpurea DNA in cereal grains, we developed a quantitative PCR assay based on the fungal internal transcribed spacer (ITS) and applied it to 137 samples from the 2014 crop year. The amount of Claviceps DNA quantified correlated strongly with the proportion of ergot sclerotia identified in each grain lot, although there was evidence that non-target organisms were responsible for some false positives with the ITS-based assay. We therefore developed a cpn60-targeted loop-mediated isothermal amplification assay and applied it to the same grain wash samples. The time to positive displayed a significant, inverse correlation to ergot levels determined by visual ratings. These results indicate that both laboratory-based and field-adaptable molecular diagnostic assays can be used to detect and quantify pathogen load in bulk commodities using cereal grain washes. PMID:28257512

[Issenheim's altarpiece: does the disease depicted on the altarpiece correspond to ergotism?].

PubMed

Faure, Michel

2010-01-01

The Issenheim altar by Mathias Grünenwald (Unterlinden museum in Colmar) shows various scenes from the life of St Antony, abbot. The Tentation panel has been considered as an illustration of the sacer ignis, or St Antony's disease (ergotism). In fact, it may more likely indicate an early representation of Syphilis, or the French disease, as discussed here.

Acute exposure to ergot alkaloids from endophyte-infected tall fescue does not alter absorptive or barrier function of the isolated ruminal epithelium

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids in endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have been shown to cause a reduction in blood flow to the rumen epithelium as well as a decrease in VFA absorption from the washed rumen of steers. Previous data also indicates that incubating an extr...

Application of Liquid Chromatography/Ion Trap Mass Spectrometry Technique to Determine Ergot Alkaloids in Grain Products

PubMed Central

Szymczyk, Krystyna; Jędrzejczak, Renata; Roszko, Marek

2015-01-01

Summary A liquid chromatography/ion trap mass spectrometry-based method to determine six ergot alkaloids and their isomers is presented. The samples were cleaned on neutral alumina-based solid-phase extraction cartridges. The following method parameters were obtained (depending on the analyte and spiking level): method recovery from 63.0 to 104.6%, relative standard deviation below 18%, linear range from 1 to 325 µg/kg, linear correlation coefficient not less than 0.98. The developed analytical procedure was applied to determine the levels of ergot alkaloids in 65 samples of selected rye-based food products (flour – 34 samples, bran – 12 samples, rye – 18 samples, flakes – 1 sample). Measurable levels of alkaloids were found in majority of the analysed samples, particularly in rye flour. Additionally, alkaloids were determined in ergot sclerotia isolated from rye grains. Total content was nearly 0.01% (97.9 mg/kg). However, the alkaloid profile was dominated by ergocristine at 45.6% (44.7 mg/kg), an alkaloid not commonly found in the tested food products. Ergocorninine at 0.2% (0.2 mg/kg) was the least abundant alkaloid. PMID:27904328

Biosynthesis of the Pharmaceutically Important Fungal Ergot Alkaloid Dihydrolysergic Acid Requires a Specialized Allele of cloA

PubMed Central

Arnold, Stephanie L.

2017-01-01

ABSTRACT Ergot alkaloids are specialized fungal metabolites that are important as the bases of several pharmaceuticals. Many ergot alkaloids are derivatives of lysergic acid (LA) and have vasoconstrictive activity, whereas several dihydrolysergic acid (DHLA) derivatives are vasorelaxant. The pathway to LA is established, with the P450 monooxygenase CloA playing a key role in oxidizing its substrate agroclavine to LA. We analyzed the activities of products of cloA alleles from different fungi relative to DHLA biosynthesis by expressing them in a mutant of the fungus Neosartorya fumigata that accumulates festuclavine, the precursor to DHLA. Transformants expressing CloA from Epichloë typhina × Epichloë festucae, which oxidizes agroclavine to LA, failed to oxidize festuclavine to DHLA. In substrate feeding experiments, these same transformants oxidized exogenously supplied agroclavine to LA, indicating that a functional CloA was produced. A genomic clone of cloA from Claviceps africana, a sorghum ergot fungus that produces a DHLA derivative, was cloned and expressed in the festuclavine-accumulating mutant of N. fumigata, but several introns in this genomic clone were not processed properly. Expression of a synthetic intron-free version of C. africana cloA resulted in the accumulation of DHLA as assessed by fluorescence high-pressure liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). In substrate feeding experiments, the C. africana CloA also accepted agroclavine as the substrate, oxidizing it to LA. The data indicate that a specialized allele of cloA is required for DHLA biosynthesis and that the pharmaceutically important compound DHLA can be produced in engineered N. fumigata. IMPORTANCE Ergot alkaloids are fungal metabolites that have impacted humankind historically as poisons and more recently as pharmaceuticals used to treat dementia, migraines, and other disorders. Much is known about the biosynthesis of ergot alkaloids that are derived from lysergic acid (LA), but important questions remain about a parallel pathway to ergot alkaloids derived from dihydrolysergic acid (DHLA). DHLA-derived alkaloids have minor structural differences compared to LA-derived alkaloids but can have very different activities. To understand how DHLA is made, we analyzed activities of a key enzyme in the DHLA pathway and found that it differed from its counterpart in the LA pathway. Our data indicate a critical difference between the two pathways and provide a strategy for producing DHLA by modifying a model fungus. The ability to produce DHLA in a model fungus may facilitate synthesis of DHLA-derived pharmaceuticals. PMID:28476772

Biosynthesis of the Pharmaceutically Important Fungal Ergot Alkaloid Dihydrolysergic Acid Requires a Specialized Allele of cloA.

PubMed

Arnold, Stephanie L; Panaccione, Daniel G

2017-07-15

Ergot alkaloids are specialized fungal metabolites that are important as the bases of several pharmaceuticals. Many ergot alkaloids are derivatives of lysergic acid (LA) and have vasoconstrictive activity, whereas several dihydrolysergic acid (DHLA) derivatives are vasorelaxant. The pathway to LA is established, with the P450 monooxygenase CloA playing a key role in oxidizing its substrate agroclavine to LA. We analyzed the activities of products of cloA alleles from different fungi relative to DHLA biosynthesis by expressing them in a mutant of the fungus Neosartorya fumigata that accumulates festuclavine, the precursor to DHLA. Transformants expressing CloA from Epichloë typhina × Epichloë festucae , which oxidizes agroclavine to LA, failed to oxidize festuclavine to DHLA. In substrate feeding experiments, these same transformants oxidized exogenously supplied agroclavine to LA, indicating that a functional CloA was produced. A genomic clone of cloA from Claviceps africana , a sorghum ergot fungus that produces a DHLA derivative, was cloned and expressed in the festuclavine-accumulating mutant of N. fumigata , but several introns in this genomic clone were not processed properly. Expression of a synthetic intron-free version of C. africana cloA resulted in the accumulation of DHLA as assessed by fluorescence high-pressure liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). In substrate feeding experiments, the C. africana CloA also accepted agroclavine as the substrate, oxidizing it to LA. The data indicate that a specialized allele of cloA is required for DHLA biosynthesis and that the pharmaceutically important compound DHLA can be produced in engineered N. fumigata IMPORTANCE Ergot alkaloids are fungal metabolites that have impacted humankind historically as poisons and more recently as pharmaceuticals used to treat dementia, migraines, and other disorders. Much is known about the biosynthesis of ergot alkaloids that are derived from lysergic acid (LA), but important questions remain about a parallel pathway to ergot alkaloids derived from dihydrolysergic acid (DHLA). DHLA-derived alkaloids have minor structural differences compared to LA-derived alkaloids but can have very different activities. To understand how DHLA is made, we analyzed activities of a key enzyme in the DHLA pathway and found that it differed from its counterpart in the LA pathway. Our data indicate a critical difference between the two pathways and provide a strategy for producing DHLA by modifying a model fungus. The ability to produce DHLA in a model fungus may facilitate synthesis of DHLA-derived pharmaceuticals. Copyright © 2017 American Society for Microbiology.

The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis.

PubMed

Delgado-Rosas, Francisco; Gómez, Raúl; Ferrero, Hortensia; Gaytan, Francisco; Garcia-Velasco, Juan; Simón, Carlos; Pellicer, Antonio

2011-11-01

Implantation of a retrogradely shed endometrium during menstruation requires an adequate blood supply, which allows the growth of endometriotic lesions. This suggests that the development of endometriosis can be impaired by inhibiting angiogenesis. The growth of endometriotic foci is impaired by commercial oncological antiangiogenic drugs used to block vascular endothelial growth factor (VEGF) signaling. The dopamine agonist cabergoline (Cb2) inhibits the growth of established endometriosis lesions by exerting antiangiogenic effects through VEGFR2 inactivation. However, the use of ergot-derived Cb2 is associated with an increased incidence of cardiac valve regurgitation. To evaluate the potential usage of non-ergot-derived dopamine agonists for the treatment of human endometriosis, we compared the efficacy of quinagolide with that of Cb2 in preventing angiogenesis and vascularization in a heterologous mouse model of endometriosis. Nude mice whose peritoneum had been implanted with eutopic human endometrial fragments were treated with vehicle, 50  μg/kg per day oral Cb2, or 50 or 200  μg/kg per day quinagolide during a 14-day period. At the end of the treatment period, the implants were excised in order to assess lesion size, cell proliferation, degree of vascularization, and angiogenic gene expression. Neoangiogenesis was inhibited and the size of active endometriotic lesions, cellular proliferation index, and angiogenic gene expression were significantly reduced by both dopamine agonists when compared with the placebo. Given that Cb2 and quinagolide were equally effective in inhibiting angiogenesis and reducing lesion size, these experiments provide the rationale for pilot studies to explore the use of non-ergot-derived dopamine agonists for the treatment of endometriosis in humans.

Ergot alkaloids from endophyte-infected tall fescue decrease reticulo-ruminal epithelial blood flow and volatile fatty acid absorption from a washed reticulorumen

USDA-ARS?s Scientific Manuscript database

An experiment was conducted to determine if ergot alkaloids affect blood flow to the absorptive surface of the rumen. Steers (n = 8) were pair-fed alfalfa cubes and received ground endophyte-infected tall fescue seed (E+; 0.015 mg ergovaline•kg BW-1•d-1) or endophyte-free tall fescue seed (E-) via r...

Ergot alkaloids: From witchcraft till in silico analysis. Multi-receptor analysis of ergotamine metabolites.

PubMed

Dellafiora, Luca; Dall'Asta, Chiara; Cozzini, Pietro

2015-01-01

The term Ergot is referred to the sclerotium of ascomycetes - a protective kernel produced during resting stage of some fungi - which replaces seeds of susceptible cereals and plants intended for human and animal diet. It contains various composition of tryptophan-derived toxins defined ergot alkaloids. Since sclerotia can be harvested and milled together with cereals, they represent a source of food and feed contamination after breakage and spreading of mycotoxins into the various milling fractions. The effects of ergot alkaloids, including those adverse for human health, have been known since the Middle Ages. Nevertheless, as recently stated by the European Food Safety Authority, further information is needed on metabolism and target receptors-binding of common alkaloids in food. Unfortunately, the experimental investigation is challenging due to the high costs in terms of time and money. This study was thus aimed at assessing whether the in silico modeling can be an effective tool to investigate the interaction between multiple serotonin receptors and a wide set of ergotamine metabolites, including experimentally detected molecules and predicted derivatives. Validated models provided precious insights about the effects exerted by metabolic modifications on the receptor-ligand interaction. Such structural information may be useful to support the design of further experimental analysis.

Foot abnormalities of wild birds

USGS Publications Warehouse

Herman, C.M.; Locke, L.N.; Clark, G.M.

1962-01-01

The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

Modulation of Ergot Alkaloids in a Grass-Endophyte Symbiosis by Alteration of mRNA Concentrations of an Ergot Alkaloid Synthesis Gene.

PubMed

Mulinti, Prashanthi; Florea, Simona; Schardl, Christopher L; Panaccione, Daniel G

2016-06-22

The profile of ergot alkaloids in perennial ryegrass (Lolium perenne) containing the endophytic fungus Epichloë typhina × festucae includes high concentrations of the early pathway metabolites ergotryptamine and chanoclavine-I in addition to the pathway end-product ergovaline. Because these alkaloids differ in activity, we investigated strategies to alter their relative concentrations. An RNAi-based approach reduced the concentration of mRNA from the gene easA, which encodes an enzyme required for a ring closure that separates ergotryptamine and chanoclavine-I from ergovaline. Lower easA mRNA concentrations correlated with lower concentrations of ergovaline and higher concentrations of ergotryptamine and chanoclavine-I. Overexpression of easA led to higher concentrations of ergovaline in leaf blades but not in pseudostems; concentrations of the early pathway metabolites were not altered in overexpression strains. The data indicate that altering the concentration of mRNA from a single gene can change alkaloid flux, but the magnitude of the change was limited and variable.

Toxic effects, metabolism, and carry-over of ergot alkaloids in laying hens, with a special focus on changes of the alkaloid isomeric ratio in feed caused by hydrothermal treatment.

PubMed

Dänicke, Sven

2016-02-01

Ergot alkaloids (EA) are mycotoxins formed by Claviceps purpurea. Due to the large variation in EA content, the mass proportion of ergot (hardened sclerotia) in animal diets is not suited to establish safe levels of EA. Therefore, the aim of the present study was to examine the dose-dependent effects of dietary EA on laying hens. Ergoty rye or ergot-free rye (control diet) was included in the diets either untreated or after hydrothermal treatment ("expansion"). The total EA levels in five different diets containing 0-3% of untreated or expanded rye were 0.1-14.56 mg/kg (untreated rye) and 0.08-13.03 mg/kg (expanded rye). The average EA reduction amounted to 11% due to expanding. The proportions of the sum of all -inine isomers however were consistently higher (19.5-48.4%) compared to the sum of their -ine isomer counterparts which decreased at the same time. Most of the laying performance and reproductive traits were significantly compromised during the test period between weeks 22 and 42 of age when the diet with the highest EA content was fed. Toxic effects were less pronounced due to expanding. Relative weights of liver, proventriculus, and gizzard as well as the aspartate aminotransferase activity, the antibody titers to Newcastle disease virus, albumin, and total bilirubin concentrations were all significantly increased in hens fed at the highest dietary ergot level whereby expanding additionally modified the albumin and total bilirubin responses. No carry-over of EA into egg yolk and albumen, blood, liver, and breast muscle was found, but bile contained quantifiable levels of ergometrine and ergometrinine. Biological recovery of ingested individual alkaloids with the excreta varied from 2 to 22% and was strongly positive linearly related to the octanol to water partition coefficient (logkOW). This suggests the lipophilicity of alkaloids as a factor influencing their metabolism and elimination. Based on the overall results of this study, a lowest observed adverse effect level (LOAEL) of 14.56 mg EA/kg for laying hen diets can be proposed, while the no observed adverse effect level (NOAEL) corresponds to a dietary EA level of 3.72 mg/kg. However, it must be stressed that these critical levels apply for the specific EA pattern tested in the present experiment, while batches of ergot containing a less typical alkaloid composition, or other expanding conditions, might contribute to variations in the LOAEL/NOAEL.

Biosynthesis and Regulation of Bioprotective Alkaloids in the Gramineae Endophytic Fungi with Implications for Herbivores Deterrents.

PubMed

Luo, Hongping; Xie, Longxiang; Zeng, Jie; Xie, Jianping

2015-12-01

Four kinds of bioprotective alkaloids-peramine, loline, ergot alkaloid, indole-diterpenes, produced by grass-fungal endophyte symbioses, are deterrents or toxic to vertebrate and invertebrate herbivores. Ergot alkaloids have pharmacological properties and widely are used clinically. The regulation of alkaloids biosynthesis is under intensive study to improve the yield for better agricultural and medicinal application. In this paper, we summarize the structure, related genes, regulation, and toxicity of alkaloids. We focus on the biosynthesis and the regulation network of alkaloids.

Acute exposure to ergot alkaloids from endophyte-infected tall fescue does not alter absorptive or barrier function of the isolated bovine ruminal epithelium.

PubMed

Foote, A P; Penner, G B; Walpole, M E; Klotz, J L; Brown, K R; Bush, L P; Harmon, D L

2014-07-01

Ergot alkaloids in endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum) have been shown to cause a reduction in blood flow to the rumen epithelium as well as a decrease in volatile fatty acids (VFA) absorption from the washed rumen of steers. Previous data also indicates that incubating an extract of endophyte-infected tall fescue seed causes an increase in the amount of VFA absorbed per unit of blood flow, which could result from an alteration in the absorptive or barrier function of the rumen epithelium. An experiment was conducted to determine the acute effects of an endophyte-infected tall fescue seed extract (EXT) on total, passive or facilitated acetate and butyrate flux across the isolated bovine rumen as well as the barrier function measured by inulin flux and tissue conductance (G t ). Flux of ergovaline across the rumen epithelium was also evaluated. Rumen tissue from the caudal dorsal sac of Holstein steers (n=6), fed a common diet, was collected and isolated shortly after slaughter and mounted between two halves of Ussing chambers. In vitro treatments included vehicle control (80% methanol, 0.5% of total volume), Low EXT (50 ng ergovaline/ml) and High EXT (250 ng ergovaline/ml). Results indicate that there is no effect of acute exposure to ergot alkaloids on total, passive or facilitated flux of acetate or butyrate across the isolate bovine rumen epithelium (P>0.51). Inulin flux (P=0.16) and G t (P>0.17) were not affected by EXT treatment, indicating no alteration in barrier function due to acute ergot alkaloid exposure. Ergovaline was detected in the serosal buffer of the High EXT treatment indicating that the flux rate is ~0.25 to 0.44 ng/cm2 per hour. Data indicate that specific pathways for VFA absorption and barrier function of the rumen epithelium are not affected by acute exposure to ergot alkaloids from tall fescue at the concentrations tested. Ergovaline has the potential to be absorbed from the rumen of cattle that could contribute to reduced blood flow and motility and lead to reduced growth rates of cattle.

Rhodococcus erythropolis MTHt3 biotransforms ergopeptines to lysergic acid.

PubMed

Thamhesl, Michaela; Apfelthaler, Elisabeth; Schwartz-Zimmermann, Heidi Elisabeth; Kunz-Vekiru, Elisavet; Krska, Rudolf; Kneifel, Wolfgang; Schatzmayr, Gerd; Moll, Wulf-Dieter

2015-03-28

Ergopeptines are a predominant class of ergot alkaloids produced by tall fescue grass endophyte Neotyphodium coenophialum or cereal pathogen Claviceps purpurea. The vasoconstrictive activity of ergopeptines makes them toxic for mammals, and they can be a problem in animal husbandry. We isolated an ergopeptine degrading bacterial strain, MTHt3, and classified it, based on its 16S rDNA sequence, as a strain of Rhodococcus erythropolis (Nocardiaceae, Actinobacteria). For strain isolation, mixed microbial cultures were obtained from artificially ergot alkaloid-enriched soil, and provided with the ergopeptine ergotamine in mineral medium for enrichment. Individual colonies derived from such mixed cultures were screened for ergotamine degradation by high performance liquid chromatography and fluorescence detection. R. erythropolis MTHt3 converted ergotamine to ergine (lysergic acid amide) and further to lysergic acid, which accumulated as an end product. No other tested R. erythropolis strain degraded ergotamine. R. erythropolis MTHt3 degraded all ergopeptines found in an ergot extract, namely ergotamine, ergovaline, ergocristine, ergocryptine, ergocornine, and ergosine, but the simpler lysergic acid derivatives agroclavine, chanoclavine, and ergometrine were not degraded. Temperature and pH dependence of ergotamine and ergine bioconversion activity was different for the two reactions. Degradation of ergopeptines to ergine is a previously unknown microbial reaction. The reaction end product, lysergic acid, has no or much lower vasoconstrictive activity than ergopeptines. If the genes encoding enzymes for ergopeptine catabolism can be cloned and expressed in recombinant hosts, application of ergopeptine and ergine degrading enzymes for reduction of toxicity of ergot alkaloid-contaminated animal feed may be feasible.

Evolutionary history of ergot with a new infrageneric classification (Hypocreales: Clavicipitaceae: Claviceps).

PubMed

Píchová, Kamila; Pažoutová, Sylvie; Kostovčík, Martin; Chudíčková, Milada; Stodůlková, Eva; Novák, Petr; Flieger, Miroslav; van der Linde, Elna; Kolařík, Miroslav

2018-06-01

The ergot, genus Claviceps, comprises approximately 60 species of specialised ovarial grass parasites famous for the production of food toxins and pharmaceutics. Although the ergot has been known for centuries, its evolution have not been resolved yet. Our approach combining multilocus phylogeny, molecular dating and the study of ecological, morphological and metabolic features shows that Claviceps originated in South America in the Palaeocene on a common ancestor of BEP (subfamilies Bambusoideae, Ehrhartoideae, Pooideae) and PACMAD (subfamilies Panicoideae, Aristidoideae, Chloridoideae, Micrairoideae, Arundinoideae, Danthonioideae) grasses. Four clades described here as sections diverged during the Paleocene and Eocene. Since Claviceps are parasitic fungi with a close relationship with their host plants, their evolution is influenced by interactions with the new hosts, either by the spread to a new continent or the radiation of the host plants. Three of the sections possess very narrow host ranges and biogeographical distributions and have relatively low toxicity. On the contrary, the section Claviceps, comprising the rye ergot, C. purpurea, is unique in all aspects. Fungi in this section of North American origin have spread all over the world and infect grasses in all subfamilies as well as sedges, and it is the only section synthesising toxic ergopeptines and secalonic acids. The evolutionary success of the Claviceps section members can be explained by high toxin presence, serving as feeding deterrents and playing a role in their protective mutualism with host plants. Closely related taxa Neoclaviceps monostipa and Cepsiclava phalaridis were combined into the genus Aciculosporium. Copyright © 2018 Elsevier Inc. All rights reserved.

Variation in the expression of ergot alkaloids between individual tillers of perennial ryegrass

NASA Astrophysics Data System (ADS)

Mace, Wade; Lunn, Kristy; Lloyd-West, Catherine

2014-11-01

Epichloë fungal endophytes of cool season grasses are well known to produce a range of alkaloids of benefit to the host. Some of these compounds are advantageous to agriculture due to qualities that promote pasture persistence (e.g. the loline class of alkaloids confer insect protection) while others are detrimental to the wellbeing of grazing livestock. The ergot alkaloids (e.g. ergovaline), produced in ryegrass and tall fescue associations, causes poor animal health in farming regions in many countries around the world and further study is required to improve our knowledge on this class of compounds. Here we present the application of a quantitative LC-MS/MS (liquid chromatography coupled to mass spectrometry) method measuring eight ergot alkaloids (chanoclavine, agroclavine, elymoclavine, lysergol, lysergic acid, ergine, lysergyl alanine, ergovaline) produced by endophyte infected grasses, to monitor levels in individual tillers from multiple plants of a single cultivar of perennial ryegrass (Lolium perenne cv. ‘Grasslands Samson’) infected with a common toxic endophyte strain (Epichloë festucae var. lolii). Monitoring the expression in individual tillers allows an estimation of the variability within a plant (between tillers) as well as between plants. The study showed that there is significant variation in the concentration of the ergot alkaloids between tillers of a single plant, at or exceeding the level of variation observed between individual plants of a population. This result emphasizes the fundamental importance of robust experimental design and sampling procedures when alkaloid expression assessment is required and these need to be rigorously tailored to the hypothesis being tested.

Controlled study on the effect of pentoxifylline and an ergot alkaloid derivative on regional cerebral blood flow in patients with chronic cerebrovascular disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hartmann, A.; Tsuda, Y.

Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic therapy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pentoxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the controlmore » group; both the pentoxifylline and the ergot alkaloid group presented with a significant increase in the CBF. This positive effect was significantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation period.« less

Antibody binding of circulating ergot alkaloids in cattle grazing tall fescue.

PubMed

Hill, N S; Thompson, F N; Dawe, D L; Stuedemann, J A

1994-03-01

Direct evidence linking alkaloids found in endophyte-infected tall fescue forage with the livestock disorder known as fescue toxicosis is lacking. Physiologic effects of fescue toxicosis include reduced serum prolactin concentration in cattle. A monoclonal antibody specific to the lysergic moiety of ergot alkaloids was developed in mice after creating an immunogen by linking lysergol to human serum albumin. The antibody was specific to the lysergic moiety and, therefore, it cross-reacted with ergot alkaloids, lysergic acid, and lysergol. The antibody did not cross-react with alkaloid derivatives that had bromated or hydrogenated lysergic ring moieties. Fescue toxicosis conditions were elicited in yearling Angus steers by permitting them to graze endophyte-infected tall fescue containing > 650 micrograms/kg of ergovaline for 60 days. Passive immunization of steers by infusion of the monoclonal antibody increased serum prolactin concentration by 7 ng/ml, beginning immediately after infusion. Control steers did not respond to treatment with bovine serum albumin. Active immunization of yearling Angus heifers with immunogens containing lysergol or ergonovine linked to human serum albumin resulted in an antibody response.

Purpurolic acid: A new natural alkaloid from Claviceps purpurea (Fr.) Tul.

PubMed

Roberts, Andrew; Beaumont, Claire; Manzarpour, Azita; Mantle, Peter

2016-01-01

A novel secondary metabolite from the sclerotia of Claviceps purpurea (Fr.) Tul. is described; the structure is based on (1)H and (13)C NMR spectroscopy and electrospray mass spectrometry. It has an elemental composition C10H16N2O7 and is comprised mainly of proline and alanine moieties, although without peptide linkage. Notably, these amino-acids are also components of the cyclic tripeptide side chain of several classic ergoline alkaloids. Designated as purpurolic acid, the new compound is the principal free amino-acid in ergot and its natural abundance exceeds that of the ergoline alkaloids with which it accumulates in parallel during parasitic development. In contrast, it does not accumulate in the fungus in axenic culture, even when ergotamine is synthesised. The extent to which the compound is a metabolite of other ergot fungi worldwide is unknown. Biological activity and metabolic significance also remain unknown, but purpurolic acid could become a biomarker for detection of ergot contamination in agricultural products of temperate latitudes. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Use of a nonhomologous end joining deficient strain (Deltaku70) of the ergot fungus Claviceps purpurea for identification of a nonribosomal peptide synthetase gene involved in ergotamine biosynthesis.

PubMed

Haarmann, Thomas; Lorenz, Nicole; Tudzynski, Paul

2008-01-01

The ergot fungus Claviceps purpurea uses mainly the nonhomologous-end-joining (NHEJ) system for integration of exogenous DNA, leading to a low frequency of homologous integration (1-2%). To improve gene targeting efficiency we deleted the C. purpurea ku70 gene in two different strains: the pathogenic strain 20.1 and the apathogenic, ergot alkaloid producing strain P1. The mutants were not impaired in vegetative and pathogenic development nor alkaloid production. Gene targeting efficiency was significantly increased (50-60%) in the Deltaku70 mutants. The P1 Deltaku70 strain (producing ergotamine and ergocryptine) was used for targeted deletion of lpsA1, one of the two trimodular NRPS genes present in the alkaloid gene cluster, encoding D-lysergyl peptide synthetases involved in formation of the tripeptide moiety of ergopeptines. Mutants lacking the lpsA1 gene were shown to be incapable of producing ergotamine but were still able to produce ergocryptine, proving that LpsA1 is involved in ergotamine biosynthesis.

Effect of ergot alkaloids on serum prolactin in non-psychotic organic brain syndrome of the elderly.

PubMed

Gross, R J; Eisdorfer, C E; Schiller, H S; Cox, G

1979-08-01

A compound of ergot alkaloids (Hydergine-Sandoz) or placebo was given to sixty elderly nursing home patients with non-psychotic organic brain syndrome. Subsequent to 12 weeks of treatment, the mean serum prolactin of the drug was significantly lower than that of the placebo group. No correlation was found between changes in prolactin and changes in behavior using Sandoz Assessment of Clinical Status Rating Form-Geriatric [SCAG]. It may be that a higher dose of Hydergine with an accompanying greater drop in prolactin would be required to observe this effect.

Claviceps purpurea expressing polygalacturonases escaping PGIP inhibition fully infects PvPGIP2 wheat transgenic plants but its infection is delayed in wheat transgenic plants with increased level of pectin methyl esterification.

PubMed

Volpi, Chiara; Raiola, Alessandro; Janni, Michela; Gordon, Anna; O'Sullivan, Donal M; Favaron, Francesco; D'Ovidio, Renato

2013-12-01

Claviceps purpurea is a biotrophic fungal pathogen of grasses causing the ergot disease. The infection process of C. purpurea on rye flowers is accompanied by pectin degradation and polygalacturonase (PG) activity represents a pathogenicity factor. Wheat is also infected by C. purpurea and we tested whether the presence of polygalacturonase inhibiting protein (PGIP) can affect pathogen infection and ergot disease development. Wheat transgenic plants expressing the bean PvPGIP2 did not show a clear reduction of disease symptoms when infected with C. purpurea. To ascertain the possible cause underlying this lack of improved resistance of PvPGIP2 plants, we expressed both polygalacturonases present in the C. purpurea genome, cppg1 and cppg2 in Pichia pastoris. In vitro assays using the heterologous expressed PGs and PvPGIP2 showed that neither PG is inhibited by this inhibitor. To further investigate the role of PG in the C. purpurea/wheat system, we demonstrated that the activity of both PGs of C. purpurea is reduced on highly methyl esterified pectin. Finally, we showed that this reduction in PG activity is relevant in planta, by inoculating with C. purpurea transgenic wheat plants overexpressing a pectin methyl esterase inhibitor (PMEI) and showing a high degree of pectin methyl esterification. We observed reduced disease symptoms in the transgenic line compared with null controls. Together, these results highlight the importance of pectin degradation for ergot disease development in wheat and sustain the notion that inhibition of pectin degradation may represent a possible route to control of ergot in cereals. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Alkaloid Cluster Gene ccsA of the Ergot Fungus Claviceps purpurea Encodes Chanoclavine I Synthase, a Flavin Adenine Dinucleotide-Containing Oxidoreductase Mediating the Transformation of N-Methyl-Dimethylallyltryptophan to Chanoclavine I ▿

PubMed Central

Lorenz, Nicole; Olšovská, Jana; Šulc, Miroslav; Tudzynski, Paul

2010-01-01

Ergot alkaloids are indole-derived secondary metabolites synthesized by the phytopathogenic ascomycete Claviceps purpurea. In wild-type strains, they are exclusively produced in the sclerotium, a hibernation structure; for biotechnological applications, submerse production strains have been generated by mutagenesis. It was shown previously that the enzymes specific for alkaloid biosynthesis are encoded by a gene cluster of 68.5 kb. This ergot alkaloid cluster consists of 14 genes coregulated and expressed under alkaloid-producing conditions. Although the role of some of the cluster genes in alkaloid biosynthesis could be confirmed by a targeted knockout approach, further functional analyses are needed, especially concerning the early pathway-specific steps up to the production of clavine alkaloids. Therefore, the gene ccsA, originally named easE and preliminarily annotated as coding for a flavin adenine dinucleotide-containing oxidoreductase, was deleted in the C. purpurea strain P1, which is able to synthesize ergot alkaloids in axenic culture. Five independent knockout mutants were analyzed with regard to alkaloid-producing capability. Thin-layer chromatography (TLC), ultrapressure liquid chromatography (UPLC), and mass spectrometry (MS) analyses revealed accumulation of N-methyl-dimethylallyltryptophan (Me-DMAT) and traces of dimethylallyltryptophan (DMAT), the first pathway-specific intermediate. Since other alkaloid intermediates could not be detected, we conclude that deletion of ccsA led to a block in alkaloid biosynthesis beyond Me-DMAT formation. Complementation with a ccsA/gfp fusion construct restored alkaloid biosynthesis. These data indicate that ccsA encodes the chanoclavine I synthase or a component thereof catalyzing the conversion of N-methyl-dimethylallyltryptophan to chanoclavine I. PMID:20118373

Alkaloid cluster gene ccsA of the ergot fungus Claviceps purpurea encodes chanoclavine I synthase, a flavin adenine dinucleotide-containing oxidoreductase mediating the transformation of N-methyl-dimethylallyltryptophan to chanoclavine I.

PubMed

Lorenz, Nicole; Olsovská, Jana; Sulc, Miroslav; Tudzynski, Paul

2010-03-01

Ergot alkaloids are indole-derived secondary metabolites synthesized by the phytopathogenic ascomycete Claviceps purpurea. In wild-type strains, they are exclusively produced in the sclerotium, a hibernation structure; for biotechnological applications, submerse production strains have been generated by mutagenesis. It was shown previously that the enzymes specific for alkaloid biosynthesis are encoded by a gene cluster of 68.5 kb. This ergot alkaloid cluster consists of 14 genes coregulated and expressed under alkaloid-producing conditions. Although the role of some of the cluster genes in alkaloid biosynthesis could be confirmed by a targeted knockout approach, further functional analyses are needed, especially concerning the early pathway-specific steps up to the production of clavine alkaloids. Therefore, the gene ccsA, originally named easE and preliminarily annotated as coding for a flavin adenine dinucleotide-containing oxidoreductase, was deleted in the C. purpurea strain P1, which is able to synthesize ergot alkaloids in axenic culture. Five independent knockout mutants were analyzed with regard to alkaloid-producing capability. Thin-layer chromatography (TLC), ultrapressure liquid chromatography (UPLC), and mass spectrometry (MS) analyses revealed accumulation of N-methyl-dimethylallyltryptophan (Me-DMAT) and traces of dimethylallyltryptophan (DMAT), the first pathway-specific intermediate. Since other alkaloid intermediates could not be detected, we conclude that deletion of ccsA led to a block in alkaloid biosynthesis beyond Me-DMAT formation. Complementation with a ccsA/gfp fusion construct restored alkaloid biosynthesis. These data indicate that ccsA encodes the chanoclavine I synthase or a component thereof catalyzing the conversion of N-methyl-dimethylallyltryptophan to chanoclavine I.

Derivatives of Ergot-alkaloids: Molecular structure, physical properties, and structure-activity relationships

NASA Astrophysics Data System (ADS)

Ivanova, Bojidarka B.; Spiteller, Michael

2012-09-01

A comprehensive screening of fifteen functionalized Ergot-alkaloids, containing bulk aliphatic cyclic substituents at D-ring of the ergoline molecular skeleton was performed, studying their structure-active relationships and model interactions with α2A-adreno-, serotonin (5HT2A) and dopamine D3 (D3A) receptors. The accounted high affinity to the receptors binding loops and unusual bonding situations, joined with the molecular flexibility of the substituents and the presence of proton accepting/donating functional groups in the studied alkaloids, may contribute to further understanding the mechanisms of biological activity in vivo and in predicting their therapeutic potential in central nervous system (CNS), including those related the Schizophrenia. Since the presented correlation between the molecular structure and properties, was based on the comprehensively theoretical computational and experimental physical study on the successfully isolated derivatives, through using routine synthetic pathways in a relatively high yields, marked these derivatives as 'treasure' for further experimental and theoretical studied in areas such as: (a) pharmacological and clinical testing; (b) molecular-drugs design of novel psychoactive substances; (c) development of the analytical protocols for determination of Ergot-alkaloids through a functionalization of the ergoline-skeleton, and more.

Ergotamine and nicergoline - facts and myths.

PubMed

Zajdel, Paweł; Bednarski, Marek; Sapa, Jacek; Nowak, Gabriel

2015-04-01

Ergotamine, being a representative of naturally occurring ergoline alkaloids, derived from d-lysergic acid, and nicergoline, a d-lumilysergic acid derivative belonging to semi-synthetic ergot-derived alkaloids, display diversified affinity for adrenergic, serotoninergic, and dopamine receptors. Although introduction of triptans marginalized use of ergotamine, nicergoline is used in cerebral metabolic-vascular disorders, and dementia. Additionally, nicergoline exhibits a safety profile comparable to that of placebo, and none of the reviewed studies reported any incidence of fibrosis or ergotism with nicergoline treatment. In line with the recent data, activation of 5-HT2B receptor by ergot derivatives i.e. ergotamine, methysergide, pergolide, and carbegoline is involved in pathogenesis of drug-induced valvulopathy. In contrary structurally related drugs - lisuride and terguride do not increase the risk of valvular heart disease. It seems, that more detailed mechanistic studies on nicergoline and ergotamine might be beneficial for determining structural requirements related to activation of G-protein as well as alternative signal transduction pathways e.g. β-arrestins or different kinases, and responsible for drug liabilities. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Long-lasting ergot lipids as new biomarkers for assessing the presence of cereals and cereal products in archaeological vessels.

PubMed

Lucejko, Jeannette J; La Nasa, Jacopo; Porta, Francesca; Vanzetti, Alessandro; Tanda, Giuseppa; Mangiaracina, Claudio Filippo; Corretti, Alessandro; Colombini, Maria Perla; Ribechini, Erika

2018-03-02

Cereals were very important in ancient diets, however evidence from archaeological sites of the vessels used for processing or storing cereals is comparatively rare. Micro-organisms, as well as chemical-physical effects can easily degrade cereals during the burial period. This can lead to a complete cereal decay and to serious difficulties in estimating the intensity of use of the cereals by ancient populations. Here, we present a novel biomarker approach entailing the detection of secondary lipid metabolites produced by ergot fungi (genus Claviceps), which are common cereal pests. The aim was to identify the original presence of Gramineae and to indirectly establish if vessels were used for cereal storage/processing. The fatty acid and TAG-estolide profiles of the remains from more than 30 archaeological vessels were investigated by gas chromatography/mass spectrometry (GC/MS) and high performance liquid chromatography/high resolution mass spectrometry (HPLC/ESI-Q-ToF). The detection of lipids derived from ergot in archaeological and historic contexts rests on its complex chemistry, providing a unique and relatively recalcitrant chemical signature for cereals. This research demonstrated that the combination of our innovative biomarker approach along with environmental and archaeological evidence can provide unprecedented insights into the incidence of cereals and related processing activities in ancient societies.

Ergot alkaloid transport across ruminant gastric tissues.

PubMed

Hill, N S; Thompson, F N; Stuedemann, J A; Rottinghaus, G W; Ju, H J; Dawe, D L; Hiatt, E E

2001-02-01

Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected tall fescue. It is generally accepted that ergovaline is the toxic component of endophyte-infected tall fescue, but there is no direct evidence to support this hypothesis. The objective of this study was to examine relative and potential transport of ergoline and ergopeptine alkaloids across isolated gastric tissues in vitro. Sheep ruminal and omasal tissues were surgically removed and placed in parabiotic chambers. Equimolar concentrations of lysergic acid, lysergol, ergonovine, ergotamine, and ergocryptine were added to a Kreb's Ringer phosphate (KRP) solution on the mucosal side of the tissue. Tissue was incubated in near-physiological conditions for 240 min. Samples were taken from KRP on the serosal side of the chambers at times 0, 30, 60, 120, 180, and 240 min and analyzed for ergot alkaloids by competitive ELISA. The serosal KRP remaining after incubation was freeze-dried and the alkaloid species quantified by HPLC. The area of ruminal and omasal tissues was measured and the potential transportable alkaloids calculated by multiplying the moles of transported alkaloids per square centimeter of each tissue type by the surface area of the tissue. Studies were conducted to compare alkaloid transport in reticular, ruminal, and omasal tissues and to determine whether transport was active or passive. Ruminal tissue had greater ergot alkaloid transport potential than omasal tissue (85 vs 60 mmol) because of a larger surface area. The ruminal posterior dorsal sac had the greatest potential for alkaloid transport, but the other ruminal tissues were not different from one another. Alkaloid transport was less among reticular tissues than among ruminal tissues. Transport of alkaloids seemed to be an active process. The alkaloids with greatest transport potential were lysergic acid and lysergol. Ergopeptine alkaloids tended to pass across omasal tissues in greater quantities than across ruminal tissues, but their transport was minimal compared to lysergic acid and lysergol.

Vasoconstrictive Responses by the Carotid and Auricular Arteries in goats to Ergot Alkaloid Exposure

NASA Astrophysics Data System (ADS)

Aiken, Glen; Flythe, Michael

2014-11-01

A fungal endophyte (Neotyphodium coenophialum) infects most plants of ‘Kentucky 31’ tall fescue (Lolium arundinaceum) and produces ergot alkaloids that cause persistent constriction of the vascular system in grazing livestock. Consequently, animals undergoing this toxicosis cannot regulate core body temperature and are vulnerable to heat and cold stresses. An experiment was conducted to determine if the caudal and auricular arteries in goats (Capra aegagrus hircus) vasoconstrict in response to ergot alkaloids. Seven, rumen fistulated goats were fed ad libitum orchardgrass (Dactylis glomeratia) hay and ruminally infused with endophtye-free seed (E-) for a 7-day adjustment period. Two periods followed with E- and endophyte-infected (E+) seed being randomly assigned to the 2 goat groups in period 1 and then switching treatments between groups in period 2. Infused E+ and E- seed were in equal proportions to the hay such that concentrations of ergovaline and ergovalanine were 0.80 µg per g dry matter for the E+ treatment. Cross-sections of both arteries were imaged using Doppler ultrasonography on days 0, 2, 4, 6, 8, and 12 in period 1 and on days 0, 1, 2, 3, 6, 7, and 9 in period 2. Differences from average baseline areas were used to determine presence or absence of alkaloid-induced vasoconstriction. Carotid arteries initiated constriction on imaging day 2 in both periods, and auricular arteries initiated constriction on imaging day 2 in period 1 and on day 6 in period 2. Luminal areas of the carotid arteries in E+ goats were 46% less than baseline areas in both periods after vasoconstriction occurred, whereas auricular arteries in E+ goats were 52% less than baseline areas in period 1 and 38% in period 2. Both arteries in E+ goats in period 1 relaxed relative to baseline areas by imaging day 2 after they were switched to the E- treatment. Results indicated that goats can vasoconstrict when exposed to ergot alkaloids that could disrupt their thermoregulation.

The key role of peltate glandular trichomes in symbiota comprising clavicipitaceous fungi of the genus periglandula and their host plants.

PubMed

Steiner, Ulrike; Kucht, Sabine Hellwig neé; Ahimsa-Müller, Mahalia A; Grundmann, Nicola; Li, Shu-Ming; Drewke, Christel; Leistner, Eckhard

2015-04-16

Clavicipitaceous fungi producing ergot alkaloids were recently discovered to be epibiotically associated with peltate glandular trichomes of Ipomoea asarifolia and Turbina corymbosa, dicotyledonous plants of the family Convolvulaceae. Mediators of the close association between fungi and trichomes may be sesquiterpenes, main components in the volatile oil of different convolvulaceous plants. Molecular biological studies and microscopic investigations led to the observation that the trichomes do not only secrete sesquiterpenes and palmitic acid but also seem to absorb ergot alkaloids from the epibiotic fungal species of the genus Periglandula. Thus, the trichomes are likely to have a dual and key function in a metabolic dialogue between fungus and host plant.

Palladium-catalyzed reactions in the synthesis of 3- and 4-substituted indoles. 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hegedus, L.S.; Sestrick, M.R.; Michaelson, E.T.

1989-08-18

4-Bromo-1-tosylindole (1) was converted to tricyclic indole enone 11, a potential intermediate in the synthesis of tetracyclic ergot alkaloids, by a series of palladium-catalyzed processes. Attempts to construct the ergot D ring by the hetero-Diels-Alder reaction of enone 11 and 1-azabutadiene 12 produced not the expected (4 + 2) adduct 13 but the benz(cd)indoline derivative 14 resulting from attack of the aza diene at the indole 2-position. The thermodynamic stability of the naphthol nucleus makes enone 11 generally susceptible to attack at the indole 2-position, as evidenced by the attack of hydride and methyl cuprate nucleophiles at this portion formingmore » indolines 16 and 17, respectively.« less

Inactivation of the indole-diterpene biosynthetic gene cluster of Claviceps paspali by Agrobacterium-mediated gene replacement.

PubMed

Kozák, László; Szilágyi, Zoltán; Vágó, Barbara; Kakuk, Annamária; Tóth, László; Molnár, István; Pócsi, István

2018-04-01

The hypocrealean fungus Claviceps paspali is a parasite of wild grasses. This fungus is widely utilized in the pharmaceutical industry for the manufacture of ergot alkaloids, but also produces tremorgenic and neurotoxic indole-diterpene (IDT) secondary metabolites such as paspalitrems A and B. IDTs cause significant losses in agriculture and represent health hazards that threaten food security. Conversely, IDTs may also be utilized as lead compounds for pharmaceutical drug discovery. Current protoplast-mediated transformation protocols of C. paspali are inadequate as they suffer from inefficiencies in protoplast regeneration, a low frequency of DNA integration, and a low mitotic stability of the nascent transformants. We adapted and optimized Agrobacterium tumefaciens-mediated transformation (ATMT) for C. paspali and validated this method with the straightforward creation of a mutant strain of this fungus featuring a targeted replacement of key genes in the putative IDT biosynthetic gene cluster. Complete abrogation of IDT production in isolates of the mutant strain proved the predicted involvement of the target genes in the biosynthesis of IDTs. The mutant isolates continued to produce ergot alkaloids undisturbed, indicating that equivalent mutants generated in industrial ergot producers may have a better safety profile as they are devoid of IDT-type mycotoxins. Meanwhile, ATMT optimized for Claviceps spp. may open the door for the facile genetic engineering of these industrially and ecologically important organisms.

Ergot species of the Claviceps purpurea group from South Africa.

PubMed

van der Linde, Elna J; Pešicová, Kamila; Pažoutová, Sylvie; Stodůlková, Eva; Flieger, Miroslav; Kolařík, Miroslav

2016-08-01

Results of a survey and study of the Claviceps purpurea group of species in South Africa are being presented and five new species are described. Morphological descriptions are based on the anamorphs and four nuclear genetic loci. Claviceps fimbristylidis sp. nov. on Fimbristylis complanata was discovered wide-spread across five provinces of the country associated with water and represents the fourth Claviceps species recorded from the Cyperaceae. Claviceps monticola sp. nov. is described from Brachypodium flexum growing in mountain forests in Mpumalanga Province, as well as the northern Drakensberg southwards into the Eastern Cape Province. Claviceps pazoutovae sp. nov. is recorded from Stipa dregeana var. dregeana and Ehrharta erecta var. erecta, also associated with these mountain ranges. Claviceps macroura sp. nov. is recorded from Cenchrus macrourus from the Eastern Cape and Claviceps capensis sp. nov. from Ehrharta villosa var. villosa is recorded from the Western Cape Province. Claviceps cyperi, only recorded from South Africa is included in the study. Ergot alkaloid profiles of all species are provided and showed similarity to C. purpurea. Only C. cyperi and in lesser degree C. capensis, C. macroura, and C. pazoutovae produced ergot alkaloids in clinically significant amounts. Several reported species infect invasive grass species, native to South Africa, and thus represent potentially invasive species. Copyright © 2016 British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Horizontal acquisition of toxic alkaloid synthesis in a clade of plant associated fungi.

PubMed

Marcet-Houben, Marina; Gabaldón, Toni

2016-01-01

Clavicipitaceae is a fungal group that comprises species that closely interact with plants as pathogens, parasites or symbionts. A key factor in these interactions is the ability of these fungi to synthesize toxic alkaloid compounds that contribute to the protection of the plant host against herbivores. Some of these compounds such as ergot alkaloids are toxic to humans and have caused important epidemics throughout history. The gene clusters encoding the proteins responsible for the synthesis of ergot alkaloids and lolines in Clavicipitaceae have been elucidated. Notably, homologs to these gene clusters can be found in distantly related species such as Aspergillus fumigatus and Penicillium expansum, which diverged from Clavicipitaceae more than 400 million years ago. We here use a phylogenetic approach to analyze the evolution of these gene clusters. We found that the gene clusters conferring the ability to synthesize ergot alkaloids and loline emerged first in Eurotiomycetes and were then likely transferred horizontally to Clavicipitaceae. Horizontal gene transfer is known to play a role in shaping the distribution of secondary metabolism clusters across distantly related fungal species. We propose that HGT events have played an important role in the capability of Clavicipitaceae to produce two key secondary metabolites that have enhanced the ability of these species to protect their plant hosts, therefore favoring their interactions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Early harvest and ensilage of forage sorghum infected with ergot (Claviceps africana) reduces the risk of livestock poisoning.

PubMed

Blaney, B J; Ryley, M J; Boucher, B D

2010-08-01

Sorghum ergot produces dihydroergosine (DHES) and related alkaloids, which cause hyperthermia in cattle. Proportions of infected panicles (grain heads), leaves and stems were determined in two forage sorghum crops extensively infected 2 to 4 weeks prior to sampling and the panicles were assayed for DHES. Composite samples from each crop, plus a third grain variety crop, were coarsely chopped and half of each sealed in plastic buckets for 6 weeks to simulate ensilation. The worst-infected panicles contained up to 55 mg DHES/kg, but dilution reduced average concentrations of DHES in crops to approximately 1 mg/kg, a relatively safe level for cattle. Ensilation significantly (P = 0.043) reduced mean DHES concentrations from 0.85 to 0.46 mg/kg.

Role of Glycols and Tweens in the Production of Ergot Alkaloids by Claviceps paspali

PubMed Central

Mizrahi, A.; Miller, G.

1969-01-01

Several glycols and Tweens markedly stimulated the production of ergot alkaloids in submerged cultures of Claviceps paspali. The role of these compounds was investigated in shake flasks and bench-scale fermentors. 2,3-Butanediol was not utilized by the fungus, and 1,2-propanediol-1-14C was not incorporated into the alkaloids. Glycols and Tweens lowered the surface tension of the basal medium and promoted the utilization of metabolites. In the presence of glycols and Tweens, an increased uptake of labeled sorbitol and succinic acid took place, whereas the specific radioactivity of the alkaloids was not affected. These results indicated that glycols and Tweens are not involved directly in the biosynthetic process; they apparently acted as surface-active agents, facilitating transport of metabolites into the cells. PMID:5776521

A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline.

PubMed

Fioravanti, Mario; Nakashima, Taku; Xu, Jun; Garg, Amit

2014-07-30

To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials. Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications. MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included. 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8). The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment. Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline

PubMed Central

Fioravanti, Mario; Nakashima, Taku; Xu, Jun; Garg, Amit

2014-01-01

Objective To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials. Design Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications. Data sources MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included. Review method 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8). Results The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment. Conclusions Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline. PMID:25079927

Association of insects and ergot (Claviceps purpurea) in Kentucky bluegrass seed production fields.

PubMed

Butler, M D; Alderman, S C; Hammond, P C; Berry, R E

2001-12-01

Insects in Kentucky bluegrass seed production fields in Oregon, Idaho, and Washington were sampled just before harvest and their association with ergot conidia of Claviceps purpurea Fr. (Tul.) was evaluated during 1996-1998. A diversity of insects was observed at all three locations. The most abundant beneficial insects collected with sweep nets were Nysium spp., Nabis spp., ichneumonid wasps, and Hippodamia spp. The cranberry girdler, Chrysoteuchia topiaria (Zeller), was the only important pest on grass seed collected by sweep net. Numbers of aphids such as Sitobion avenae (F.), cicadellids and thrips such as Anaphothrips spp. and Aptinothrips spp. that were collected with all aphid sampler were below economic thresholds. Other insect groups occurred in low numbers. Noctuid moths collected in universal blacklight traps included nine species of cutworms and armyworms. Protogrotis obscura (B. & McD.) was the most common cutworm species and was present in all fields. The moth Chortodes rufostrigata (Pack.) previously reported only from wet meadows in northeast and south central Oregon was found in Kentucky bluegrass fields in central Oregon, suggesting that irrigated Kentucky bluegrass seed production fields may simulate a montane meadow habitat. Conidia of C. purpurea were found on a diversity of insects, including moths, flies, leafhoppers, and thrips. Up to 100% of moths and 75% of flies collected from some fields carried conidia of C. purpurea. No correlation between ergot honeydew present in a field and number of insects with conidia of C. purpurea was detected.

Tall fescue ergot alkaloids are vasoactive in equine vasculature

USDA-ARS?s Scientific Manuscript database

Mares grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundinaceum) typically exhibit reproductive dysfunction rather than problems associated with peripheral vasoconstriction as a primary sign of the fescue toxicosis syndrome. Research using Doppler ultrasonography demonstrate...

Pharmacotherapy for organic brain syndrome in late life. Evaluation of an ergot derivative vs placebo.

PubMed

Gaitz, C M; Varner, R V; Overall, J E

1977-07-01

Evaluation of treatment modalities, including pharmacotherapy, for organic brain syndrome (OBS) has been difficult because of sampling and methodological problems, and comparisons of research studies are all but impossible. In this study, an ergot derivative, a combination of dihydroergocornine mesylate, dihydroergocristine mesylate, and dihydroergokryptine mesylate (Hydergine) was compared with placebo, using a double-blind technique in a sample of nursing home residents with evidence of OBS. An 18-category symptom rating scale was used for periodic assessment over a six-month interval. Comparisons of the two groups of subjects disclosed that the Hydergine-treated group showed statistically significantly more improvement in most of the variables measured, especially during the last three months of treatment. Furthermore, sophisticated analysis revealed that positive changes in cognitive function cannot be accounted for as a mere reflection, or "halo" effect, associated with improved mood and general sense of well-being.

Molecular cloning and analysis of the ergopeptine assembly system in the ergot fungus Claviceps purpurea.

PubMed

Correia, Telmo; Grammel, Nicolas; Ortel, Ingo; Keller, Ullrich; Tudzynski, Paul

2003-12-01

Claviceps purpurea produces the pharmacological important ergopeptines, a class of cyclol-structured alkaloid peptides containing D-lysergic acid. These compounds are assembled from D-lysergic acid and three different amino acids by the nonribosomal peptide synthetase enzymes LPS1 and LPS2. Cloning of alkaloid biosynthesis genes from C. purpurea has revealed a gene cluster including two NRPS genes, cpps 1 and cpps 2. Protein sequence data had assigned earlier cpps1 to encode the trimodular LPS1 assembling the tripeptide portion of ergopeptines. Here, we show by transcriptional analysis, targeted inactivation, analysis of disruption mutants, and heterologous expression that cpps 2 encodes the monomodular LPS2 responsible for D-lysergic acid activation and incorporation into the ergopeptine backbone. The presence of two distinct NRPS subunits catalyzing formation of ergot peptides is the first example of a fungal NRPS system consisting of different NRPS subunits.

Cultural characteristics, morphology, and variation within Claviceps africana and C. sorghi from India.

PubMed

Muthusubramanian, Venkateshwaran; Bandyopadhyay, Ranajit; Rajaram Reddy, Daram; Tooley, Paul W

2006-04-01

Sorghum ergot in India is caused by Claviceps africana and C. sorghi. The distributions of these two species in India is not known. Eighty-nine sorghum ergot isolates were cultured from young sphacelia obtained from male sterile sorghum plants artificially inoculated using inoculum collected in the field. Based on cultural characteristics, the isolates were separated into two groups which differed distinctly in the morphology of their sphacelia, conidia, and sclerotia. Marked differences also were observed in rates of secondary conidial production and disease spread between the groups. In combination with molecular evidence, our results confirm that the isolates placed in Group I represent C. africana and Group II isolates represent C. sorghi. C. africana was found to be widely distributed in all sorghum growing areas of India. The species first described as occuring in India, C. sorghi, appears to be restricted to a few locations in the states of Maharashtra, Andhra Pradesh, and Karnataka.

Induced parasexual processes in Claviceps sp. strain SD58.

PubMed Central

Brauer, K L; Robbers, J E

1987-01-01

A homokaryotic, clavine alkaloid-producing strain of ergot, Claviceps sp. strain SD 58, was used in an attempt to demonstrate parasexuality. Genetically marked auxotrophic strains were produced by mutation with N-methyl-N'-nitro-N-nitrosoguanidine. Protoplast fusion of pairs of unlike doubly auxotrophic strains and isolation of stable prototrophic fusion products were carried out. By growth of the fusion products on complete medium, selective pressure for prototrophy was removed and auxotrophic segregants were allowed to form. Analysis of these and recovery of segregants with nonleaky, non-parent-type combinations of auxotrophic characteristics has provided strong evidence that a parasexual cycle can function in Claviceps sp. strain SD 58. Preliminary work suggests that the genetics of ergot might be studied by mitotic analysis and that protoplast fusion and selection procedures might be useful for the enhancement of favorable characteristics in Claviceps strains. PMID:3827250

Developments in mycotoxin analysis: an update for 2016-2017

USDA-ARS?s Scientific Manuscript database

This review summarizes developments in the determination of mycotoxins over a period between mid-2016 and mid-2017. Analytical methods to determine aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxins, patulin, trichothecenes and zearalenone are covered in individual sections. Adv...

Developments in mycotoxin analysis: an update for 2015-2016

USDA-ARS?s Scientific Manuscript database

This review summarises developments in the determination of mycotoxins over a period between mid-2015 and mid-2016. Analytical methods to determine aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxins, patulin, trichothecenes, and zearalenone are covered in individual sections. Ad...

Developments in mycotoxin analysis: an update for 2014-2015

USDA-ARS?s Scientific Manuscript database

This review summarizes developments in the determination of mycotoxins over a period between mid-2014 and mid-2015. In tradition with previous articles of this series, analytical methods to determine aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxins, patulin, trichothecenes, an...

Developments in mycotoxin analysis: an update for 2010 - 2011

USDA-ARS?s Scientific Manuscript database

This review highlights developments in mycotoxin analysis and sampling over a period between mid-2010 and mid-2011. It covers the major mycotoxins aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxin, patulin, trichothecenes, and zearalenone. Analytical methods for mycotoxins conti...

Developments in mycotoxin analysis: an update for 2009 - 2010

USDA-ARS?s Scientific Manuscript database

This review highlights developments in mycotoxin analysis and sampling over a period between mid-2009 and mid-2010. It covers the major mycotoxins aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxin, patulin, trichothecenes, and zearalenone. New and improved methods for mycotoxins...

Developments in mycotoxin analysis: an update for 2011-2012

USDA-ARS?s Scientific Manuscript database

This review highlights developments in mycotoxin analysis and sampling over a period between mid-2011 and mid-2012. It covers the major mycotoxins aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxin, patulin, trichothecenes, and zearalenone. A section on mycotoxins in botanicals a...

Tackle fescue toxicosis with spring strategies

USDA-ARS?s Scientific Manuscript database

Understanding times of the year when pastures are most toxic can be useful in developing management approaches to alleviate or reduce the severity of toxicosis. Content of ergot alkaloids in fescue vary considerably during the growing season, with the trends generally following the seasonal growth ...

7 CFR 810.302 - Definitions of other terms.

Code of Federal Regulations, 2010 CFR

2010-01-01

... computation of total dockage. (e) Ergot. Sclerotia (sclerotium, sing.) of the fungus, Claviceps species, which.... (h) Sclerotia (Sclerotium, sing.). Dark colored or black resting bodies of the fungi Sclerotinia and Claviceps. (i) Sclerotinia. Genus name which includes the fungus Sclerotinia sclerotiorum which produces...

7 CFR 810.302 - Definitions of other terms.

Code of Federal Regulations, 2011 CFR

2011-01-01

... computation of total dockage. (e) Ergot. Sclerotia (sclerotium, sing.) of the fungus, Claviceps species, which.... (h) Sclerotia (Sclerotium, sing.). Dark colored or black resting bodies of the fungi Sclerotinia and Claviceps. (i) Sclerotinia. Genus name which includes the fungus Sclerotinia sclerotiorum which produces...

Developments in mycotoxin analysis: an update for 2012 – 2013

USDA-ARS?s Scientific Manuscript database

This review highlights developments in mycotoxin analysis and sampling over a period between mid-2012 and mid-2013. It covers the major mycotoxins: aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxin, patulin, trichothecenes, and zearalenone. A wide range of analytical methods for...

Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

USDA-ARS?s Scientific Manuscript database

The ergot alkaloid ergovaline has demonstrated a persistent and sustained contractile response in several different vascular models. It was hypothesized that different alkaloids isolated from tall fescue (Lolium arundinaceum) will contribute to this contractile response differently. The objective wa...

Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax

USDA-ARS?s Scientific Manuscript database

The ergot alkaloid, ergovaline has demonstrated a persistent binding and sustained contractile response in several vascular models. It was hypothesized that different alkaloids isolated from tall fescue (Lolium arundinaceum) will contribute to this response differently. The objective was to compare ...

Tall fescue seed extraction and partial purification of ergot alkaloids

PubMed Central

Ji, Huihua; Fannin, F.; Klotz, J.; Bush, Lowell

2014-01-01

Many substances in the tall fescue/endophyte association (Schedonorus arundinaceus/Epichloë coenophiala) have biological activity. Of these compounds only the ergot alkaloids are known to have significant mammalian toxicity and the predominant ergot alkaloids are ergovaline and ergovalinine. Because synthetically produced ergovaline is difficult to obtain, we developed a seed extraction and partial purification protocol for ergovaline/ergovalinine that provided a biologically active product. Tall fescue seed was ground and packed into several different sized columns for liquid extraction. Smaller particle size and increased extraction time increased efficiency of extraction. Our largest column was a 114 × 52 × 61 cm (W × L × D) stainless steel tub. Approximately 150 kg of seed could be extracted in this tub. The extraction was done with 80% ethanol. When the solvent front migrated to bottom of the column, flow was stopped and seed was allowed to steep for at least 48 h. Light was excluded from the solvent from the beginning of this step to the end of the purification process. Following elution, ethanol was removed from the eluate by evaporation at room temperature and the resulting syrup was freeze-dried. About 80% recovery of alkaloids was achieved with 18-fold increase in concentration of ergovaline. Initial purification of the dried product was accomplished by extracting with hexane/water (6:1, v/v). The aqueous fraction was extracted with chloroform, the aqueous layer discarded, after which the chloroform was removed with a resulting 20-fold increase of ergovaline. About 65% of the ergovaline was recovered from the chloroform residue for an overall recovery of 50%. The resultant partially purified ergovaline had biological activities in in vivo and in vitro bovine bioassays that approximate that of synthetic ergovaline. PMID:25566528

Combinatorial assembly of simple and complex D-lysergic acid alkaloid peptide classes in the ergot fungus Claviceps purpurea.

PubMed

Ortel, Ingo; Keller, Ullrich

2009-03-13

The ergot fungus Claviceps purpurea produces both ergopeptines and simple d-lysergic acid alkylamides. In the ergopeptines, such as ergotamine, d-lysergic acid is linked to a bicyclic tripeptide in amide-like fashion, whereas in the d-lysergylalkanolamides it is linked to an amino alcohol derived from alanine. We show here that these compound classes are synthesized by a set of three non-ribosomal lysergyl peptide synthetases (LPSs), which interact in a combinatorial fashion for synthesis of the relevant product. The trimodular LPS1 assembles with LPS2, the d-lysergic acid recruiting module, to synthesize the d-lysergyltripeptide precursors of ergopeptines from d-lysergic acid and the three amino acids of the peptide chain. Alternatively, LPS2 can assemble with a distinct monomodular non-ribosomal peptide synthetase (NRPS) subunit (ergometrine synthetase) to synthesize the d-lysergic acid alkanolamide ergometrine from d-lysergic acid and alanine. The synthesis proceeds via covalently bound d-lysergyl alanine and release of dipeptide as alcohol with consumption of NADPH. Enzymatic and immunochemical analyses showed that ergometrine synthetase is most probably the enzyme LPS3 whose gene had been identified previously as part of the ergot alkaloid biosynthesis gene cluster in C. purpurea. Inspections of all LPS sequences showed no recognizable peptide linkers for their protein-protein interactions as in NRPS subunits of bacteria. Instead, they all carry conserved N-terminal domains (C0-domains) with similarity to the C-terminal halves of NRPS condensation domains pointing to an alternative mechanism of subunit-subunit interactions in fungal NRPS systems. Phylogenetic analysis of LPS modules and the C0-domains suggests that these enzyme systems most probably evolved by module duplications and rearrangements from a bimodular ancestor.

Combinatorial Assembly of Simple and Complex d-Lysergic Acid Alkaloid Peptide Classes in the Ergot Fungus Claviceps purpurea*S⃞

PubMed Central

Ortel, Ingo; Keller, Ullrich

2009-01-01

The ergot fungus Claviceps purpurea produces both ergopeptines and simple d-lysergic acid alkylamides. In the ergopeptines, such as ergotamine, d-lysergic acid is linked to a bicyclic tripeptide in amide-like fashion, whereas in the d-lysergylalkanolamides it is linked to an amino alcohol derived from alanine. We show here that these compound classes are synthesized by a set of three non-ribosomal lysergyl peptide synthetases (LPSs), which interact in a combinatorial fashion for synthesis of the relevant product. The trimodular LPS1 assembles with LPS2, the d-lysergic acid recruiting module, to synthesize the d-lysergyltripeptide precursors of ergopeptines from d-lysergic acid and the three amino acids of the peptide chain. Alternatively, LPS2 can assemble with a distinct monomodular non-ribosomal peptide synthetase (NRPS) subunit (ergometrine synthetase) to synthesize the d-lysergic acid alkanolamide ergometrine from d-lysergic acid and alanine. The synthesis proceeds via covalently bound d-lysergyl alanine and release of dipeptide as alcohol with consumption of NADPH. Enzymatic and immunochemical analyses showed that ergometrine synthetase is most probably the enzyme LPS3 whose gene had been identified previously as part of the ergot alkaloid biosynthesis gene cluster in C. purpurea. Inspections of all LPS sequences showed no recognizable peptide linkers for their protein-protein interactions as in NRPS subunits of bacteria. Instead, they all carry conserved N-terminal domains (C0-domains) with similarity to the C-terminal halves of NRPS condensation domains pointing to an alternative mechanism of subunit-subunit interactions in fungal NRPS systems. Phylogenetic analysis of LPS modules and the C0-domains suggests that these enzyme systems most probably evolved by module duplications and rearrangements from a bimodular ancestor. PMID:19139103

Tall fescue seed extraction and partial purification of ergot alkaloids

NASA Astrophysics Data System (ADS)

Bush, Lowell

2014-12-01

Many substances in the tall fescue/endophyte association (Schedonorus arundinaceus/Epichloë coenophiala) have biological activity. Of these compounds only the ergot alkaloids are known to have significant mammalian toxicity and the predominant ergot alkaloids are ergovaline and ergovalinine. Because synthetically produced ergovaline is difficult to obtain, we developed a seed extraction and partial purification protocol for ergovaline/ergovalinine that provided a biologically active product. Tall fescue seed was ground and packed into several different sized columns for liquid extraction. Smaller particle size and increased extraction time increased efficiency of extraction. Our largest column was a 114 × 52 × 61 cm (W×L×D) stainless steel tub. Approximately 150 kg of seed could be extracted in this tub. The extraction was done with 80% ethanol. When the solvent front migrated to bottom of the column, flow was stopped and seed was allowed to steep for at least 48 h. Light was excluded from the solvent from the beginning of this step to the end of the purification process. Following elution, ethanol was removed from the eluate by evaporation at room temperature. Resulting syrup was freeze-dried. About 80% recovery of alkaloids was achieved with 18-fold increase in concentration of ergovaline. Initial purification of the dried product was accomplished by extracting with hexane/water (6:1, v/v) and the hexane fraction was discarded. The aqueous fraction was extracted with chloroform, the aqueous layer discarded, after which the chloroform was removed with a resulting 20-fold increase of ergovaline. About 65% of the ergovaline was recovered from the chloroform residue for an overall recovery of 50%. The resultant partially purified ergovaline had biological activities in in vivo and in vitro bovine bioassays that approximate that of synthetic ergovaline.

Transdermal Patch of Rotigotine Attenuates Freezing of Gait in Patients with Parkinson's Disease: An Open-Label Comparative Study of Three Non-Ergot Dopamine Receptor Agonists.

PubMed

Ikeda, Ken; Hirayama, Takehisa; Takazawa, Takanori; Kawabe, Kiyokazu; Iwasaki, Yasuo

Objective Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic neurons. Rotigotine is a non-ergot dopamine receptor agonist (DA). Its transdermal patch maintains the effective concentrations for 24 hours. Freezing of gait (FOG) is a common and devastating symptom in PD patients. Little is known about therapeutic effects of rotigotine on FOG in PD patients. Herein we compared how three non-ergot DAs of rotigotine, pramipexole LA and ropinirole CR influence FOG, besides classical motor deficits in PD patients. Methods Rotigotine (maintenance doses of 9-27 mg/day) was administered in 51 patients, 36 patients received pramipexole LA (1.5-4.5 mg/day) and 35 patients received ropinirole CR (8-16 mg/day). The Unified PD Rating Scale (UPDRS) parts I-IV, FOG questionnaire (16 items) and wearing off time were examined from baseline to 7 months after DA administration. UPDRS parts I-IV were evaluated during on time and FOG was recorded during off time if patients experienced wearing off. Results A total of 111 patients completed the study. UPDRS parts II-III scores and wearing off time were significantly reduced after each DA treatment compared to baseline. FOG was found in 54 patients (49%). Most patients developed FOG during off time only. FOG scores were significantly decreased at 2 months after rotigotine treatment whereas pramipexole LA and ropinirole treatment did not alter FOG scores. Conclusion The present study indicates that transdermal patch of rotigotine attenuated the FOG off time. The similar binding affinities to dopamine receptors between rotigotine and dopamine, and 24 hours steady hemodynamics could contribute to the therapeutic mechanism of rotigotine on FOG in PD patients with wearing off.

Transdermal Patch of Rotigotine Attenuates Freezing of Gait in Patients with Parkinson's Disease: An Open-Label Comparative Study of Three Non-Ergot Dopamine Receptor Agonists

PubMed Central

Ikeda, Ken; Hirayama, Takehisa; Takazawa, Takanori; Kawabe, Kiyokazu; Iwasaki, Yasuo

2016-01-01

Objective Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic neurons. Rotigotine is a non-ergot dopamine receptor agonist (DA). Its transdermal patch maintains the effective concentrations for 24 hours. Freezing of gait (FOG) is a common and devastating symptom in PD patients. Little is known about therapeutic effects of rotigotine on FOG in PD patients. Herein we compared how three non-ergot DAs of rotigotine, pramipexole LA and ropinirole CR influence FOG, besides classical motor deficits in PD patients. Methods Rotigotine (maintenance doses of 9-27 mg/day) was administered in 51 patients, 36 patients received pramipexole LA (1.5-4.5 mg/day) and 35 patients received ropinirole CR (8-16 mg/day). The Unified PD Rating Scale (UPDRS) parts I-IV, FOG questionnaire (16 items) and wearing off time were examined from baseline to 7 months after DA administration. UPDRS parts I-IV were evaluated during on time and FOG was recorded during off time if patients experienced wearing off. Results A total of 111 patients completed the study. UPDRS parts II-III scores and wearing off time were significantly reduced after each DA treatment compared to baseline. FOG was found in 54 patients (49%). Most patients developed FOG during off time only. FOG scores were significantly decreased at 2 months after rotigotine treatment whereas pramipexole LA and ropinirole treatment did not alter FOG scores. Conclusion The present study indicates that transdermal patch of rotigotine attenuated the FOG off time. The similar binding affinities to dopamine receptors between rotigotine and dopamine, and 24 hours steady hemodynamics could contribute to the therapeutic mechanism of rotigotine on FOG in PD patients with wearing off. PMID:27725534

Rotigotine Transdermal Patch Does Not Make Parkinson Disease Patients Sleepy During Daytime.

PubMed

Ohta, Kouichi; Osada, Takashi

2015-01-01

To assess quantitatively the influence of rotigotine transdermal patch on daytime sleepiness, the most common adverse event by non-ergot dopamine agonists (DAs), in Parkinson disease (PD) patients. An open-label study enrolled PD patients with unsatisfactory control of motor symptoms. Treatment with rotigotine transdermal patch was titrated to optimal dose (4-8 mg/24 hours) over 2 to 4 weeks. Primary outcome was Epworth Sleepiness Scale (ESS) for daytime sleepiness. Secondary outcomes included Hoehn&Yahr stage, time spent with dyskinesia, Clinical Global Impression of Improvement (CGI-I) of motor symptoms, adverse events, and compliance. The subjects were 31 PD patients (age 72 ± 8, Hoehn &Yahr stage 2.7 ± 0.9, mean ± SD). The ESS did not increase after rotigotine treatment (7.2 ± 4.9 before treatment, 6.2 ± 4.0 with 4 mg/24 hour, and 8.1 ± 6.4 with 8 mg/24 hour). The CGI-I score improved after treatment; responder rate reached 88.9% with 8 mg/24 hours. No patients showed worsening in other secondary outcomes. In 13 patients treated with equivalent doses of rotigotine switched from other DAs (pramipexole, ropinirole, and cabergoline), ESS did not increase after treatment (10.0 ± 4.6 before and 8.6 ± 4.5 after treatment) and decreased without worsening of CGI-I in 54% patients. Other secondary outcomes did not worsen after treatment. Twenty four-hour transdermal delivery of rotigotine at doses up to 8 mg/24 hours does not worsen the daytime sleepiness in PD patients and often improves it when switched from other non-ergot DAs. This is achieved together with satisfactory improvement in motor symptoms, demonstrating that this new modality of non-ergot DA is well tolerated and beneficial in PD patients.

Developments in mycotoxin analysis: an update for 2013 – 2014

USDA-ARS?s Scientific Manuscript database

This review highlights developments in the determination of mycotoxins over a period between mid-2013 and mid-2014. It continues in the format of the previous articles of this series, emphasising on analytical methods to determine aflatoxins, Alternaria toxins, ergot alkaloids, fumonisins, ochratoxi...

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Vol. 47/No. RR-4.

DTIC Science & Technology

1998-04-17

antihista- mines (e.g., astemizole or terfenadine); sedative-hypnotics (e.g., alprazolam , midazolam, or triazolam); calcium channel blockers (e.g...acetate, propafenone, or quinidine); ergot alkaloid derivatives; cisapride; sedative-hypnotics (e.g., alprazolam , clorazepate, diazepam, estazo- lam

Afternoon ascospore release in Claviceps purpurea optimizes perennial ryegrass infection

USDA-ARS?s Scientific Manuscript database

In Kentucky bluegrass, Claviceps purpurea, the causal agent of ergot, typically releases ascospores during the early morning hours, between about midnight and 10:00 a.m., corresponding to time of flowering, when the unfertilized ovaries are most susceptible for infection. During aeromycology studies...

Ergovaline recovery from digested residues of grazed tall fescue seedheads

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by the endophyte [Neotyphodium coenophialum (Morgan-Jones and Gams) Glenn, Bacon, and Hanlin] of tall fescue [Lolium arundinaceum (Schreb.) Darbysh.] are a common problem faced by livestock producers. While these toxins are often concentrated within the seedheads, there has...

Influence of tryptophan and related compounds on ergot alkaloid formation in Claviceps purpurea (FR.) Tul.

PubMed

Erge, D; Schumann, B; Gröger, D

1984-01-01

L-Tryptophan did not exert any influence on peptide alkaloid formation in an ergotamine and in an ergosine-accumulating C. purpurea strain. A different picture was observed in a series of related C. purpurea strains. Tryptophan showed a slight stimulatory effect on the ergotoxine producer Pepty 695/S. A blocked mutant of it, designated as Pepty 695/ch which was able to accumulate secoclavines gave similar results. In a high-yielding elymoclavine strain Pepty 695/e, the progeny of the former one, tryptophan up to a concentration of 25 mM stimulated remarkably clavine biosynthesis. Furthermore, tryptophan could overcome the block of synthesis by inorganic phosphate. Increased specific activities of chanoclavine cyclase but not DMAT synthetase were observed in cultures of strain Pepty 695/e supplemented with tryptophan. 5-Methyltryptophan and bioisosteres of tryptophan were ineffective in alkaloid stimulation. These results are compared with those obtained with the grass ergot strain SD 58 and discussed with the relation to other induction phenomena.

In vitro pathogenicity assay for the ergot fungus Claviceps purpurea.

PubMed

Scheffer, Jan; Tudzynski, Paul

2006-04-01

The pathogenic development of the biotrophic ergot fungus Claviceps purpurea is strictly limited to the ovary of grasses. Early colonization stages occur within a defined spatio-temporal course of events, including the directed growth to the vascular tissue for nutrient supply. To characterize mutant strains with putative defects in pathogenicity, the close observation of the infection pathway is therefore indispensable. Here, we describe the establishment of a new pathogenicity assay, based on the in vitro cultivation of isolated rye ovaries. The pathogenic development of a wild-type strain of C. purpurea was compared with the infection of mature rye flowers on whole plants. Up to the sixth day post inoculation, the route of infection within the isolated ovaries was maintained and temporally equal to that seen in mature flowers. Therefore, the in vitro pathogenicity assay is an effective alternative to the whole-plant infection tests, and suitable for detailed infection studies and screening high numbers of mutants for defects in early pathogenesis.

New insights into ergot alkaloid biosynthesis in Claviceps purpurea: an agroclavine synthase EasG catalyses, via a non-enzymatic adduct with reduced glutathione, the conversion of chanoclavine-I aldehyde to agroclavine.

PubMed

Matuschek, Marco; Wallwey, Christiane; Xie, Xiulan; Li, Shu-Ming

2011-06-07

Ergot alkaloids are indole derivatives with diverse structures and biological activities. They are produced by a wide range of fungi with Claviceps purpurea as the most important producer for medical use. Chanoclavine-I aldehyde is proposed as a branch point via festuclavine or pyroclavine to clavine-type alkaloids in Trichocomaceae and via agroclavine to ergoamides and ergopeptines in Clavicipitaceae. Here we report the conversion of chanoclavine-I aldehyde to agroclavine by EasG from Claviceps purpurea, a homologue of the festuclavine synthase FgaFS in Aspergillus fumigatus, in the presence of reduced glutathione and NADPH. EasG comprises 290 amino acids with a molecular mass of about 31.9 kDa. The soluble monomeric His(6)-EasG was purified after overproduction in E. coli by affinity chromatography and used for enzyme assays. The structure of agroclavine was unequivocally elucidated by NMR and MS analyses.

Safety of nicergoline as an agent for management of cognitive function disorders.

PubMed

Saletu, Bernd; Garg, Amit; Shoeb, Ahsan

2014-01-01

Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency's (EMEA's) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders.

Safety of Nicergoline as an Agent for Management of Cognitive Function Disorders

PubMed Central

2014-01-01

Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency's (EMEA's) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders. PMID:25243157

Homo Economicus and the Salem Witch Trials.

ERIC Educational Resources Information Center

Mixon, Franklin G., Jr.

2000-01-01

Provides background information on the Salem Witch Trials (Salem, Massachusetts) and the medical explanation of the young village girls' behavior in Salem called ergotism (bread poisoning). Presents an economic interpretation of those trials, stating that the ministers employed religious beliefs about witchcraft to maintain their churchs' monopoly…

7 CFR 810.302 - Definitions of other terms.

Code of Federal Regulations, 2013 CFR

2013-01-01

...) Conspicuous Admixture. All matter other than canola, including but not limited to ergot, sclerotinia, and... crushed, exhibit a distinctly green color. (d) Dockage. All matter other than canola that can be removed.... (h) Sclerotia (Sclerotium, sing.). Dark colored or black resting bodies of the fungi Sclerotinia and...

7 CFR 810.302 - Definitions of other terms.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) Conspicuous Admixture. All matter other than canola, including but not limited to ergot, sclerotinia, and... crushed, exhibit a distinctly green color. (d) Dockage. All matter other than canola that can be removed.... (h) Sclerotia (Sclerotium, sing.). Dark colored or black resting bodies of the fungi Sclerotinia and...

7 CFR 810.302 - Definitions of other terms.

Code of Federal Regulations, 2014 CFR

2014-01-01

...) Conspicuous Admixture. All matter other than canola, including but not limited to ergot, sclerotinia, and... crushed, exhibit a distinctly green color. (d) Dockage. All matter other than canola that can be removed.... (h) Sclerotia (Sclerotium, sing.). Dark colored or black resting bodies of the fungi Sclerotinia and...

Feeding co-product feeds to cattle on fescue pastures

USDA-ARS?s Scientific Manuscript database

Tall fescue is the predominant cool-season perennial grass utilized for forage in Kentucky. Popularity of the grass is due to its productivity, persistence, and low cost of management. A fungal endophyte infects most plants of tall fescue produces ergot alkaloid toxins that, unfortunately, cause a...

Doppler ultrasonography for evaluating vascular responses to ergopeptine alkaloids in livestock

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids are produced by non-spore producing fungal endophytes that infect certain species of grasses, most notably tall fescue [Lolium arundinaceum (Schreb.) Darbysh.] and perennial ryegrass (Lolium perenne L.), and the spore producing Claviceps spp. that infect seed heads of certain grasses...

Increased milk production by Holstein cows consuming endophyte-infected fescue seed during the dry period.

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and may reduce milk production of cows consuming endophyte-infected grasses. We hypothesized that consumption of endophyte-infected fescue during the dry period inhibits mammary differentiation and subsequent milk produ...

Host status of endophyte-infected and noninfected tall fescue grass to Meloidogyne spp.

USDA-ARS?s Scientific Manuscript database

Tall fescue grass cultivars with or without endophytes were evaluated for their susceptibility to Meloidogyne incognita in the greenhouse. Tall fescue cultivars evaluated included, i) wild-type Jesup (E+, ergot-producing endophyte present), ii) endophyte-free Jesup (E-, no endophyte present), iii) ...

Tall fescue management: Pasture and cattle responses to endophyte and fertilization

USDA-ARS?s Scientific Manuscript database

Yearling heifers grazing tall fescue pastures had greatest performance in winter and spring on endophyte-free and novel endophyte associations, because of high forage quality and lack of ergot alkaloids produced by a common “wild” tall fescue-endophyte association. Pasture and cattle responses were...

Effect of fescue toxicosis on nitrogen and energy balance in Holstein steers

USDA-ARS?s Scientific Manuscript database

Animals consuming infected fescue exhibit reduced weight gain and feed intake, with the most severe effects occurring during summer months. Heat stress and plane of nutrition have independent effects on metabolic activity (Birkelo, et al., 1991; O’Brien, et al., 2010). While, ergot alkaloids reduce ...

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid loci

USDA-ARS?s Scientific Manuscript database

The fungal family Clavicipitaceae includes plant symbionts and pathogens that produce neurotropic alkaloids with diverse effects on vertebrate and invertebrate animals. For example, ergot alkaloids are historically linked to mass poisonings (St. Anthony's fire) and sociological effects such as the ...

Simple sequence repeat markers that identify Claviceps species and strains

USDA-ARS?s Scientific Manuscript database

Claviceps purpurea is a pathogen that infects most members of the Pooideae subfamily and causes ergot, a floral disease in which the ovary is replaced with a sclerotium. This study was initiated to develop Simple Sequence Repeat (SSRs) markers for rapid identification of C. purpurea. SSRs were desi...

Pharmacologic assessment of bovine ruminal and mesenteric vascular serotonin receptor populations

USDA-ARS?s Scientific Manuscript database

Prior work using a contractility bioassay determined that the serotonin (5-HT) receptor subtype 5-HT2A is present in bovine lateral saphenous veins and plays a role in ergot alkaloid-induced vascular contraction in steers grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundina...

Ergovaline stability in tall fescue based on sample handling and storage methods

USDA-ARS?s Scientific Manuscript database

Ergovaline is an ergot alkaloid produced by the endophyte Neotyphodium coenophialum (Morgan-Jones and Gams) found in tall fescue [Schedonorus arundinacea (Schreb.) Dumort.] and blamed for a multitude of livestock disorders. Ergovaline is known to be unstable and affected by many variables. The objec...

Ergovaline recovery from digested residues of grazed tall fescue seedheads

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by the endophyte [Neotyphodium coenophialum] of tall fescue [Lolium arundinaceum] induce a toxicosis in cattle that is a common problem in the southeastern USA. While these toxins are heavily concentrated within the seedheads, there is a lack of information on the degree th...

Steer consumption and ergovaline recovery from in vitro digested residues of tall fescue seedheads

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids produced by the endophyte [Neotyphodium coenophialum (Morgan-Jones and Gams) Glenn, Bacon, and Hanlin] of tall fescue [Lolium arundinaceum (Schreb.) Darbysh.] are a common problem faced by cattle producers. These toxins are concentrated within seedheads of tall fescue tillers, which...

From the Lab Bench: It’s Spring time and the fescue is productive and hot with alkaloids

USDA-ARS?s Scientific Manuscript database

An article was written that discussed options in alleviating or mitigating fescue toxicosis in the spring and summer. Seedheads of tall fescue are highly concentrated with toxic ergot alkaloids and the cattle selectively graze immature seedheads of tall fescue. Removal of the seedheads is an appro...

From the Lab Bench: Why the heat and cold stresses on tall fescue pasture

USDA-ARS?s Scientific Manuscript database

A column is written to provide information on why cattle that graze toxic endophyte infected tall fescue are vulnerable to both heat and cold stress. Peer reviewed research conducted by scientists at the USDA-ARS Forage-Animal Production Research Unit demonstrated that ergot alkaloids produced by t...

Consumption of endophyte-infected fescue seed during the dry period does not decrease milk production in the following lactation

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and may reduce milk production of cows consuming endophyte-infected grasses. We investigated the effects of consuming endophyte-infected fescue during late lactation and the dry period on mammary growth, differentiation ...

From the Lab Bench: Should you plant a non-toxic endophyte tall fescue?

USDA-ARS?s Scientific Manuscript database

A column was written to discuss planting novel endophyte tall fescue for alleviating fescue toxicosis. Endophyte-free tall fescue cultivars can be grazed as a non-toxic alternative, but it maust be understood that it is the endophyte, through production of alkaloids other than ergot alkaloids, that...

From the Lab Bench: Can cattle meet their nutrient needs on toxic tall fescue pasture?

USDA-ARS?s Scientific Manuscript database

A column is written to provide information on nutrient utilization by cattle grazing toxic endophyte-infected tall fescue. We have considerable knowledge and understanding of ergot alkaloid-induced constriction of blood flow to peripheral tissues, but what about blood flow to other parts of the bod...

Constriction of bovine vasculature caused by endophyte-infected tall fescue seed extract is similar to pure ergovaline

USDA-ARS?s Scientific Manuscript database

A mixture of ergot alkaloids does not increase the contractile response of peripheral bovine vasculature, but may increase the contractile response of foregut vasculature. Preliminary data indicated that an extract of tall fescue seed induced a greater contractile response in ruminal artery and vein...

The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria

PubMed Central

Metzger, Ute; Schall, Christoph; Zocher, Georg; Unsöld, Inge; Stec, Edyta; Li, Shu-Ming; Heide, Lutz; Stehle, Thilo

2009-01-01

Ergot alkaloids are toxins and important pharmaceuticals that are produced biotechnologically on an industrial scale. The first committed step of ergot alkaloid biosynthesis is catalyzed by dimethylallyl tryptophan synthase (DMATS; EC 2.5.1.34). Orthologs of DMATS are found in many fungal genomes. We report here the x-ray structure of DMATS, determined at a resolution of 1.76 Å. A complex of DMATS from Aspergillus fumigatus with its aromatic substrate L-tryptophan and with an analogue of its isoprenoid substrate dimethylallyl diphosphate reveals the structural basis of this enzyme-catalyzed Friedel-Crafts reaction, which shows strict regiospecificity for position 4 of the indole nucleus of tryptophan as well as unusual independence of the presence of Mg2+ ions. The 3D structure of DMATS belongs to a rare β/α barrel fold, called prenyltransferase barrel, that was recently discovered in a small group of bacterial enzymes with no sequence similarity to DMATS. These bacterial enzymes catalyze the prenylation of aromatic substrates in the biosynthesis of secondary metabolites (i.e., a reaction similar to that of DMATS). PMID:19706516

Brachypodium distachyon as alternative model host system for the ergot fungus Claviceps purpurea.

PubMed

Kind, Sabine; Schurack, Selma; Hinsch, Janine; Tudzynski, Paul

2018-04-01

To investigate its susceptibility to ergot infection, we inoculated Brachypodium distachyon with Claviceps purpurea and compared the infection symptoms with those on rye (Secale cereale). We showed that, after inoculation of Brachypodium with Claviceps, the same disease symptoms occurred in comparable temporal and spatial patterns to those on rye. The infection rate of Claviceps on this host was reduced compared with rye, but the disease could be surveyed by fungal genomic DNA quantification. Mutants of Claviceps which were virulence attenuated on rye were also affected on Brachypodium. We were able to show that pathogenesis-related gene expression changed in a typical manner for biotrophic pathogen attack. Our results indicated that the Claviceps-Brachypodium interaction was dependent on salicylic acid, cytokinin and auxin. We consider Brachypodium to be a suitable and useful alternative host; the increased sensitivity compared with rye will be valuable for the identification of infection mechanisms. Future progess in understanding the Claviceps-plant interaction will be facilitated by the use of a well-characterized model host system. © 2017 BSPP AND JOHN WILEY & SONS LTD.

Symptomatology and morphology of Claviceps cyperi on yellow nut sedge in South Africa.

PubMed

van der Linde, Elna J; Wehner, F C

2007-01-01

Symptoms of ergot on yellow nut sedge, germination of sclerotia of the causal organism, Claviceps cyperi, and morphology of fresh specimens of the pathogen are described for the first time. The initial symptom of infection was a black sooty layer on inflorescences of infected plants due to colonization of the ergot honeydew by Cladosporium cladosporioides. Sclerotia of C. cyperi started to develop in March and April and could be discerned as small protuberances on inflorescences in the place of seed. Mature sclerotia were purplish-black. They generally remained viable for less than a year and germinated without prior cold treatment, although exposure for 21 d to 5 C before incubation significantly increased the germination rate. Under moist conditions at 24 C in the laboratory, germination commenced within 4-8 wk. Stromata took about 12 d to mature. Mature capitula were distinctly lobulate with a perithecium embedded in each lobe and a collar-like appendage around the base. Although dimensions of sclerotia, stipes, capitula, asci and ascospores were larger than in the original description, the general morphology supports treatment of C. cyperi as a distinct species.

Pituitary genomic expression profiles of steers are altered by grazing of high vs. low endophyte-infected tall fescue forages.

PubMed

Li, Qing; Hegge, Raquel; Bridges, Phillip J; Matthews, James C

2017-01-01

Consumption of ergot alkaloid-containing tall fescue grass impairs several metabolic, vascular, growth, and reproductive processes in cattle, collectively producing a clinical condition known as "fescue toxicosis." Despite the apparent association between pituitary function and these physiological parameters, including depressed serum prolactin; no reports describe the effect of fescue toxicosis on pituitary genomic expression profiles. To identify candidate regulatory mechanisms, we compared the global and selected targeted mRNA expression patterns of pituitaries collected from beef steers that had been randomly assigned to undergo summer-long grazing (89 to 105 d) of a high-toxic endophyte-infected tall fescue pasture (HE; 0.746 μg/g ergot alkaloids; 5.7 ha; n = 10; BW = 267 ± 14.5 kg) or a low-toxic endophyte tall fescue-mixed pasture (LE; 0.023 μg/g ergot alkaloids; 5.7 ha; n = 9; BW = 266 ± 10.9 kg). As previously reported, in the HE steers, serum prolactin and body weights decreased and a potential for hepatic gluconeogenesis from amino acid-derived carbons increased. In this manuscript, we report that the pituitaries of HE steers had 542 differentially expressed genes (P < 0.001, false discovery rate ≤ 4.8%), and the pattern of altered gene expression was dependent (P < 0.001) on treatment. Integrated Pathway Analysis revealed that canonical pathways central to prolactin production, secretion, or signaling were affected, in addition to those related to corticotropin-releasing hormone signaling, melanocyte development, and pigmentation signaling. Targeted RT-PCR analysis corroborated these findings, including decreased (P < 0.05) expression of DRD2, PRL, POU1F1, GAL, and VIP and that of POMC and PCSK1, respectively. Canonical pathway analysis identified HE-dependent alteration in signaling of additional pituitary-derived hormones, including growth hormone and GnRH. We conclude that consumption of endophyte-infected tall fescue alters the pituitary transcriptome profiles of steers in a manner consistent with their negatively affected physiological parameters.

Functionalized Ergot-alkaloids as potential dopamine D3 receptor agonists for treatment of schizophrenia

NASA Astrophysics Data System (ADS)

Ivanova, Bojidarka; Spiteller, Michael

2012-12-01

The relationship between the molecular structure and physical properties of functionalized naturally occurred Ergot-alkaloids as potential dopamine D3 receptor agonists is presented. The molecular modeling of the ergoline-skeleton is based on the comprehensive theoretical study of the binding affinity of the isolated chemicals towards the active sites of the D3 sub-type receptor (D3R) loops. The studied proton accepting ability under physiological conditions allows classifying four types of monocationics, characterizing with the different binding modes to D3R involving selected amino acid residues to the active sites. These results marked the pharmaceutical potential and clinical usage of the reported compounds as antipsychotic drugs for Schizophrenia treatment, since they allowed evaluating the highlights of the different hypothesizes of the biochemical causes the illness. The applied complex approach for theoretical and experimental elucidation, including quantum chemistry method, electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) mass spectrometric (MS) methods, nuclear magnetic resonance and vibrational IR and Raman spectroscopy on the isolated fifteen novel derivatives (1)-(15) and their different protonated forms (1a)-(15a) evidenced a strong dependence of molecular conformation, physical properties and binding affinity. Thus, the semi-synthetic functionalization of the naturally occurred products (NPs), provided significant possibilities to further molecular drugs-design and development of novel derivatives with wanted biological function, using the established profile of selected classes/families of NPs. The work described chiefly the non-linear (NL) approach for the interpretation of the mass chromatograms on the performed hybrid high performance liquid chromatography (HPLC) tandem MS/MS and MS/MS/MS experiments, discussing the merits and great diversity of instrumentation flexibility, thus achieving fundamental structural information, indispensable for the analysis of Ergot-alkaloid derivatives, which under the physiological conditions easily converted to d-lysergic acid (LSD).

Simple sequence repeat markers that identify Claviceps species and strains.

PubMed

Gilmore, Barbara S; Alderman, Stephen C; Knaus, Brian J; Bassil, Nahla V; Martin, Ruth C; Dombrowski, James E; Dung, Jeremiah K S

2016-01-01

Claviceps purpurea is a pathogen that infects most members of Pooideae, a subfamily of Poaceae, and causes ergot, a floral disease in which the ovary is replaced with a sclerotium. When the ergot body is accidently consumed by either man or animal in high enough quantities, there is extreme pain, limb loss and sometimes death. This study was initiated to develop simple sequence repeat (SSRs) markers for rapid identification of  C. purpurea . SSRs were designed from sequence data stored at the National Center for Biotechnology Information database. The study consisted of 74 ergot isolates, from four different host species, Lolium perenne , Poa pratensis , Bromus inermis , and Secale cereale plus three additional Claviceps species, C. pusilla , C. paspali and C. fusiformis. Samples were collected from six different counties in Oregon and Washington over a 5-year period. Thirty-four SSR markers were selected, which enabled the differentiation of each isolate from one another based solely on their molecular fingerprints. Discriminant analysis of principle components was used to identify four isolate groups, CA Group 1, 2, 3, and 4, for subsequent cluster and molecular variance analyses. CA Group 1 consisting of eight isolates from the host species P. pratensis , was separated on the cluster analysis plot from the remaining three groups and this group was later identified as C. humidiphila . The other three groups were distinct from one another, but closely related. These three groups contained samples from all four of the host species. These SSRs are simple to use, reliable and allowed clear differentiation of C. humidiphila from C. purpurea . Isolates from the three separate species, C. pusilla , C. paspali and C. fusiformis , also amplified with these markers. The SSR markers developed in this study will be helpful in defining the population structure and genetics of Claviceps strains. They will also provide valuable tools for plant breeders needing to identify resistance in crops or for researchers examining fungal movements across environments.

Consumption of endophyte-infected fescue seed during the dry period and lactation affects mammary gland gene expression in dairy cows

USDA-ARS?s Scientific Manuscript database

Ergot alkaloids in endophyte-infected grasses inhibit prolactin (PRL) secretion and reduce milk production when fed to lactating cows. However, we have shown this affect is temporal in that pre-partum consumption of inflected seed throughout the dry period does not inhibit subsequent milk productio...

Identification of environmental factors related to Claviceps purpurea ascospore production in perennial ryegrass seed fields and development of predictive models

USDA-ARS?s Scientific Manuscript database

Claviceps purpurea, the causal agent of ergot of perennial ryegrass seed crops, overwinters as sclerotia in the soil and releases airborne ascospores in the spring that infect flower ovaries and replace seed with sclerotia. Burkard spore traps were used to quantify the dispersal phenology and concen...

Interaction between a tannin-containing legume and endophyte-infected tall fescue seed on lambs’ feeding behavior and physiology

USDA-ARS?s Scientific Manuscript database

It was hypothesized that a tannin-rich legume like sainfoin reduces the negative postingestive effects of ergot alkaloids in tall fescue. Thirty-two 3-month-old lambs were individually penned and randomly assigned to a 2X2 factorial experimental design with two legume species (1-sainfoin [SF; tannin...

Occurrence of trends of weed seed and pathogen contaminants in bentgrass seed lots in Oregon

USDA-ARS?s Scientific Manuscript database

Nearly all of the bentgrass seed grown in the United States is produced in Oregon. However, little is known about the occurrence of weed seed or pathogen propagule contaminants in bentgrass seed lots. This study was conducted to assess the diversity and frequency of occurrence of weed seeds, ergot (...

Hemodynamics are Altered in the Caudal Artery of Beef Heifers Fed Different Ergot Alkaloid Concentrations

USDA-ARS?s Scientific Manuscript database

Tall fescue is a cool-season perennial grass that is widely utilized for grazing in a region covering the transition zone between the temperate northeast and the subtropical southeast Although tall fescue is well adapted to the climate and soils in the region, an endophytic fungus infects fescue pla...

7 CFR 810.805 - Special grades and special grade requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... grain. Mixed grain in which barley predominates and that contains more than 4.0 percent of fungus-damaged and/or mold-damaged barley kernels. (b) Ergoty mixed grain. (1) Mixed grain in which rye or wheat... than 0.10 percent ergot. (c) Garlicky mixed grain. (1) Mixed grain in which wheat, rye, or triticale...

Interaction between a tannin-containing legume and endophyte-infected tall fescue seed on lambs’ feeding behavior and physiology

USDA-ARS?s Scientific Manuscript database

It was hypothesized that a tannin-rich legume like sainfoin reduces the negative post-ingestive effects of ergot alkaloids in tall fescue. Thirty-two 4-month-old lambs were individually penned and randomly assigned to a 2X2 factorial arrangement with two legume species (1-sainfoin [SAN; ' 3% condens...

Contractile response of bovine lateral saphenous vein to ergovaline serotonin2A a2A- and a2C-adrenergic receptor agonists relative to time off endophyte-infected tall fescue

USDA-ARS?s Scientific Manuscript database

Previous research has demonstrated differences in contractile responses to ergot alkaloids, serotonin (5HT), and adrenergic agonists by lateral saphenous veins collected from cattle that grazed either endophyte (Neotyphodium coenophialum)-infected or endophyte-free tall fescue (Lolium arundinaceum),...

7 CFR 810.1205 - Special grades and special grade requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... that contains more than 0.30 percent of ergot. (b) Garlicky rye. Rye that contains in a 1,000-gram...) Light garlicky rye. Rye that contains in a 1,000-gram portion two or more, but not more than six, green... has an unmistakable odor of smut, or that contains in a 250-gram portion smut balls, portions of smut...

7 CFR 810.1205 - Special grades and special grade requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... that contains more than 0.30 percent of ergot. (b) Garlicky rye. Rye that contains in a 1,000-gram...) Light garlicky rye. Rye that contains in a 1,000-gram portion two or more, but not more than six, green... has an unmistakable odor of smut, or that contains in a 250-gram portion smut balls, portions of smut...

7 CFR 810.1205 - Special grades and special grade requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... that contains more than 0.30 percent of ergot. (b) Garlicky rye. Rye that contains in a 1,000-gram...) Light garlicky rye. Rye that contains in a 1,000-gram portion two or more, but not more than six, green... has an unmistakable odor of smut, or that contains in a 250-gram portion smut balls, portions of smut...

Indole-diterpenes and ergot alkaloids in Cynodon dactylon (Bermuda grass) infected with Claviceps cynodontis from an outbreak of tremors in cattle.

PubMed

Uhlig, Silvio; Botha, Christo J; Vrålstad, Trude; Rolén, Elin; Miles, Christopher O

2009-12-09

Tremorgenic syndromes in mammals are commonly associated with indole-diterpenoid alkaloids of fungal origin. Cattle are sometimes affected by tremors (also called "staggers") when they graze on toxic grass pastures, and Bermuda grass ( Cynodon dactylon , kweek) has been known to be associated with tremors for several decades. This study reports the identification of paspalitrems and paspaline-like indole-diterpenes in the seedheads of Claviceps cynodontis -infected Bermuda grass collected from a pasture that had caused a staggers syndrome in cattle in South Africa and thereby links the condition to specific mycotoxins. The highest concentration (about 150 mg/kg) was found for paspalitrem B. Ergonovine and ergine (lysergic acid amide), together with their C-8 epimers, were found to co-occur with the indole-diterpenes at concentrations of about 10 microg/kg. The indole-diterpene profile of the extract from the ergotized Bermuda grass was similar to that of Claviceps paspali sclerotia. However, the C. paspali sclerotia contained in addition agroclavine and elymoclavine. This is the first study linking tremors associated with grazing of Bermuda grass to specific tremorgenic indole-diterpenoid mycotoxins.

Degradation and epimerization of ergot alkaloids after baking and in vitro digestion.

PubMed

Merkel, Stefan; Dib, Baha; Maul, Ronald; Köppen, Robert; Koch, Matthias; Nehls, Irene

2012-11-01

The degradation and epimerization of ergot alkaloids (EAs) in rye flour were investigated after baking cookies and subsequently subjecting them to an in vitro digestion model. Different steps of digestion were analyzed using salivary, gastric, and duodenal juices. The degradation and bidirectional conversion of the toxicologically relevant (R)-epimers and the biologically inactive (S)-epimers for seven pairs of EAs were determined by a HPLC method coupled with fluorescence detection. Baking cookies resulted in degradation of EAs (2-30 %) and a shift in the epimeric ratio toward the (S)-epimer for all EAs. The applied digestion model led to a selective toxification of ergotamine and ergosine, two ergotamine-type EAs. The initial percentage of the toxic (R)-epimer in relation to the total toxin content was considerably increased after digestion of cookies. Ergotamine and ergosine increased from 32 to 51 % and 35 to 55 %, respectively. In contrast, EAs of the ergotoxine type (ergocornine, α- and β-ergocryptine, and ergocristine) showed an epimeric shift toward their biologically inactive (S)-epimers. Further experiments indicated that the selective epimerization of ergotamine EAs occurs in the duodenal juice only. These results demonstrate that toxification of EAs in the intestinal tract should be taken into consideration.

Sequential Formation and Accumulation of Primary and Secondary Shunt Metabolic Products in Claviceps purpurea1

PubMed Central

Taber, W. A.

1964-01-01

The fungus Claviceps purpurea was grown on a rich and a limited nutrient medium such that alkaloid was produced after 8 days on the former medium and after 3 days on the latter medium. Cultures grown on both were assayed for the primary shunt metabolic products, polyols, trehalose, lipids, ribonucleic acid, and polyphosphate, and the secondary metabolic product, ergot alkaloid. Although differing considerably in composition, the two media nevertheless allowed formation of both primary and secondary shunt products. In both instances, however, the secondary product, ergot alkaloid, did not form until formation and accumulation of the primary products had ceased and the mycelial content of these products was actually decreasing. In both instances, alkaloid formation took place after the total dry weight of the mycelium had begun to decrease but while the dry weight of the residual, or structural portion of the mycelium, was either constant or increasing. The dilution of labeling in mannitol isolated from mycelia grown on rich medium containing 1,6-C14-labeled mannitol was 2.2. Thus, about half of the mycelial mannitol was actually mannitol which had been taken up directly from the medium. PMID:14199021

De novo biosynthesis of cytokinins in the biotrophic fungus Claviceps purpurea.

PubMed

Hinsch, Janine; Vrabka, Josef; Oeser, Birgitt; Novák, Ondřej; Galuszka, Petr; Tudzynski, Paul

2015-08-01

Disease symptoms of some phytopathogenic fungi are associated with changes in cytokinin (CK) levels. Here, we show that the CK profile of ergot-infected rye plants is also altered, although no pronounced changes occur in the expression of the host plant's CK biosynthesis genes. Instead, we demonstrate a clearly different mechanism: we report on the first fungal de novo CK biosynthesis genes, prove their functions and constitute a biosynthetic pathway. The ergot fungus Claviceps purpurea produces substantial quantities of CKs in culture and, like plants, expresses enzymes containing the isopentenyltransferase and lonely guy domains necessary for de novo isopentenyladenine production. Uniquely, two of these domains are combined in one bifunctional enzyme, CpIPT-LOG, depicting a novel and potent mechanism for CK production. The fungus also forms trans-zeatin, a reaction catalysed by a CK-specific cytochrome P450 monooxygenase, which is encoded by cpp450 forming a small cluster with cpipt-log. Deletion of cpipt-log and cpp450 did not affect virulence of the fungus, but Δcpp450 mutants exhibit a hyper-sporulating phenotype, implying that CKs are environmental factors influencing fungal development. © 2015 Society for Applied Microbiology and John Wiley & Sons Ltd.

1-Methoxy-agroclavine from Penicillium sp. WC75209, a novel inhibitor of the Lck tyrosine kinase.

PubMed

Padmanabha, R; Shu, Y Z; Cook, L S; Veitch, J A; Donovan, M; Lowe, S; Huang, S; Pirnik, D; Manly, S P

1998-03-17

A high-throughput screen was developed and implemented to identify inhibitors of the Lck tyrosine kinase. This report describes the identification of a specific inhibitor of this enzyme from the solid fermentation culture of the Penicillium sp., WC75209. The active compound was isolated and structurally characterized as 1-methoxy-5R, 10S-agroclavine, a new member of the ergot alkaloid family.

[The Piscine Probatica, a painted canvas of the Hotel-Dieu of Rheims, documentation of an epidemic at the end of the 15th century].

PubMed

Ségal, Alain

2011-01-01

The Piscina Probatica theme is the highly distinctive iconography in an impressive painted canvas from the ancient Rheims hôtel-Dieu, dating back to the late 15th or early 16th century. In the first place, it is interesting to note that the actual site of the pool has been located, so that archaeological findings bring confirmation to testament scriptures. Through the choice of the painted-canvas medium, and thanks to his great pictorial skill, the anonymous Rheims artist has given us a document of exceptional value, concerning the signs and symptoms of an illness which wrought havoc in the Rheims area in his own lifetime, namely ignis plaga or "mal des ardents". Other great artists of the same period, such as J. Bosch, have testified to the horror of the illness. As a matter-of-fact, the illness has been fully documented, from the 17th century onwards, and the medical expert H.A. Tessier, also acting as an agricultural expert, has demonstrated that ergotized rye is responsible for the fatal condition known as ergotism, and for the heavy toll it has levied on human lives in the course of centuries.

Phylogenetic evidence for an animal pathogen origin of ergot and the grass endophytes.

PubMed

Spatafora, J W; Sung, G-H; Sung, J-M; Hywel-Jones, N L; White, J F

2007-04-01

Grass-associated fungi (grass symbionts) in the family Clavicipitaceae (Ascomycota, Hypocreales) are species whose host range is restricted to the plant family Poaceae and rarely Cyperaceae. The best-characterized species include Claviceps purpurea (ergot of rye) and Neotyphodium coenophialum (endophyte of tall fescue). They have been the focus of considerable research due to their importance in agricultural and grassland ecosystems and the diversity of their bioactive secondary metabolites. Here we show through multigene phylogenetic analyses and ancestral character state reconstruction that the grass symbionts in Clavicipitaceae are a derived group that originated from an animal pathogen through a dynamic process of interkingdom host jumping. The closest relatives of the grass symbionts include the genera Hypocrella, a pathogen of scale insects and white flies, and Metarhizium, a generalist arthropod pathogen. These data do not support the monophyly of Clavicipitaceae, but place it as part of a larger clade that includes Hypocreaceae, a family that contains mainly parasites of other fungi. A minimum of 5-8 independent and unidirectional interkingdom host jumps has occurred among clavicipitaceous fungi, including 3-5 to fungi, 1-2 to animals, and 1 to plants. These findings provide a new evolutionary context for studying the biology of the grass symbionts, their role in plant ecology, and the evolution of host affiliation in fungal symbioses.

Ergot Alkaloids in Fattening Chickens (Broilers): Toxic Effects and Carry over Depending on Dietary Fat Proportion and Supplementation with Non-Starch-Polysaccharide (NSP) Hydrolyzing Enzymes.

PubMed

Dänicke, Sven

2017-03-28

Ergot alkaloids (EA) are mycotoxins produced by Claviceps purpurea . EA-toxicity is poorly characterized for fattening chickens. Therefore, a dose-response study was performed to identify the lowest, and no observed adverse effect levels (LOAEL and NOAEL, respectively) based on several endpoints. Non-starch-polysaccharide (NSP) cleaving enzyme addition and dietary fat content were additionally considered as factors potentially influencing EA-toxicity. Feed intake was proven to respond most sensitively to the EA presence in the diets. This sensitivity appeared to be time-dependent. While LOAEL corresponded to a total dietary EA content of 5.7 mg/kg until Day 14 of age, it decreased to 2.03 mg/kg when birds were exposed for a period of 35 days. Consequently, NOAEL corresponded to an EA content of 2.49 mg/kg diet until Day 14 of age, while 1.94 mg/kg diet applied until Day 35 of age. Liver lesions indicating enzyme activities in serum were increased after 14 days of exposure. Dietary fat content and NSP-enzyme supplementation modified EA toxicity in an interactive manner. The EA residues in serum, bile, liver and breast meat were <5 ng/g suggesting a negligible carry over of intact EA.

Delimitation of cryptic species inside Claviceps purpurea.

PubMed

Pažoutová, Sylvie; Pešicová, Kamila; Chudíčková, Milada; Šrůtka, Petr; Kolařík, Miroslav

2015-01-01

Claviceps purpurea is an ovarian parasite infecting grasses (Poaceae) including cereals and forage plants. This fungus produces toxic alkaloids and consumption of contaminated grains can cause ergotism in humans and other mammals. Recent molecular genetics studies have indicated that it included three cryptic species (G1, G2, G3). In this study, reproductive isolation amongst these groups and among material from Phragmites and Molinia was tested using gene flow statistics for five polymorphic loci, and to support these data, phylogenetic affiliations based on gene trees and a multigene phylogeny were used. The four recognized species are characterized based on morphology and host spectrum and formal taxonomic names are proposed. Claviceps purpurea sensu stricto (G1 group) represents a typical rye ergot, but infects various other grasses. Typical hosts of Claviceps humidiphila (new name for G2 species), like Phalaris arundinacea, belong to grasses preferring humid locations. Claviceps spartinae (G3) is specific to chloridoid grasses from salt barches. The material from Phragmites and Molinia can be authenticated with the species Claviceps microcephala for which the new name Claviceps arundinis is proposed here. The divergence time between species was estimated and the tools for species identification are discussed. Copyright © 2014 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Ergot Alkaloids in Fattening Chickens (Broilers): Toxic Effects and Carry over Depending on Dietary Fat Proportion and Supplementation with Non-Starch-Polysaccharide (NSP) Hydrolyzing Enzymes

PubMed Central

Dänicke, Sven

2017-01-01

Ergot alkaloids (EA) are mycotoxins produced by Claviceps purpurea. EA-toxicity is poorly characterized for fattening chickens. Therefore, a dose–response study was performed to identify the lowest, and no observed adverse effect levels (LOAEL and NOAEL, respectively) based on several endpoints. Non-starch-polysaccharide (NSP) cleaving enzyme addition and dietary fat content were additionally considered as factors potentially influencing EA-toxicity. Feed intake was proven to respond most sensitively to the EA presence in the diets. This sensitivity appeared to be time-dependent. While LOAEL corresponded to a total dietary EA content of 5.7 mg/kg until Day 14 of age, it decreased to 2.03 mg/kg when birds were exposed for a period of 35 days. Consequently, NOAEL corresponded to an EA content of 2.49 mg/kg diet until Day 14 of age, while 1.94 mg/kg diet applied until Day 35 of age. Liver lesions indicating enzyme activities in serum were increased after 14 days of exposure. Dietary fat content and NSP-enzyme supplementation modified EA toxicity in an interactive manner. The EA residues in serum, bile, liver and breast meat were <5 ng/g suggesting a negligible carry over of intact EA. PMID:28350362

New Prescriptions for Migraine in the Emergency Department

PubMed Central

Lane, Peter L.

1992-01-01

Migraine headache is a common affliction and presenting symptom in the emergency department. Its diagnosis is entirely clinical, and the treating physician should ensure precise diagnosis before commencing therapy. General non-pharmacological measures and oral medications are usually effective in relieving the symptoms. Occasionally, patients with fixed migraines require parenteral therapy. Some medications used for migraine are antiemetic agents, ergot preparations, narcotic agents, phenothiazines (particularly chlorpromazine), and newer selective serotonin agonists. PMID:21221402

Mycotoxins

PubMed Central

Bennett, J. W.; Klich, M.

2003-01-01

Mycotoxins are secondary metabolites produced by microfungi that are capable of causing disease and death in humans and other animals. Because of their pharmacological activity, some mycotoxins or mycotoxin derivatives have found use as antibiotics, growth promotants, and other kinds of drugs; still others have been implicated as chemical warfare agents. This review focuses on the most important ones associated with human and veterinary diseases, including aflatoxin, citrinin, ergot akaloids, fumonisins, ochratoxin A, patulin, trichothecenes, and zearalenone. PMID:12857779

Quantitative and qualitative transcriptome analysis of four industrial strains of Claviceps purpurea with respect to ergot alkaloid production.

PubMed

Majeská Čudejková, Mária; Vojta, Petr; Valík, Josef; Galuszka, Petr

2016-09-25

The fungus Claviceps purpurea is a biotrophic phytopathogen widely used in the pharmaceutical industry for its ability to produce ergot alkaloids (EAs). The fungus attacks unfertilized ovaries of grasses and forms sclerotia, which represent the only type of tissue where the synthesis of EAs occurs. The biosynthetic pathway of EAs has been extensively studied; however, little is known concerning its regulation. Here, we present the quantitative transcriptome analysis of the sclerotial and mycelial tissues providing a comprehensive view of transcriptional differences between the tissues that produce EAs and those that do not produce EAs and the pathogenic and non-pathogenic lifestyle. The results indicate metabolic changes coupled with sclerotial differentiation, which are likely needed as initiation factors for EA biosynthesis. One of the promising factors seems to be oxidative stress. Here, we focus on the identification of putative transcription factors and regulators involved in sclerotial differentiation, which might be involved in EA biosynthesis. To shed more light on the regulation of EA composition, whole transcriptome analysis of four industrial strains differing in their alkaloid spectra was performed. The results support the hypothesis proposing the composition of the amino acid pool in sclerotia to be an important factor regulating the final structure of the ergopeptines produced by Claviceps purpurea. Copyright © 2016 Elsevier B.V. All rights reserved.

Expressed sequence tags from the flower pathogen Claviceps purpurea.

PubMed

Oeser, Birgitt; Beaussart, François; Haarmann, Thomas; Lorenz, Nicole; Nathues, Eva; Rolke, Yvonne; Scheffer, Jan; Weiner, January; Tudzynski, Paul

2009-09-01

SUMMARY The ascomycete Claviceps purpurea (ergot) is a biotrophic flower pathogen of rye and other grasses. The deleterious toxic effects of infected rye seeds on humans and grazing animals have been known since the Middle Ages. To gain further insight into the molecular basis of this disease, we generated about 10 000 expressed sequence tags (ESTs)-about 25% originating from axenic fungal culture and about 75% from tissues collected 6-20 days after infection of rye spikes. The pattern of axenic vs. in planta gene expression was compared. About 200 putative plant genes were identified within the in planta library. A high percentage of these were predicted to function in plant defence against the ergot fungus and other pathogens, for example pathogenesis-related proteins. Potential fungal pathogenicity and virulence genes were found via comparison with the pathogen-host interaction database (PHI-base; http://www.phi-base.org) and with genes known to be highly expressed in the haustoria of the bean rust fungus. Comparative analysis of Claviceps and two other fungal flower pathogens (necrotrophic Fusarium graminearum and biotrophic Ustilago maydis) highlighted similarities and differences in their lifestyles, for example all three fungi have signalling components and cell wall-degrading enzymes in their arsenal. In summary, the analysis of axenic and in planta ESTs yielded a collection of candidate genes to be evaluated for functional roles in this plant-microbe interaction.

GLUTAMIC DECARBOXYLASE OF ERGOT, CLAVICEPS PURPUREA

PubMed Central

Anderson, John A.; Cheldelin, Vernon H.; King, Tsoo E.

1961-01-01

Anderson, John A. (Oregon State University, Corvallis), Vernon H. Cheldelin, and Tsoo E. King. Glutamic decarboxylase of ergot, Claviceps purpurea. J. Bacteriol. 82:354–358. 1961.—l-Glutamic acid is the only naturally occurring amino acid which can be decarboxylated by cell-free extracts of Claviceps purpurea. This decarboxylase was partially purified and the properties of the enzyme studied. The specific activity of the purified preparation was 111 μliters per 10 min per mg of protein. The products formed, stability, inhibition, stimulation of activity with pyridoxal phosphate, and pH activity curve were typical of l-glutamic decarboxylase in Escherichia coli and other microorganisms. The substrate constants at pH 4.6, 5.25, and 5.65 were 0.0169 m, 0.0174 m, and 0.0139 m, respectively. The respective maximal velocities at these pH values were 104, 104, and 90 μliters per 10 min. The pH optimum was 4.8 to 5.2. The enzyme was unstable below pH 4.5 and it was suggested that the fall in activity at the lower end of the pH curve was due to inactivation of the enzyme. The decrease in activity above pH 5.2 did not appear to be due to a change in affinity of enzyme for substrate but to a change of the enzyme-substrate complex into an inactive form. PMID:13683214

Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study.

PubMed

Lipton, Richard B; Munjal, Sagar; Buse, Dawn C; Bennett, Alix; Fanning, Kristina M; Burstein, Rami; Reed, Michael L

2017-07-01

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n  =  5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Among eligible participants, the mean age was 46 years, and 82.5% were women. The triptan use group had better outcomes than other medication groups for 2hPF (OR range: 2.00-2.63, all significant except ergot alkaloids) and 24hPR (OR range: 2.10-6.22, all significant). No significant medication effects were found for the 24hSPR outcome. The presence of allodynia was associated with significantly worse outcomes for both 2hPF (OR range: 1.42-1.55, all significant) and 24hPR (OR range: 1.30-1.32, all significant, except for ergot alkaloids, P  =  .051). Allodynia effects were not significant for the 24hSPR. The interaction between medication and allodynia was also not significant (OR range for 2hPF: .68-2.02; OR range for 2hPR: .35-1.34; OR range for 24hSPR: 1.21-2.72) in any of the models, suggesting allodynia is an important predictor of treatment response regardless of the medication group prescribed. The use of triptan medication was associated with significantly better 2hPF (except vs ergot alkaloids) and significantly better 24hPR outcomes compared with other acute medication categories. The presence of allodynia significantly increased the likelihood of an inadequate treatment response for both of these outcomes. Triptan use was generally associated with the best outcomes. Because allodynia was associated with inadequate outcomes for all medication groups, we suggest that allodynia is an area of unmet treatment need. © 2017 American Headache Society.

Exo-metabolites of mycelial fungi isolated in production premises of cheese-making and meat-processing plants.

PubMed

Kozlovsky, A G; Zhelifonova, V P; Antipova, T V; Baskunov, B P; Ivanushkina, N E; Ozerskaya, S M

2014-01-01

Data were obtained on the species composition of mycelial fungi isolated from the air of workrooms and production premises in cheese-making and meat-processing plants. The strains studied were shown to be capable of producing various low molecular weight compounds. Many of them are mycotoxins such as α-cyclopiazonic acid (CPA), mycophenolic acid (MPA), citrinin, cladosporin, roquefortine and ergot alkaloids. The profiles of the secondary metabolites were used to elucidate the species' names of the isolated strains.

Translations on USSR Science and Technology, Biomedical and Behavioral Sciences, Number 44

DTIC Science & Technology

1978-09-07

one can sometimes even taste sweet honeydew , or "manna" on the ears and grains. However, " honeydew " is unnoticeable or barely noticeable in most cases...affliction is severe: Appearance of a sweet or slightly sweet exudate—" honeydew " or "manna"—on ears and kernels due to carbo- hydrate hydrolysis and...34 honeydew " on rye ears infected by ergot, but it is distinctly different in that single-celled colorless spores typical of the latter are absent

Update on the use of pramipexole in the treatment of Parkinson’s disease

PubMed Central

Constantinescu, Radu

2008-01-01

Pramipexole is a non-ergot dopamine agonist shown to be efficacious in the treatment of Parkinson’s disease (PD). This review addresses the literature concerning pramipexole’s efficacy in treating motor and non-motor symptoms in PD, its impact on the development of dyskinesias and response fluctuations, the issue of neuroprotection, and the risk for developing adverse events such as increased somnolence, attacks of sudden onset of sleep, cardiac valvulopathy and impulse control disturbances. PMID:18728740

Rotigotine transdermal patch for the treatment of Parkinson's Disease.

PubMed

Perez-Lloret, Santiago; Rey, María Verónica; Ratti, Pietro Lucca; Rascol, Olivier

2013-02-01

Rotigotine, a non-ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson's disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term 'rotigotine' and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non-ergot dopamine agonists in PD. Application-site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa-related motor complications. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.

Pasture Management Strategies for Sequestering Soil Carbon - Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franzluebbers, Alan J.

Pasturelands account for 51 of the 212 Mha of privately held grazing land in the USA. Tall fescue is the most important cool-season perennial forage for many beef cattle producers in the humid region of the USA. A fungal endophyte, Neotyphodium coenophialum, infects the majority of tall fescue stands with a mutualistic association. Ergot alkaloids produced by the endophyte have negative impacts on cattle performance. However, there are indications that endophyte infection of tall fescue is a necessary component of productive and persistent pasture ecology. The objectives of this research were to characterize and quantify changes in soil organic carbonmore » and associated soil properties under tall fescue pastures with and without endophyte infection of grass. Pastures with high endophyte infection had greater concentration of soil organic carbon, but lower concentration of biologically active soil carbon than pastures with low endophyte infection. A controlled experiment suggested that endophyte-infected leaf tissue may directly inhibit the activity of soil microorganisms. Carbon forms of soil organic matter were negatively affected and nitrogen forms were positively affected by endophyte addition to soil. The chemical compounds in endophyte-infected tall fescue (ergot alkaloids) that are responsible for animal health disorders were found in soil, suggesting that these chemicals might be persistent in the environment. Future research is needed to determine whether ergot alkaloids or some other chemicals are responsible for increases in soil organic matter. Scientists will be able to use this information to better understand the ecological impacts of animals grazing tall fescue, and possibly to identify and cultivate other similar associations for improving soil organic matter storage. Another experiment suggested that both dry matter production and soil microbial activity could be affected by the endophyte. Sampling of the cumulative effects of 20 years of tall fescue management indicated that soil organic carbon and nitrogen storage were greater with than without endophyte only under high soil fertility. This extra carbon and nitrogen in soil due to the presence of the endophyte was further found to be located in intermediately sized soil aggregates, which are important for reducing water runoff and improving water quality. These results suggest that well-fertilized tall fescue pastures with a high percentage of plants infected with the endophyte have the potential to help offset the rising carbon dioxide in the atmosphere. This research has also shown positive ecological implications of tall fescue-endophyte association.« less

Ergot alkaloids produced by submerged cultures of Claviceps zizaniae.

PubMed

Kantorová, Michaela; Kolínská, Renata; Pazoutová, Sylvie; Honzátko, Ales; Havlícek, Vladimír; Flieger, Miroslav

2002-07-01

Two ergopeptine alkaloids, alpha-ergocryptine (1) and its C(8) epimer alpha-ergocryptinine, have been isolated from the mycelium and fermentation broth of submerged cultures of Claviceps zizaniae CCM 8240. The structure of 1 was determined by HPLC/positive ion APCI MS and NMR analysis. Alkaloid concentrations of 10 microg/mL in 14-day-old fermentation broth and 1 mg/g of dry mycelium mass were found. These results are of considerable biotechnological interest since these were the only detectable alkaloids produced. Toxicity of naturally occurring sclerotia of C. zizaniae cannot be excluded.

[Optimization of conditions for storage and cultivation of the fungus Claviceps sp.--a producer of the ergot alkaloid agroclavine].

PubMed

Boĭchenko, L V; Zelenkova, N F; Arinbasarov, M U; Reshetilova, T A

2003-01-01

Conditions of agroclavine biosynthesis by the mutant Claviceps sp. strain s 106 were studied. The content of agroclavine was maximum (1.5-2 g/l) on days 15-16 of cultivation in the complex medium T25, containing sucrose, citric acid, and yeast extract. Agroclavine was the major component of the alkaloid fraction (90-95%). Storage of the culture at -70 degrees C in T25 supplemented by 7% glycerol provided a stable level of alkaloid formation.

Heart valve disease associated with treatment with ergot-derived dopamine agonists: a clinical and echocardiographic study of patients with Parkinson's disease.

PubMed

Rasmussen, V G; Poulsen, S H; Dupont, E; Østergaard, K; Safikhany, G; Egeblad, H

2008-01-01

To elucidate the association between treatment with ergot-derived dopamine agonists (EDDA) and valvular abnormalities amongst patients with idiopathic Parkinson's disease (IPD) and secondly, to analyse the yield of clinical screening for valvular heart disease. A cross-sectional controlled study. The cohort of IPD patients treated in the outpatient clinic, Department of Neurology, Aarhus University Hospital, Denmark. A total of 138 IPD patients [median age 64 (39-87) years, 62% men] treated with either EDDA (n = 85) or non-EDDA (n = 53) for at least 6 months. Interventions. Patients were screened for valvular heart disease by clinical means and by examiner-blinded echocardiography. Main outcome measure was valvular regurgitation revealed by echocardiography. Severe aortic regurgitation (n = 4) or moderate aortic (n = 12), mitral (n = 3) or tricuspidal valve regurgitation (n = 5) was found in 22 EDDA patients (25.9%). Two patients had coexistent moderate mitral and tricuspid valvular regurgitation. Two non-EDDA patients had moderate valve insufficiency (3.8%, P < 0.05). The adjusted relative risk for at least moderate valve insufficiency in the EDDA patients was 7.2% (P < 0.05). The sensitivity of detecting at least moderate valvular disease by cardiac murmur, dyspnoea, or the heart failure marker NT-proBNP (natriuretic peptide) was 62% for the neurologists and 93% for the cardiologist but with equally low specificity (30-35%). EDDA was associated with a clinically important and statistically significant risk of at least moderate valve regurgitation. Clinical screening for valve disease was inadequate and it seems advisable to offer EDDA patients control with echocardiography.

A review of ropinirole prolonged release in Parkinson’s disease

PubMed Central

Nashatizadeh, Muhammad M; Lyons, Kelly E; Pahwa, Rajesh

2009-01-01

Ropinirole prolonged release is a once-daily, 24-hour formulation of ropinirole, a non-ergot dopamine agonist. It is approved as monotherapy and as an adjunct to levodopa in the treatment of Parkinson’s disease (PD). Several potential advantages of ropinirole prolonged release compared to the immediate release formulation include maintaining more consistent dopaminergic activity with steadier plasma levels, increased tolerability, greater compliance from a simpler once-daily dosing regimen and ease in dose titration. In a randomized, double-blind, non-inferiority, crossover study, ropinirole prolonged release was shown to have comparable efficacy and tolerability to immediate release ropinirole in early PD patients, with significantly greater compliance. Subjects were converted overnight between ropinirole formulations without loss of efficacy and with good tolerability. In a randomized, double-blind, placebo-controlled study in advanced PD, daily “off” time was reduced by an average of 2.1 hours with ropinirole prolonged release compared to 0.4 hours with placebo. Patients on ropinirole prolonged release were also more likely to require less daily levodopa. Ropinirole prolonged release is well tolerated with a similar adverse effect profile to other non-ergot dopamine agonists. The most common adverse effects include dyskinesia, nausea, dizziness, hallucinations, somnolence, abdominal pain or discomfort and orthostatic hypotension. Ropinirole prolonged release is a safe and effective treatment option for both early and advanced PD. This manuscript briefly reviews the current pharmacological treatment options for PD and provides a more detailed review of the currently available data regarding ropinirole prolonged release as a treatment option for PD. PMID:19503779

Characterization of Epichloë coenophiala within the U.S.: are all tall fescue endophytes created equal?

NASA Astrophysics Data System (ADS)

Young, Carolyn; Charlton, Nikki; Takach, Johanna; Swoboda, Ginger; Trammell, Michael; Huhman, David; Hopkins, Andrew

2014-11-01

Tall fescue (Lolium arundinaceum) is a valuable and broadly adapted forage grass that occupies approximately 14 million hectares across the United States. A native to Europe, tall fescue was likely introduced into the U.S. around the late 1800’s. Much of the success of tall fescue can be attributed to Epichloë coenophiala (formerly Neotyphodium coenophialum) a seed borne symbiont that aids in host persistence. Epichloë species are capable of producing a range of alkaloids (ergot alkaloids, indole-diterpenes, lolines and peramine) that provide protection to the plant host from herbivory. Unfortunately, most tall fescue within the U.S., commonly referred to as KY31, harbors the endophyte E. coenophiala that causes toxicity to grazing livestock due to the production of ergot alkaloids. Molecular analyses of tall fescue endophytes have identified four independent associations, representing tall fescue with E. coenophiala, Epichloë sp. FaTG-2, Epichloë sp. FaTG-3 or Epichloë sp. FaTG-4. Each of these Epichloë species can be further distinguished based on genetic variation that equates to differences in the alkaloid gene loci. Tall fescue samples were evaluated using markers to SSR and alkaloid biosynthesis genes to determine endophyte strain variation present within continental U.S. Samples represented seed and tillers from the Suiter farm (Menifee County, KY), which is considered the originating site of KY31, as well as plant samples collected from 14 states, breeder’s seed and plant introduction lines (National Plant Germplasm System, NPGS). This study revealed two prominent E. coenophiala genotypes based on presence of alkaloid biosynthesis genes and SSR markers and provides insight into endophyte variation within continental U.S. across historical and current tall fescue samples.

Two distinct Epichloë species symbiotic with Achnatherum inebrians, drunken horse grass.

PubMed

Chen, Li; Li, Xiuzhang; Li, Chunjie; Swoboda, Ginger A; Young, Carolyn A; Sugawara, Koya; Leuchtmann, Adrian; Schardl, Christopher L

2015-01-01

Achnatherum inebrians, colloquially known as drunken horse grass, is associated with livestock toxicity in northern China. Epichloë gansuensis (Eg) was described from endophyte isolates from A. inebrians in Sunan County, Gansu Province, whereas a morphologically distinct variety, E. gansuensis var. inebrians (Ei), was described based on two isolates from A. inebrians seeds collected in Urumqi County, Xinjiang Province. Genome sequencing and alkaloid analyses also distinguish these taxa; the Ei isolates produce neurotropic lysergic acid amides (ergot alkaloids), and an Eg isolate produces paxilline (an indole-diterpene alkaloid). To better elucidate the taxonomic diversity of Epichloë spp. symbiotic with A. inebrians, we surveyed eight populations in Xinjiang, Gansu and Inner Mongolia provinces of China and analyzed their genotypes by multiplex PCR for alkaloid biosynthesis genes and mating-type genes. Genotypes consistent with Ei were present in all eight populations, of which they dominated seven. The Ei isolates were all mating type A and tested positive for the ergot alkaloid gene, dmaW. In contrast Eg isolates were all mating type B and had the indole-diterpene gene, idtG. The genome was sequenced from an Ei isolate from seeds collected in Xiahe County, Gansu, and compared to that of the varietal ex type isolate from Urumqi. Alkaloid genes and four different housekeeping genes were nearly identical between the two sequenced Ei isolates and were distinct from a sequenced Eg isolate. Phylogenetic analysis placed Ei, Eg and Epichloë sibirica into respective subclades of a clade that emanated from the base of the Epichloë phylogeny. Given its chemotypic, genotypic, morphological and phylogenetic distinctiveness, its widespread occurrence in rangelands of northern China, and its importance in livestock toxicity, we propose raising Ei to species rank as Epichloë inebrians. © 2015 by The Mycological Society of America.

Comparison of Ergot Alkaloid Biosynthesis Gene Clusters in Claviceps Species Indicates Loss of Late Pathway Steps in Evolution of C. fusiformis▿

PubMed Central

Lorenz, Nicole; Wilson, Ella V.; Machado, Caroline; Schardl, Christopher L.; Tudzynski, Paul

2007-01-01

The grass parasites Claviceps purpurea and Claviceps fusiformis produce ergot alkaloids (EA) in planta and in submerged culture. Whereas EA synthesis (EAS) in C. purpurea proceeds via clavine intermediates to lysergic acid and the complex ergopeptines, C. fusiformis produces only agroclavine and elymoclavine. In C. purpurea the EAS gene (EAS) cluster includes dmaW (encoding the first pathway step), cloA (elymoclavine oxidation to lysergic acid), and the lpsA/lpsB genes (ergopeptine formation). We analyzed the corresponding C. fusiformis EAS cluster to investigate the evolutionary basis for chemotypic differences between the Claviceps species. Other than three peptide synthetase genes (lpsC and the tandem paralogues lpsA1 and lpsA2), homologues of all C. purpurea EAS genes were identified in C. fusiformis, including homologues of lpsB and cloA, which in C. purpurea encode enzymes for steps after clavine synthesis. Rearrangement of the cluster was evident around lpsB, which is truncated in C. fusiformis. This and several frameshift mutations render CflpsB a pseudogene (CflpsBΨ). No obvious inactivating mutation was identified in CfcloA. All C. fusiformis EAS genes, including CflpsBΨ and CfcloA, were expressed in culture. Cross-complementation analyses demonstrated that CfcloA and CflpsBΨ were expressed in C. purpurea but did not encode functional enzymes. In contrast, CpcloA catalyzed lysergic acid biosynthesis in C. fusiformis, indicating that C. fusiformis terminates its EAS pathway at elymoclavine because the cloA gene product is inactive. We propose that the C. fusiformis EAS cluster evolved from a more complete cluster by loss of some lps genes and by rearrangements and mutations inactivating lpsB and cloA. PMID:17720822

Comparison of ergot alkaloid biosynthesis gene clusters in Claviceps species indicates loss of late pathway steps in evolution of C. fusiformis.

PubMed

Lorenz, Nicole; Wilson, Ella V; Machado, Caroline; Schardl, Christopher L; Tudzynski, Paul

2007-11-01

The grass parasites Claviceps purpurea and Claviceps fusiformis produce ergot alkaloids (EA) in planta and in submerged culture. Whereas EA synthesis (EAS) in C. purpurea proceeds via clavine intermediates to lysergic acid and the complex ergopeptines, C. fusiformis produces only agroclavine and elymoclavine. In C. purpurea the EAS gene (EAS) cluster includes dmaW (encoding the first pathway step), cloA (elymoclavine oxidation to lysergic acid), and the lpsA/lpsB genes (ergopeptine formation). We analyzed the corresponding C. fusiformis EAS cluster to investigate the evolutionary basis for chemotypic differences between the Claviceps species. Other than three peptide synthetase genes (lpsC and the tandem paralogues lpsA1 and lpsA2), homologues of all C. purpurea EAS genes were identified in C. fusiformis, including homologues of lpsB and cloA, which in C. purpurea encode enzymes for steps after clavine synthesis. Rearrangement of the cluster was evident around lpsB, which is truncated in C. fusiformis. This and several frameshift mutations render CflpsB a pseudogene (CflpsB(Psi)). No obvious inactivating mutation was identified in CfcloA. All C. fusiformis EAS genes, including CflpsB(Psi) and CfcloA, were expressed in culture. Cross-complementation analyses demonstrated that CfcloA and CflpsB(Psi) were expressed in C. purpurea but did not encode functional enzymes. In contrast, CpcloA catalyzed lysergic acid biosynthesis in C. fusiformis, indicating that C. fusiformis terminates its EAS pathway at elymoclavine because the cloA gene product is inactive. We propose that the C. fusiformis EAS cluster evolved from a more complete cluster by loss of some lps genes and by rearrangements and mutations inactivating lpsB and cloA.

The different conformations and crystal structures of dihydroergocristine

NASA Astrophysics Data System (ADS)

Mönch, B.; Kraus, W.; Köppen, R.; Emmerling, F.

2016-02-01

The identification of different forms of dihydroergocristine (DHEC) was carried out by crystallization from different organic solvents. DHEC was identified as potential template for molecularly imprinted polymers (MIPs) for the epimeric specific analysis of ergot alkaloids (EAs) in food. DHEC was crystallized from different solvents in order to mimic the typical MIP synthesis conditions. Four new solvatomorphs of DHEC were obtained. All solvatomorphs contain a water molecule in the crystal structure, whereas three compounds contain an additional solvent molecule. Based on the conformation of DHEC a comparison with typical EA molecules was possible. The analysis showed that DHEC is a suitable template for MIPs for EAs.

[Dancing manias. Between culture and medicine].

PubMed

Prochwicz, Katarzyna; Sobczyk, Artur

2011-01-01

Dancing mania is a clinical and cultural phenomenon which occurred in Western Europe between 13th and 18th centuries. The term dancing mania is derived from the Greek words choros, a dance, and mania, a madness. An Italian variant was known as tarantism as victims were believed to have been bitten by tarantula spider. Although symptoms of dancing manias were well documented in contemporary writings the exact aetiology of dancing plaques is still unclear. Several causes for dancing mania have been postulated: demonic possession, the bite of tarantula, ergot poisoning, epilepsy, mass hysterias, exotics religious cults. The article contains a review of hypothesis of epidemic dances included both medical and psychological factors.

The dancing plague: a public health conundrum.

PubMed

Donaldson, L J; Cavanagh, J; Rankin, J

1997-07-01

The phenomenon of mass, frenzied dancing affected large populations in various parts of Europe from the thirteenth century and lasted, on and off, for three centuries. The exact aetiology of the Dancing Plague (or Dancing Mania) is still unclear. Retrospective historical review of this public health problem reveals claims for causative factors including demonic possession, epilepsy, the bite of a tarantula, ergot poisoning and social adversity. It seems unlikely that Dancing Mania resulted from a single cause but rather resulted from multiple factors combining with a predisposing cultural background and triggered by adverse social circumstances. Dancing Mania remains one of the unresolved mysteries of public health.

Uterine atony: definition, prevention, nonsurgical management, and uterine tamponade.

PubMed

Breathnach, Fionnuala; Geary, Michael

2009-04-01

Uterine atony, or failure of the uterus to contract following delivery, is the most common cause of postpartum hemorrhage. This review serves to examine the prevention and treatment of uterine atony, including risk-factor recognition and active management of the third stage of labor. A range of uterotonic agents will be compared for efficacy, safety, and ease of administration. Oxytocin and ergot alkaloids represent the cornerstone of uterotonic therapy, while prostaglandin therapy has been studied more recently as an attractive alternative, particularly for resource-poor settings. Newer supplementary medical therapies, such as recombinant factor VII and hemostatic agents, and adjunctive nonsurgical methods aimed at achieving uterine tamponade will be evaluated.

Ergot alkaloids from endophyte-infected tall fescue decrease reticuloruminal epithelial blood flow and volatile fatty acid absorption from the washed reticulorumen.

PubMed

Foote, A P; Kristensen, N B; Klotz, J L; Kim, D H; Koontz, A F; McLeod, K R; Bush, L P; Schrick, F N; Harmon, D L

2013-11-01

An experiment was conducted to determine if ergot alkaloids affect blood flow to the absorptive surface of the rumen. Steers (n=8) were pair-fed alfalfa cubes and received ground endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum; E+) seed (0.015 mg ergovaline·kg BW(-1)·d(-1)) or endophyte-free tall fescue (E-) seed via the rumen cannula 2x daily for 7 d at thermoneutral (TN; 22°C) and heat stress (HS; 32°C) conditions. On d 8, the rumen was emptied and rinsed. A buffer containing VFA was incubated in the following sequence: control (CON), 15 μg ergovaline·kg BW(-1) (1×EXT) from a tall fescue seed extract, and 45 μg ergovaline·kg BW(-1) (3×EXT). For each buffer treatment there were two 30-min incubations: a 30-min incubation of a treatment buffer with no sampling followed by an incubation of an identical sampling buffer with the addition of Cr-EDTA and deuterium oxide (D2O). Epithelial blood flow was calculated as ruminal clearance of D2O corrected for influx of physiological water and liquid outflow. Feed intake decreased with dosing E+ seed at HS but not at thermoneutral conditions (TN; P<0.02). Dosing E+ seed decreased serum prolactin (P<0.005) at TN. At HS, prolactin decreased in both groups over the 8-d experiment (P<0.0001), but there was no difference in E+ and E- steers (P=0.33). There was a seed treatment×buffer treatment interaction at TN (P=0.038), indicating that E+ seed treatment decreased reticuloruminal epithelial blood flow at TN during the CON incubation, but the two groups of steers were not different during 1×EXT and 3×EXT (P>0.05). Inclusion of the extract in the buffer caused at least a 50% reduction in epithelial blood flow at TN (P=0.004), but there was no difference between 1×EXT and 3×EXT. There was a seed × buffer treatment interaction at HS (P=0.005), indicating that the reduction of blood flow induced by incubating the extract was larger for steers receiving E- seed than E+ seed. Volatile fatty acid flux was reduced during the 1×EXT and 3×EXT treatments (P<0.01). An additional experiment was conducted to determine the effect of time on blood flow and VFA flux because buffer sequence could not be randomized. Time either increased (P=0.05) or did not affect blood flow (P=0.18) or VFA flux (P>0.80), indicating that observed differences are due to the presence of ergot alkaloids in the rumen. A decrease in VFA absorption could contribute to the signs of fescue toxicosis including depressed growth and performance.

Neuropsychiatric and metabolic aspects of dopaminergic therapy: perspectives from an endocrinologist and a psychiatrist

PubMed Central

Athanasoulia-Kaspar, Anastasia P; Popp, Kathrin H; Stalla, Gunter Karl

2018-01-01

The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies. PMID:29378769

Temporal and spatial variation in alkaloid levels in Achnatherum robustum, a native grass infected with the endophyte Neotyphodium.

PubMed

Faeth, Stanley H; Gardner, Dale R; Hayes, Cinnamon J; Jani, Andrea; Wittlinger, Sally K; Jones, Thomas A

2006-02-01

The native North American perennial grass Achnatherum robustum (Vasey) Barkworth [= Stipa robusta (Vasey) Scribn.] or sleepygrass is toxic and narcotic to livestock. The causative agents are alkaloidal mycotoxins produced from infections by a systemic and asexual Neotyphodium endophyte. Recent studies suggest that toxicity is limited across the range of sleepygrass in the Southwest USA. We sampled 17 populations of sleepygrass with varying distance from one focal population known for its high toxicity levels near Cloudcroft, NM, USA. For some, we sampled individual plants twice within the same growing season and over successive years (2001-2004). We also determined infection levels in each population. In general, all populations were highly infected, but infection levels were more variable near the focal population. Only infected plants within populations near the Cloudcroft area produced alkaloids. The ergot alkaloid, ergonovine, comprised the bulk of the alkaloids, with lesser amounts of lysergic and isolysergic acid amides and ergonovinine alkaloids. Levels of all alkaloids were positively correlated among individual plants within and between growing seasons. Infected plants that produced no alkaloids in 1 yr did not produce any alkaloids within the same growing season or in other years. Levels of alkaloids in sleepygrass populations declined with distance from the Cloudcroft population, although infection levels increased. Infected plants in populations in northern New Mexico and southern Colorado produced no alkaloids at all despite 100% infectivity. Our results suggest that only specific Neotyphodium haplotypes or specific Neotyphodium-grass combinations produce ergot alkaloids in sleepygrass. The Neotyphodium haplotype or host-endophyte combination that produces toxic levels of alkaloids appears restricted to one locality across the range of sleepygrass. Because of the wide variation in alkaloid levels among populations, interactions between the endophyte and host, and consequences for herbivores, competitors, and pathogens and other components of the community, are likely to vary widely across the geographic range of this native grass.

Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci.

PubMed

Schardl, Christopher L; Young, Carolyn A; Hesse, Uljana; Amyotte, Stefan G; Andreeva, Kalina; Calie, Patrick J; Fleetwood, Damien J; Haws, David C; Moore, Neil; Oeser, Birgitt; Panaccione, Daniel G; Schweri, Kathryn K; Voisey, Christine R; Farman, Mark L; Jaromczyk, Jerzy W; Roe, Bruce A; O'Sullivan, Donal M; Scott, Barry; Tudzynski, Paul; An, Zhiqiang; Arnaoudova, Elissaveta G; Bullock, Charles T; Charlton, Nikki D; Chen, Li; Cox, Murray; Dinkins, Randy D; Florea, Simona; Glenn, Anthony E; Gordon, Anna; Güldener, Ulrich; Harris, Daniel R; Hollin, Walter; Jaromczyk, Jolanta; Johnson, Richard D; Khan, Anar K; Leistner, Eckhard; Leuchtmann, Adrian; Li, Chunjie; Liu, JinGe; Liu, Jinze; Liu, Miao; Mace, Wade; Machado, Caroline; Nagabhyru, Padmaja; Pan, Juan; Schmid, Jan; Sugawara, Koya; Steiner, Ulrike; Takach, Johanna E; Tanaka, Eiji; Webb, Jennifer S; Wilson, Ella V; Wiseman, Jennifer L; Yoshida, Ruriko; Zeng, Zheng

2013-01-01

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses.

Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

NASA Astrophysics Data System (ADS)

Mcculley, Rebecca; Bush, Lowell; Carlisle, Anna; Ji, Huihua; Nelson, Jim

2014-10-01

Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue’s ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause ‘fescue toxicosis’ in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3oC) and growing season precipitation (+30% of the long-term mean) from 2009 - 2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30-40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue toxicosis.

Warming reduces tall fescue abundance but stimulates toxic alkaloid concentrations in transition zone pastures of the U.S.

PubMed Central

McCulley, Rebecca L.; Bush, Lowell P.; Carlisle, Anna E.; Ji, Huihua; Nelson, Jim A.

2014-01-01

Tall fescue pastures cover extensive acreage in the eastern half of the United States and contribute to important ecosystem services, including the provisioning of forage for grazing livestock. Yet little is known concerning how these pastures will respond to climate change. Tall fescue's ability to persist and provide forage under a warmer and wetter environment, as is predicted for much of this region as a result of climate change, will likely depend on a symbiotic relationship the plant can form with the fungal endophyte, Epichloë coenophiala. While this symbiosis can confer environmental stress tolerance to the plant, the endophyte also produces alkaloids toxic to insects (e.g., lolines) and mammals (ergots; which can cause “fescue toxicosis” in grazing animals). The negative animal health and economic consequences of fescue toxicosis make understanding the response of the tall fescue symbiosis to climate change critical for the region. We experimentally increased temperature (+3°C) and growing season precipitation (+30% of the long-term mean) from 2009–2013 in a mixed species pasture, that included a tall fescue population that was 40% endophyte-infected. Warming reduced the relative abundance of tall fescue within the plant community, and additional precipitation did not ameliorate this effect. Warming did not alter the incidence of endophyte infection within the tall fescue population; however, warming significantly increased concentrations of ergot alkaloids (by 30–40%) in fall-harvested endophyte-infected individuals. Warming alone did not affect loline alkaloid concentrations, but when combined with additional precipitation, levels increased in fall-harvested material. Although future warming may reduce the dominance of tall fescue in eastern U.S. pastures and have limited effect on the incidence of endophyte infection, persisting endophyte-infected tall fescue will have higher concentrations of toxic alkaloids which may exacerbate fescue toxicosis. PMID:25374886

[Verrucous pastern dermatitis syndrome in heavy draught horses. Part II: Clinical findings].

PubMed

Geburek, F; Deegen, E; Hewicker-Trautwein, M; Ohnesorge, B

2005-07-01

In the present field study the skin of the feet of 37 heavy draught horses of different breeds showing verrucous pastern dermatitis was examined clinically. Included were the degree of severity of the disease and the prevalence of anatomically normal structures associated with the skin: fetlock tufts of hair ("feathering"), ergots, chestnuts, bulges in the pastern region, cannon circumference. Each horse was examined for Chorioptes sp. skin mites. Information was also collected on the development of the skin alterations and housing conditions and feeding. These individual data were correlated with the clinical degree of severity of verrucous pastern dermatitis, which was evaluated using a numerical code (scoring system). In addition, punch biopsies were taken from the diseased skin of the feet and from healthy skin of the neck for comparative patho-histological examination (see Part III). Verrucous pastern dermatitis is a chronic disease which can be divided into four groups: scaling (group I), hyperkeratotic and hyperplastic plaque-like lesions (group II), tuberous skin masses (group III), and verrucous skin lesions with rugged surfaces (group IV). No correlation was found between the clinical degree of severity of the skin lesions and sex, breed, amount of work, use of stallions for breeding, grooming condition of the hair, white markings in the foot region, or Chorioptes sp. infestation. In regard to feeding it was found that the amount of maize and oats fed had some influence on the clinical degree of severity. Statistical analysis revealed a significant correlation between the clinical degree of severity and the age, the grooming condition of the hooves, and the mean cannon circumference. The prevalence of fetlock tufts of hair, chestnuts, ergots, and anatomically normal bulges in the pastern region also increased significantly with the clinical degree of severity. Furthermore the study revealed that the clinical degree of severity depended on the hygienic conditions of the stables and of the ground where the horses were kept outdoors.

Deoxynivalenol, deoxynivalenol-3-glucoside, and enniatins: the major mycotoxins found in cereal-based products on the Czech market.

PubMed

Malachova, Alexandra; Dzuman, Zbynek; Veprikova, Zdenka; Vaclavikova, Marta; Zachariasova, Milena; Hajslova, Jana

2011-12-28

Fusarium toxins, Alternaria toxins, and ergot alkaloids represent common groups of mycotoxins that can be found in cereals grown under temperate climatic conditions. Because most of them are chemically and thermally stable, these toxic fungal secondary metabolites might be transferred from grains into the final products. To get information on the commensurate contamination of various cereal-based products collected from the Czech retail market in 2010, the occurrence of "traditional" mycotoxins such as groups of A and B trichothecenes and zearalenone, less routinely determined Alternaria toxins (alternariol, alternariol monomethyl ether and altenuene), ergot alkaloids (ergosine, ergocryptine, ergocristine, and ergocornine) and "emerging" mycotoxins (enniatins A, A1, B, and B1 and beauvericin) were monitored. In a total 116 samples derived from white flour and mixed flour, breakfast cereals, snacks, and flour, only trichothecenes A and B and enniatins were found. Deoxynivalenol was detected in 75% of samples with concentrations ranging from 13 to 594 μg/kg, but its masked form, deoxynivalenol-3-β-d-glucoside, has an even higher incidence of 80% of samples, and concentrations ranging between 5 and 72 μg/kg were detected. Nivalenol was found only in three samples at levels of 30 μg/kg. For enniatins, all of the samples investigated were contaminated with at least one of four target enniatins. Enniatin A was detected in 97% of samples (concentration range of 20-2532 μg/kg) followed by enniatin B with an incidence in 91% of the samples (concentration range of 13-941 μg/kg) and enniatin B1 with an incidence of 80% in the samples tested (concentration range of 8-785 μg/kg). Enniatin A1 was found only in 44% of samples at levels ranging between 8 and 851 μg/kg.

Plant-Symbiotic Fungi as Chemical Engineers: Multi-Genome Analysis of the Clavicipitaceae Reveals Dynamics of Alkaloid Loci

PubMed Central

Schardl, Christopher L.; Young, Carolyn A.; Hesse, Uljana; Amyotte, Stefan G.; Andreeva, Kalina; Calie, Patrick J.; Fleetwood, Damien J.; Haws, David C.; Moore, Neil; Oeser, Birgitt; Panaccione, Daniel G.; Schweri, Kathryn K.; Voisey, Christine R.; Farman, Mark L.; Jaromczyk, Jerzy W.; Roe, Bruce A.; O'Sullivan, Donal M.; Scott, Barry; Tudzynski, Paul; An, Zhiqiang; Arnaoudova, Elissaveta G.; Bullock, Charles T.; Charlton, Nikki D.; Chen, Li; Cox, Murray; Dinkins, Randy D.; Florea, Simona; Glenn, Anthony E.; Gordon, Anna; Güldener, Ulrich; Harris, Daniel R.; Hollin, Walter; Jaromczyk, Jolanta; Johnson, Richard D.; Khan, Anar K.; Leistner, Eckhard; Leuchtmann, Adrian; Li, Chunjie; Liu, JinGe; Liu, Jinze; Liu, Miao; Mace, Wade; Machado, Caroline; Nagabhyru, Padmaja; Pan, Juan; Schmid, Jan; Sugawara, Koya; Steiner, Ulrike; Takach, Johanna E.; Tanaka, Eiji; Webb, Jennifer S.; Wilson, Ella V.; Wiseman, Jennifer L.; Yoshida, Ruriko; Zeng, Zheng

2013-01-01

The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloë and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some—including the infamous ergot alkaloids—have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses. PMID:23468653

Toxic effects of mycotoxins in humans.

PubMed Central

Peraica, M.; Radić, B.; Lucić, A.; Pavlović, M.

1999-01-01

Mycotoxicoses are diseases caused by mycotoxins, i.e. secondary metabolites of moulds. Although they occur more frequently in areas with a hot and humid climate, favourable for the growth of moulds, they can also be found in temperate zones. Exposure to mycotoxins is mostly by ingestion, but also occurs by the dermal and inhalation routes. Mycotoxicoses often remain unrecognized by medical professionals, except when large numbers of people are involved. The present article reviews outbreaks of mycotoxicoses where the mycotoxic etiology of the disease is supported by mycotoxin analysis or identification of mycotoxin-producing fungi. Epidemiological, clinical and histological findings (when available) in outbreaks of mycotoxicoses resulting from exposure to aflatoxins, ergot, trichothecenes, ochratoxins, 3-nitropropionic acid, zearalenone and fumonisins are discussed. PMID:10534900

Pramipexole in the treatment of Parkinson's disease: new developments.

PubMed

Möller, J Carsten; Oertel, Wolfgang H

2005-09-01

The nonergot dopamine agonist pramipexole is an efficient and safe drug for the treatment of Parkinson's disease. Clinicians may favor pramipexole over other dopamine agonists because of its suggested higher tolerability with respect to peripheral dopaminergic side effects. Importantly, nonergot dopamine agonists such as pramipexole may not cause restrictive valvular heart disease and may therefore represent the first choice in patients with valvular lesions under treatment with ergot dopamine agonists. However, particular caution has to be exercised in younger Parkinson's disease patients with a shorter disease duration regarding the occurrence of sudden onset of sleep. In light of cost-effectiveness and quality-of-life issues, its final significance for the initial treatment of patients with early Parkinson's disease remains to be determined.

Penicillium roqueforti: a multifunctional cell factory of high value-added molecules.

PubMed

Mioso, R; Toledo Marante, F J; Herrera Bravo de Laguna, I

2015-04-01

This is a comprehensive review, with 114 references, of the chemical diversity found in the fungus Penicillium roqueforti. Secondary metabolites of an alkaloidal nature are described, for example, ergot alkaloids such as festuclavine, isofumigaclavines A and B, and diketopiperazine alkaloids such as roquefortines A-D, which are derived from imidazole. Other metabolites are marcfortines A-C, PR-toxin, eremofortines A-E, mycophenolic and penicillic acids, and some γ-lactones. Also, recent developments related to the structural characteristics of botryodiplodin and andrastin are studied-the latter has anticancer properties. Finally, we discuss the enzymes of P. roqueforti, which can participate in the biotechnological production of high value-added molecules, as well as the use of secondary metabolite profiles for taxonomic purposes. © 2014 The Society for Applied Microbiology.

Development of a methodology to measure the effect of ergot alkaloids on forestomach motility using real-time wireless telemetry

NASA Astrophysics Data System (ADS)

Egert, Amanda; Klotz, James; McLeod, Kyle; Harmon, David

2014-10-01

The objectives of these experiments were to characterize rumen motility patterns of cattle fed once daily using a real-time wireless telemetry system, determine when to measure rumen motility with this system, and determine the effect of ruminal dosing of ergot alkaloids on rumen motility. Ruminally cannulated Holstein steers (n = 8) were fed a basal diet of alfalfa cubes once daily. Rumen motility was measured by monitoring real-time pressure changes within the rumen using wireless telemetry and pressure transducers. Experiment 1 consisted of three 24-h rumen pressure collections beginning immediately after feeding. Data were recorded, stored, and analyzed using iox2 software and the rhythmic analyzer. All motility variables differed (P < 0.01) between hours and thirds (8-h periods) of the day. There were no differences between days for most variables. The variance of the second 8-h period of the day was less than (P < 0.01) the first for area and less than the third for amplitude, frequency, duration, and area (P < 0.05). These data demonstrated that the second 8-h period of the day was the least variable for many measures of motility and would provide the best opportunity for testing differences in motility due to treatments. In Exp. 2, the steers (n = 8) were pair-fed the basal diet of Exp. 1 and dosed with endophyte-free (E-) or endophyte-infected (E+; 0 or 10 μg ergovaline + ergovalinine / kg BW; respectively) tall fescue seed before feeding for 15 d. Rumen motility was measured for 8 h beginning 8 h after feeding for the first 14 d of seed dosing. Blood samples were taken on d 1, 7, and 15, and rumen content samples were taken on d 15. Baseline (P = 0.06) and peak (P = 0.04) pressure were lower for E+ steers. Water intake tended (P = 0.10) to be less for E+ steers the first 8 hour period after feeding. The E+ seed treatment at this dosage under thermoneutral conditions did not significantly affect rumen motility, ruminal fill, or dry matter of rumen contents.

Therapeutic use of nicergoline.

PubMed

Winblad, Bengt; Fioravanti, Mario; Dolezal, Tomas; Logina, Inara; Milanov, Ivan Gospodinov; Popescu, Dinu Cristian; Solomon, Alina

2008-01-01

The ergot alkaloid derivative nicergoline became clinically available about 35 years ago in the 1970s. Nicergoline has a broad spectrum of action: (i) as an alpha(1)-adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow; (ii) it enhances cholinergic and catecholaminergic neurotransmitter function; (iii) it inhibits platelet aggregation; (iv) it promotes metabolic activity, resulting in increased utilization of oxygen and glucose; and (v) it has neurotrophic and antioxidant properties. Acting on several basic pathophysiological mechanisms, nicergoline has therapeutic potential in a number of disorders. This article provides an overview of the published clinical evidence relating to the efficacy and safety of nicergoline (30 mg twice daily) in the treatment of dementia (including Alzheimer's disease and vascular dementia) and vascular and balance disorders. For dementia of different aetiologies, the therapeutic benefit of nicergoline has been established, with up to 89% of patients showing improvements in cognition and behaviour. After as little as 2 months of treatment, symptom improvement is apparent compared with placebo, and most patients are still improved or stable after 12 months. Concomitant neurophysiological changes in the brain indicate (after only 4-8 weeks' treatment) improved vigilance and information processing. In patients with balance disorders, mean improvements of 44-78% in symptom severity and quality of life have been observed with nicergoline. Although clinical experience with nicergoline in vascular disorders is limited to relatively short-term, small-scale studies, it has been successfully used in rehabilitation therapy of patients with chronic ischaemic stroke. Open-label evaluations suggest that nicergoline may also be valuable in glaucoma, depression and peripheral arterio-pathy. Adverse events of nicergoline, if any, are related to the central nervous system, the metabolic system and the overall body. Most are considered typical symptoms of ergot derivatives. Because of their generally mild and transient nature, treatment discontinuations occur relatively infrequently. The efficacy of nicergoline combined with a favourable safety and tolerability profile at commonly applied doses (60 mg/day) make this agent a valuable therapy in patients with mild to moderate dementia, vascular diseases and balance disorders.

Osler on migraine.

PubMed

Boes, Christopher J

2015-03-01

William Osler's 1892 textbook The Principles and Practice of Medicine became the dominant medical text in the English-speaking world. Osler was labeled a therapeutic nihilist by some. The topic of migraine, including treatment, was succinctly covered in his text. The objectives of this study were to review Osler's thoughts on migraine, and outline his therapeutic recommendations. Preventively Osler mentioned bromides, iron, arsenic, nitroglycerin, and cannabis. Acutely he recommended coffee, chloroform, cannabis, antipyrin, antifebrin, phenacetin, caffeine citrate, nux vomica, or ergot. He thought cannabis was the most satisfactory remedy. Osler was not a therapeutic nihilist when it came to migraine, and his treatment recommendations were similar to other writers of his time. Osler did not draw upon his personal experience to contribute new knowledge about migraine. Regardless, given the popularity and clarity of his text, Osler's well-summarized migraine chapter had a great influence on practicing physicians.

Alkaloids of Stipa robusta (sleepygrass) infected with an Acremonium endophyte.

PubMed

Petroski, R J; Powell, R G; Clay, K

1992-01-01

Stipa robusta (= Stipa vaseyi) is a perennial grass found in certain areas of the southwestern United States. It is commonly known as sleepygrass, as horses that ingest this grass may become profoundly somnolent or stuporous for periods of time lasting up to several days. In an attempt to determine the active principle(s), fractionation of a methanolic extract of sleepygrass infected with an Acremonium endophyte has yielded lysergic acid amide (20 micrograms/g dry wt), isolysergic amide (8), 8-hydroxylsergic acid amide (0.3), ergonovine (7), chanoclavine-I (15), and N-formylloline (18). Related alkaloids have been found in many endophyte-infected grasses. The dominant alkaloid constituent in sleepygrass, lysergic acid amide, has not previously been identified in a grass in such high concentration. Lysergic acid amide is likely to be the basis for the extreme sedative effects on animals, given past pharmacological work on the compound from the ergot fungus Claviceps paspali.

The diagnosis and treatment of chronic migraine

PubMed Central

2015-01-01

Migraine is the most common disabling brain disorder. Chronic migraine, a condition characterized by the experience of migrainous headache on at least 15 days per month, is highly disabling. Patients with chronic migraine present to primary care, are often referred for management to secondary care, and make up a large proportion of patients in specialist headache clinics. Many patients with chronic migraine also have medication overuse, defined as using a compound analgesic, opioid, triptan or ergot derivative on at least 10 days per month. All doctors will encounter patients with chronic headaches. A basic working knowledge of the common primary headaches, and a rational manner of approaching the patient with these conditions, allows a specific diagnosis of chronic migraine to be made quickly and safely, and by making this diagnosis one opens up a substantial number of acute and preventive treatment options. This article discusses the current state of management of chronic migraine. PMID:25954496

Chemical and biological approaches for mycotoxin control: a review.

PubMed

Edlayne, Gonçalez; Simone, Aquino; Felicio, Joana D

2009-06-01

Mycotoxins are metabolites and toxic substances produced by certain filamentous fungi that frequently contaminate food and agriculture commodities, which cause disease in animals or man. The toxigenic fungi belong to mainly three genera: Aspergillus, Penicillium and Fusarium. Examples of mycotoxins of greatest public health and agroeconomic significance include aflatoxins, ochratoxins, trichothecenes, zearalenone, fumonisins, patulin and ergot alkaloids. Commodities susceptible to direct contamination with mycotoxins include nuts, oilseeds and grains. Chemical and biological treatments have been attempted to minimize the risk of mycotoxins contamination or eliminate the fungi of food and feeds. One way to prevent or interfere with fungal growth and mycotoxin production is by use of synthetic or natural agents. Bacteria have been studied to control the mycotoxins production and fungal growth in food. Plant genotypes resistant to infection by toxigenic fungi have been also studied. This review will approach same patented methods applied to degrade, prevent and control of mycotoxins in food and feeds.

The role of the Oregon State University Endophyte Service Laboratory in diagnosing clinical cases of endophyte toxicoses.

PubMed

Craig, A Morrie; Blythe, Linda L; Duringer, Jennifer M

2014-07-30

The Oregon State University Colleges of Veterinary Medicine and Agricultural Sciences instituted the Endophyte Service Laboratory to aid in diagnosing toxicity problems associated with cool-season grasses in livestock. The endophyte (Neotyphodium coenophalum) present in tall fescue (Festuca arundinacea) produces ergopeptine alkaloids, of which ergovaline is the molecule used to determine exposure and toxicity thresholds for the vasoconstrictive conditions "fescue foot" and "summer slump". Another vasoconstrictive syndrome, "ergotism," is caused by a parasitic fungus, Claviceps purpurea, and its primary toxin, ergotamine. "Ryegrass staggers" is a neurological condition that affects livestock consuming endophyte (Neotyphodium lolii)-infected perennial ryegrass (Lolium perenne) with high levels of lolitrem B. HPLC-fluorescent analytical methods for these mycotoxins are described and were used to determine threshold levels of toxicity for ergovaline and lolitrem B in cattle, sheep, horses, and camels. In addition, six clinical cases in cattle are presented to illustrate diagnosis of these three diseases.

Case Series of HIV Infection-Associated Arteriopathy: Diagnosis, Management, and Outcome Over a 5-Year period at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University.

PubMed

Orrapin, Saritphat; Reanpang, Termpong; Orrapin, Saranat; Arwon, Supapong; Kattipathanapong, Thanate; Lekwanavijit, Suree; Rerkasem, Kittipan

2015-09-01

Patients infected with human immunodeficiency virus (HIV) can present with 4 pathology types: drug-induced vasospasm (ergotism), arterial limb ischemia, critical limb ischemia, and aneurysm. Although these problems are common vascular problems, they result in increased morbidity and mortality in HIV-infected patients, especially aneurysm. Patients with these problems tend to be diagnosed with difficulty because of atypical symptoms and signs. Because of lack of data in treatment outcome literature, our report explores and provides information on HIV infection-related arteriopathy. There were 17 patients in our 5-year review. There was no death in patients except the aneurysm type. The survival of aneurysm patients was significantly lower than from other pathologies (P = .003). Our case series showed good short-term outcome, and patients were not at risk for less beneficial surgical procedures. © The Author(s) 2015.

Mycotoxins in foods in Lower Saxony (Germany): results of official control analyses performed in 2009.

PubMed

Reinhold, Lilli; Reinhardt, Katja

2011-05-01

In this presentation, the mycotoxin levels-as analysed by the analytical centre for mycotoxin surveillance of the state food laboratory (LAVES Braunschweig)-for approximately 500 food samples are reported. The samples were collected in the year 2009 at retail in the German federal state of Lower Saxony. Aflatoxin and ochratoxin A were analysed in dried fruits, spices, cereals and tree nuts. Ochratoxin A was detected in all samples of dried vine fruits, at levels up to 8.1 μg/kg. Aflatoxins and ochratoxin A were also found in nutmeg and curry powder: the maximum regulatory levels for aflatoxins were exceeded in 25% of the nutmeg samples. Nearly all samples of basmati rice contained aflatoxins, although at levels below the maximum regulatory level in all but one sample. Aflatoxins were also detected in about 50% of hazelnut samples, in 20% of the samples the maximum levels was exceeded (maximum 23.2 μg/kg). In contrast, aflatoxin contents in pistachios were surprisingly low. Fusarium toxins were analysed in cereals and cereal products such as flour, bread, and pasta. Deoxynivalenol (DON) was the predominant toxin found in these samples: DON was found in about 40% of the samples, although the maximum levels were not exceeded (max. 418 μg/kg). Fumonisins (FBs) and zearalenone (ZEA) were specifically analysed in maize products (snacks, flour and oil). Most of these samples (80%) were positive, but at levels not exceeding the maximum levels. Maximum levels were 98 μg/kg (ZEA) and 577 μg/kg (sum of FB1 and FB2). Ergot alkaloids (six major alkaloids) were analysed in rye flour, and approximately 50% were positive. The highest concentration of ergot alkaloids was 1,063 μg/kg; the predominant alkaloids were ergotamine and ergocristine. In conclusion, the results indicate that continuous and efficient control measures for mycotoxins in a wide range of critical foods are necessary to ensure compliance with maximum levels. Although the mycotoxin levels in the vast majority of samples were below maximum levels, year-to-year variation and changes in the production of relevant commodities may result in a different picture in the future.

Radiation Breeding of Apomictic Prostrate Dallisgrass, Paspalum dilatatum Var. Pauciciliatum1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burton, Glenn W.; Jackson, J. E.

1962-01-01

A study was made of spaced plants and progeny of the meiotically irregular prostrate dallisgrass from seed untreated and treated with l5 and 30 hours of thermal neutron and 20 and 30 Kr of x rays. It was concluded that the best radiation treatment, 20 hours of thermal neutrons, increased the frequency of R 1 vegetative and tloral mutants over 4-fold and nearly doubled the number of vegetative mutant classes. Radiation-induced mutants continued to reproduce by apomixis. Radiation did not induce sexuality in this obligate apomict. No evidence of ergot resistance could be found in some 4,000 R 2 andmore » some 16,000 R 2 plants. Since radiation did no break apomixis, R 2 plants should be designated R 1A 1 (first radiation generation followed by the first apomictic generation), The limited radiation breeding practiced in this study failed to lead to the development of higher yielding strains capable of producing more and higher quality seed.« less

Haloperidol-induced changes in glutathione and energy metabolism: effect of nicergoline.

PubMed

Vairetti, M; Feletti, F; Battaglia, A; Pamparana, F; Canonico, P L; Richelmi, P; Bertè, F

1999-02-12

The aim of this study was to evaluate the possible effects of nicergoline, a semisynthetic ergot derivative, on the biochemical changes observed during chronic treatment with haloperidol in male Sprague-Dawley rats. Chronic treatment with haloperidol induced a significant decrease in the cellular glutathione (GSH) content in selected areas of the brain (cerebellum, striatum and cortex) and in the liver. Prolonged nicergoline administration was able to antagonize the haloperidol-induced GSH decrease, maintaining the GSH concentration at levels comparable to those observed in the control group. Analysis of the energy charge revealed changes similar to those observed for GSH: haloperidol induced a significant decrease in ATP and energy charge that was completely reversed by repeated nicergoline administration. In conclusion, chronic treatment with the classical antipsychotic haloperidol induces profound biochemical changes in the brain and in the liver. Nicergoline treatment is able to counteract the haloperidol-induced decrease in GSH levels and energy charge, suggesting a potential role of the drug in the treatment of neuroleptic-induced side effects.

Effects of selected combinations of tall fescue alkaloids on the vasoconstrictive capacity of fescue-naive bovine lateral saphenous veins.

PubMed

Klotz, J L; Kirch, B H; Aiken, G E; Bush, L P; Strickland, J R

2008-04-01

Vasoconstriction is a response associated with consumption of toxic endophyte-infected tall fescue. It is not known if endophyte-produced alkaloids act alone or collectively in mediating the response. Therefore, the objective of this study was to examine the vasoconstrictive potentials of selected ergot alkaloids, individually or in paired combinations, using bovine lateral saphenous veins biopsied from fescue-naïve cattle. Segments (2 to 3 cm) of vein were surgically biopsied from healthy crossbred yearling heifers (n = 22; 330 +/- 8 kg of BW). Veins were trimmed of excess fat and connective tissue, sliced into 2- to 3-mm sections, and suspended in a myograph chamber containing 5 mL of oxygenated Krebs-Henseleit buffer (95% O(2)/5% CO(2); pH = 7.4; 37 degrees C). Increasing doses of ergovaline, lysergic acid, and N-acetylloline individually or in combination were evaluated. Contractile data were normalized as a percentage of the contractile response induced by a reference dose of norepinephrine (1 x 10(- 4) M). Increasing concentrations of lysergic acid did not result in an appreciable contractile response until the addition of 1 x 10(- 4) M lysergic acid. In contrast, the vascular response to increasing concentrations of ergovaline was apparent at 1 x 10(- 8) M and increased to a maximum of 104.2 +/- 6.0% with the addition of 1 x 10(- 4) M ergovaline. The presence of N-acetylloline did not alter the onset or magnitude of vascular response to either lysergic acid or ergovaline. The presence of 1 x 10(- 5) M lysergic acid with increasing concentrations of N-acetylloline and ergovaline generated an increased contractile response during the initial additions compared with the responses of N-acetylloline and ergovaline alone. In the presence of 1 x 10(- 7) M ergovaline, the contractile response increased with increasing concentrations of N-acetylloline and lysergic acid. Neither N-acetylloline nor lysergic acid elicited an intense contractile response individually (maximum contractile responses of 1.9 +/- 0.3% and 22.6 +/- 4.1%, respectively), suggesting that this was the result of the repetitive addition of 1 x 10(- 7) M ergovaline. These data indicate that ergovaline is a more potent vascular toxicant than lysergic acid or N-acetylloline. The contractile responses of the ergovaline and lysergic acid combinations appeared to differ from the individual dose responses. These data support the possibility that an additive alkaloid exposure effect may exist and should be considered during evaluations of ergot alkaloids.

Ultrasonographic assessment of the equine palmar tendons

PubMed Central

Padaliya, N. R.; Ranpariya, J. J.; Kumar, Dharmendra; Javia, C. B.; Barvalia, D. R.

2015-01-01

Aim: The present study was conducted to evaluate the equine palmar tendon by ultrasonography (USG) in standing the position. Materials and Methods: USG of palmar tendons was performed in 40 adult horses using linear transducer having frequency of 10-18 MHz (e-soate, My Lab FIVE) and L52 linear array transducer (Titan, SonoSite) with frequencies ranging from 8 to 10 MHz. Palmar tendon was divided into 7 levels from distal to accessory carpal bone up to ergot in transverse scanning and 3 levels in longitudinal scanning. Results: The USG evaluation was very useful for diagnosis of affections of the conditions such as chronic bowed tendon, suspensory ligament desmitis, carpal sheath tenosynovitis and digital sheath effusions. The mean cross-sectional area (cm2) of affected tendons was significantly increased in affected than normal tendons. The echogenicity was also found reduced in affected tendons and ligaments along with disorganization of fiber alignment depending on the severity of lesion and injury. Conclusion: USG proved ideal diagnostic tool for diagnosis and post-treatment healing assessment of tendon injuries in horses. PMID:27047074

Non-functional tricuspid valve disease

PubMed Central

2017-01-01

Only 75% of severe tricuspid regurgitation is classified as functional, or related primarily to pulmonary hypertension, right ventricular dysfunction, or a combination of both. Non-functional tricuspid regurgitation occurs when there is damage to the tricuspid leaflets, chordae, papillary muscles, or annulus, independent of right ventricular dysfunction or pulmonary hypertension. The entities that cause non-functional tricuspid regurgitation include rheumatic and myxomatous disease, acquired and genetic connective tissue disorders, endocarditis, sarcoid, pacing, RV biopsy, blunt trauma, radiation, carcinoid, ergot alkaloids, dopamine agonists, fenfluramine, cardiac tumors, atrial fibrillation, and congenital malformations. Over time, severe tricuspid regurgitation that is initially non-functional, can blend into functional tricuspid regurgitation, related to progressive right ventricular dysfunction. Symptoms and signs, including a falling right ventricular ejection fraction, cardiac cirrhosis, ascites, esophageal varices, and anasarca, may occur insidiously and late, but are associated with substantial morbidity and mortality. Attempted valve repair or replacement at late stages carries a high mortality. Crucial to following patients with severe non-functional tricuspid regurgitation is attention to echo quantification of the tricuspid regurgitation and right ventricular function, patient symptoms, and the physical examination. PMID:28706863

[Approaching the "evidence-practice gap" in pharmaceutical risk management: analysis of healthcare claim data].

PubMed

Nakayama, Takeo

2012-01-01

The concept of evidence-based medicine (EBM) has promulgated among healthcare professionals in recent years, on the other hand, the problem of underuse of useful clinical evidence is coming to be important. This is called as evidence-practice gap. The major concern about evidence-practice gap is insufficient implementation of evidence-based effective treatment, however, the perspective can be extended to measures to improve drug safety and prevention of drug related adverse events. First, this article reviews the characteristics of the database of receipt (healthcare claims) and the usefulness for research purpose of pharmacoepidemiology. Second, as the real example of the study on evidence-practice gap by using the receipt database, the case of ergot-derived anti-Parkinson drugs, of which risk of valvulopathy has been identified, is introduced. The receipt analysis showed that more than 70% of Parkinson's disease patients prescribed with cabergoline or pergolide did not undergo echocardiography despite the revision of the product label recommendation. Afterwards, the issues of pharmaceutical risk management and risk communication will be discussed.

Non-functional tricuspid valve disease.

PubMed

Adler, Dale S

2017-05-01

Only 75% of severe tricuspid regurgitation is classified as functional, or related primarily to pulmonary hypertension, right ventricular dysfunction, or a combination of both. Non-functional tricuspid regurgitation occurs when there is damage to the tricuspid leaflets, chordae, papillary muscles, or annulus, independent of right ventricular dysfunction or pulmonary hypertension. The entities that cause non-functional tricuspid regurgitation include rheumatic and myxomatous disease, acquired and genetic connective tissue disorders, endocarditis, sarcoid, pacing, RV biopsy, blunt trauma, radiation, carcinoid, ergot alkaloids, dopamine agonists, fenfluramine, cardiac tumors, atrial fibrillation, and congenital malformations. Over time, severe tricuspid regurgitation that is initially non-functional, can blend into functional tricuspid regurgitation, related to progressive right ventricular dysfunction. Symptoms and signs, including a falling right ventricular ejection fraction, cardiac cirrhosis, ascites, esophageal varices, and anasarca, may occur insidiously and late, but are associated with substantial morbidity and mortality. Attempted valve repair or replacement at late stages carries a high mortality. Crucial to following patients with severe non-functional tricuspid regurgitation is attention to echo quantification of the tricuspid regurgitation and right ventricular function, patient symptoms, and the physical examination.

Claviceps nigricans and Claviceps grohii: their alkaloids and phylogenetic placement.

PubMed

Pazoutová, Sylvie; Olsovská, Jana; Sulc, Miroslav; Chudícková, Milada; Flieger, Miroslav

2008-06-01

Claviceps purpurea, C. grohii, C. zizaniae, C. cyperi, and C. nigricans are closely related ergot fungi and form a monophyletic clade inside the genus Claviceps. Analysis of alkaloid content in C. nigricans sclerotia using UPLC detected ergocristine (1), ergosine (2), alpha-ergocryptine (3), and ergocristam (4). Alkaloids 1, 3, and 4 were found in the sclerotia of C. grohii. The content of 4 in the mixture of alkaloids from C. nigricans and C. grohii (over 8% and over 20%, respectively) was unusually high. Submerged shaken cultures of C. nigricans produced no alkaloids, whereas C. grohii culture formed small amounts (15 mg L (-1)) of extracellular clavines and 1. In the previously used HPLC method the ergocristam degradation product could have been obscured by the ergosine peak. Therefore sclerotia of a C. purpurea habitat-specific population G2 with the dominant production of 1 and 2 have been reanalyzed, but no 4 was detected. The phylogeny of the C. purpurea-related species group is discussed with regard to alkaloid-specific nonribosomal peptide synthetase duplication leading to the production of two main ergopeptines instead of a single product.

The small GTPase Rac and the p21-activated kinase Cla4 in Claviceps purpurea: interaction and impact on polarity, development and pathogenicity.

PubMed

Rolke, Yvonne; Tudzynski, Paul

2008-04-01

Claviceps purpurea, the ergot fungus, is a highly specialized pathogen of grasses; its colonization of host ovarian tissue requires an extended period of strictly polarized, oriented growth towards the vascular tissue. To understand this process, we study the role of signalling factors affecting polarity and differentiation. We showed that the small GTPase Cdc42 is involved in polarity, sporulation and in planta growth in C. purpurea. Here we present evidence that the GTPase Rac has an even stronger and, in some aspects, inverse impact on growth and development: Deltarac mutants form coralline-like colonies, show hyper-branching, loss of polarity, sporulation and ability to penetrate. Functional analyses and yeast two-hybrid studies prove that the p21-activated kinase Cla4 is a major downstream partner of Rac. Phosphorylation assays of MAP kinases and expression studies of genes encoding reactive oxygen species (ROS)-scavenging and -generating enzymes indicate a function of Rac and Cla4 in fungal ROS homoeostasis which could contribute to their drastic impact on differentiation.

Analysis of Claviceps africana and C. sorghi from India using AFLPs, EF-1alpha gene intron 4, and beta-tubulin gene intron 3.

PubMed

Tooley, Paul W; Bandyopadhyay, Ranajit; Carras, Marie M; Pazoutová, Sylvie

2006-04-01

Isolates of Claviceps causing ergot on sorghum in India were analysed by AFLP analysis, and by analysis of DNA sequences of the EF-1alpha gene intron 4 and beta-tubulin gene intron 3 region. Of 89 isolates assayed from six states in India, four were determined to be C. sorghi, and the rest C. africana. A relatively low level of genetic diversity was observed within the Indian C. africana population. No evidence of genetic exchange between C. africana and C. sorghi was observed in either AFLP or DNA sequence analysis. Phylogenetic analysis was conducted using DNA sequences from 14 different Claviceps species. A multigene phylogeny based on the EF-1alpha gene intron 4, the beta-tubulin gene intron 3 region, and rDNA showed that C. sorghi grouped most closely with C. gigantea and C. africana. Although the Claviceps species we analysed were closely related, they colonize hosts that are taxonomically very distinct suggesting that there is no direct coevolution of Claviceps with its hosts.

Neuroreceptor Activation by Vibration-Assisted Tunneling

PubMed Central

Hoehn, Ross D.; Nichols, David; Neven, Hartmut; Kais, Sabre

2015-01-01

G protein-coupled receptors (GPCRs) constitute a large family of receptor proteins that sense molecular signals on the exterior of a cell and activate signal transduction pathways within the cell. Modeling how an agonist activates such a receptor is fundamental for an understanding of a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as a model for the mechanism by which olfactory GPCRs are activated by a bound agonist. We apply this hyothesis to GPCRs within the mammalian nervous system using quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a particular IET spectral aspect both amongst each other and with the serotonin molecule: a peak whose intensity scales with the known agonist potencies. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its deuterated isotopologues; we also provide theoretical predictions for comparison to experiment. If validated our theory may provide new avenues for guided drug design and elevate methods of in silico potency/activity prediction. PMID:25909758

Epidemics of mold poisoning past and present.

PubMed

Meggs, William J

2009-01-01

Molds are ubiquitous throughout the biosphere of planet earth and cause infectious, allergic, and toxic diseases. Toxic diseases arise from exposure to mycotoxins produced by molds. Throughout history, there have been a number of toxic epidemics associated with exposure to mycotoxins. Acute epidemics of ergotism are caused by consumption of grain infested by fungi of the genus Claviceps, which produce the bioactive amine ergotamine that mimics the neurotransmitters norepinephrine, serotonin, and dopamine. Acute aflatoxin outbreaks have occurred from ingestion of corn stored in damp conditions that potentiate growth of the molds of the species Aspergillus. Contemporary construction methods that use cellulose substrates such as fiber board and indoor moisture have caused an outbreak of contaminated buildings with Stachybotrys chartarum, with the extent of health effects still a subject of debate and ongoing research. This article reviews several of the more prominent epidemics and discusses the nature of the toxins. Two diseases that were leading causes of childhood mortality in England in the 1970s and vanished with changing dietary habits, putrid malignant fever, and slow nervous fever were most likely toxic mold epidemics.

Radioimmunoassay of lysergic acid diethylamide (LSD) in serum and urine by using antisera of different specificities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ratcliffe, W.A.; Fletcher, S.M.; Moffat, A.C.

We raised high-titre antisera to two LSD-bovine serum albumin conjugates, one linked via the indole nitrogen, the other via the amide side-chain. The antisera were specific for different parts of the LSD molecule, as demonstrated by cross-reactivity studies with LSD, its metabolites, ergot alkaloids, and closely related compounds. The antisera were used to develop a double-antibody radioimmunoassay with a detection limit of about 0.4 ..mu..g of LSD per liter of unextracted urine or serum. We saw no nonspecific interference by urine, serum, or from a series of commonly used drugs. There was good correlation between immunoassay values obtained with themore » two antisera (r = 0.91). However, the antiserum linked via the indole nitrogen gave consistently higher results for samples from persons who had taken LSD, owing to greater cross-reactivity with LSD metabolites. Radioimmunoassay by use of two such antisera is a more specific screening procedure for LSD abuse than has been available previously. In addition, antisera cross-reacting with LSD metabolites allow measurement of these compounds, for which there is no satisfactory method at the concentrations found in biological fluids in man.« less

Specificity of the Antibody Receptor Site to D-Lysergamide: Model of a Physiological Receptor for Lysergic Acid Diethylamide

PubMed Central

Vunakis, Helen Van; Farrow, John T.; Gjika, Hilda B.; Levine, Lawrence

1971-01-01

Antibodies to D-lysergic acid have been produced in rabbits and guinea pigs and a radioimmunoassay for the hapten was developed. The specificity of this lysergamide-antilysergamide reaction was determined by competitive binding with unlabeled lysergic acid diethylamide (LSD), psychotomimetic drugs, neurotransmitters, and other compounds with diverse structures. LSD and several related ergot alkaloids were potent competitors, three to seven times more potent than lysergic acid itself. The N,N-dimethyl derivatives of several compounds, including tryptamine, 5-hydroxytryptamine, 4-hydroxytryptamine, 5-methoxytryptamine, tyramine, and mescaline, were only about ten times less effective than lysergic acid, even though these compounds lack some of the ring systems of lysergic acid. The pattern of inhibition by related compounds with various substituents suggests that the antibody receptor site recognizes structural features resembling the LSD molecule. In particular, the aromatic nucleus and the dimethylated ethylamine side chain in phenylethylamine and tryptamine derivatives may assume in solution a conformation resembling ring A and the methylated nitrogen in ring C of LSD. Among the tryptamine derivatives, a large percentage of the most potent competitors are also psychotomimetic compounds. PMID:5283939

The NADPH oxidase Cpnox1 is required for full pathogenicity of the ergot fungus Claviceps purpurea.

PubMed

Giesbert, Sabine; Schürg, Timo; Scheele, Sandra; Tudzynski, Paul

2008-05-01

The role of reactive oxygen species (ROS) in interactions between phytopathogenic fungi and their hosts is well established. An oxidative burst mainly caused by superoxide formation by membrane-associated NADPH oxidases is an essential element of plant defence reactions. Apart from primary effects, ROS play a major role as a second messenger in host response. Recently, NADPH oxidase (nox)-encoding genes have been identified in filamentous fungi. Functional analyses have shown that these fungal enzymes are involved in sexual differentiation, and there is growing evidence that they also affect developmental programmes involved in fungus-plant interactions. Here we show that in the biotrophic plant pathogen Claviceps purpurea deletion of the cpnox1 gene, probably encoding an NADPH oxidase, has impact on germination of conidia and pathogenicity: Deltacpnox1 mutants can penetrate the host epidermis, but they are impaired in colonization of the plant ovarian tissue. In the few cases where macroscopic signs of infection (honeydew) appear, they are extremely delayed and fully developed sclerotia have never been observed. C. purpurea Nox1 is important for the interaction with its host, probably by directly affecting pathogenic differentiation of the fungus.

Staggers in horses grazing paspalum infected with Claviceps paspali.

PubMed

Cawdell-Smith, A J; Scrivener, C J; Bryden, W L

2010-10-01

Invasion of the flowering heads of grasses by Claviceps spp. can produce sclerotia (ergots) containing several toxins. Ingestion of these toxins, through the consumption of paspalum (Paspalum dilatatum), can induce a range of clinical symptoms, including staggers. Cattle are the most commonly affected species, but although sheep and horses have been reported affected there are no published descriptions of paspalum staggers in horses. We describe two occurrences of paspalum staggers, the first in three Australian Stockhorse foals and the second in mature Standardbred horses. All three foals presented with ataxia in all limbs after consuming infected paspalum. One foal died from misadventure and the other two recovered within 1 week of removal from the infected paddock. In the second case, two of eight mares and geldings grazing in an irrigation channel developed hindquarter paresis. After removal of all horses from the area, one of the affected horses continued to deteriorate. Both horses were treated with antibiotics. The more severely affected horse was also treated with fluids and electrolytes, but had to be euthanased. The second affected horse recovered after 2 days. Paspalum pastures should inspected for Claviceps paspali infection before the introduction of horses. © 2010 The Authors. Australian Veterinary Journal © 2010 Australian Veterinary Association.

Alterations of epidermal proliferation and cytokeratin expression in skin biopsies from heavy draught horses with chronic pastern dermatitis.

PubMed

Geburek, Florian; Ohnesorge, Bernhard; Deegen, Eckehard; Doeleke, Renate; Hewicker-Trautwein, Marion

2005-12-01

We report the historical, clinical and histopathological characteristics of skin lesions in biopsies from 37 heavy draught horses with chronic pastern dermatitis. The skin lesions were divided into four macroscopic groups: scaling (group I, n=5), hyperkeratotic and hyperplastic plaque-like lesions (group II, n=14), nodular skin masses (group III, n=16) and verrucous skin lesions (group IV, n=2). The principal histological findings were hyperkeratosis and epidermal hyperplasia. There was a gradual increase in epidermal hyperplasia from groups I to IV, suggesting that the lesions represent different stages of disease. In all cases, there was perivascular dermatitis dominated by T lymphocytes with an increase in MHC class II-positive dendritic-like cells. Immunohistochemical labelling for cytokeratins CK5/6(4), CK10 and CK14 indicated a change in their expression pattern. This correlated with the degree of epidermal hyperplasia, indicating abnormal differentiation of keratinocytes. There was a statistically significant correlation between the severity of skin lesions and several other factors including increasing age, increasing cannon circumference, prominence of anatomical structures such as fetlock tufts of hairs, ergots and chestnuts, and bulges in the fetlock region.

Ergotamine-derived dopamine agonists and left ventricular function in Parkinson patients: systolic and diastolic function studied by conventional echocardiography, tissue Doppler imaging, and two-dimensional speckle tracking.

PubMed

Rasmussen, Vibeke Guldbrand; Poulsen, Steen Hvitfeldt; Dupont, Erik; Ostergaard, Karen; Safikhany, Gholamhossein; Egeblad, Henrik

2008-11-01

Ergot-derived dopamine agonists (EDDA) induce fibrotic heart valve disease. We aimed to investigate whether EDDA treatment also affects left ventricular (LV) function. Myocardial function was evaluated in 110 Parkinson patients [mean age (63.4 +/- 9.0 years)] treated for at least 6 months with either EDDA (n = 71) or non-EDDA (n = 39). LV ejection fraction did not differ between EDDA and non-EDDA patients [63 +/- 4% vs. 65 +/- 4% (ns)]. There was no difference in prevalence of diastolic dysfunction between EDDA and non-EDDA patients [7% vs. 8% (ns)]. Finally, averaged LV systolic myocardial strain and longitudinal displacement analysed by means of two-dimensional speckle tracking showed no difference between EDDA and non-EDDA patients [strain: 19 +/- 3% vs. 19 +/- 2% (ns) and longitudinal displacement: 12 +/- 2 mm vs. 12 +/- 2 mm (ns)]. Elevated p-NT-proBNP was found in 38% of EDDA patients and in 59% of non-EDDA patients (ns). In contrast to the well-established association between EDDA treatment and valvular fibrosis, EDDA did not have a detectable adverse impact on myocardial systolic and diastolic function.

Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock.

PubMed

Philippe, Guerre

2016-02-15

Different group of alkaloids are produced during the symbiotic development of fungal endophytes of the genus Epichloë in grass. The structure and toxicity of the compounds vary considerably in mammalian herbivores and in crop pests. Alkaloids of the indole-diterpene group, of which lolitrem B is the most toxic, were first characterized in endophyte-infected perennial ryegrass, and are responsible for "ryegrass staggers." Ergot alkaloids, of which ergovaline is the most abundant ergopeptide alkaloid produced, are also found in ryegrass, but generally at a lower rate than lolitrem B. Other alkaloids such as lolines and peramine are toxic for crop pests but have weak toxicological properties in mammals. The purpose of this review is to present indole-diterpene alkaloids produced in endophyte infected ryegrass from the first characterization of ryegrass staggers to the determination of the toxicokinetics of lolitrem B and of their mechanism of action in mammals, focusing on the different factors that could explain the worldwide distribution of the disease. Other indole diterpene alkaloids than lolitrem B that can be found in Epichloë infected ryegrass, and their tremorgenic properties, are presented in the last section of this review.

Metabolomics of fescue toxicosis in grazing beef steers.

PubMed

Mote, Ryan S; Hill, Nicholas S; Uppal, Karan; Tran, ViLinh T; Jones, Dean P; Filipov, Nikolay M

2017-07-01

Fescue toxicosis (FT) results from consumption of tall fescue (Lolium arundinaceum) infected with an endophyte (Epichloë coenophiala) that produces ergot alkaloids (EA), which are considered key etiological agents of FT. Decreased weight gains, hormonal imbalance, circulating cholesterol disruption, and decreased volatile fatty acid absorption suggest toxic (E+) fescue-induced metabolic perturbations. Employing untargeted high-resolution metabolomics (HRM) to analyze E+ grazing-induced plasma and urine metabolome changes, fescue-naïve Angus steers were placed on E+ or non-toxic (Max-Q) fescue pastures and plasma and urine were sampled before, 1, 2, 14, and 28 days after pasture assignment. Plasma and urine catecholamines and urinary EA concentrations were also measured. In E+ steers, urinary EA appeared early and peaked at 14 days. 13,090 urinary and 20,908 plasma HRM features were detected; the most significant effects were observed earlier (2 days) in the urine and later (≥14 days) in the plasma. Alongside EA metabolite detection, tryptophan and lipid metabolism disruption were among the main consequences of E+ consumption. The E+ grazing-associated metabolic pathways and signatures described herein may accelerate development of novel early FT detection and treatment strategies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Characterization of nicergoline polymorphs crystallized in several organic solvents.

PubMed

Malaj, Ledjan; Censi, Roberta; Capsoni, Doretta; Pellegrino, Luca; Bini, Marcella; Ferrari, Stefania; Gobetto, Roberto; Massarotti, Vincenzo; Di Martino, Piera

2011-07-01

Nicergoline (NIC), a poorly water-soluble semisynthetic ergot derivative, was crystallized from several organic solvents, obtaining two different polymorphic forms, the triclinic form I and the orthorhombic form II. NIC samples were then characterized by several techniques such as (13)C cross-polarization magic angle spinning solid-state spectroscopy, room-temperature and high-temperature X-ray powder diffraction, differential scanning calorimetry, and by analysis of weight loss, solvent content, powder density, morphology, and particle size. Solubility and intrinsic dissolution rates determined for the two polymorphic forms in water and hydrochloride solutions (HCl 0.1 N) were always higher for form II than for form I, which is actually the form used for the industrial preparation of NIC medicinal products. Preformulation studies might encourage industry for the evaluation of polymorph II, as it is more suitable for pharmaceutical applications. Results in drug delivery, as well as those obtained by the above-mentioned techniques, and the application of Burger-Ramberger's rules make it possible to conclude that there is a thermodynamic relation of monotropy between the two polymorphs. This last assumption may help formulators in predicting the relative stability of the two forms. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

Alkaloids in the human food chain--natural occurrence and possible adverse effects.

PubMed

Koleva, Irina I; van Beek, Teris A; Soffers, Ans E M F; Dusemund, Birgit; Rietjens, Ivonne M C M

2012-01-01

Alkaloid-containing plants are an intrinsic part of the regular Western diet. The present paper summarizes the occurrence of alkaloids in the food chain, their mode of action and possible adverse effects including a safety assessment. Pyrrolizidine alkaloids are a reason for concern because of their bioactivation to reactive alkylating intermediates. Several quinolizidine alkaloids, β-carboline alkaloids, ergot alkaloids and steroid alkaloids are active without bioactivation and mostly act as neurotoxins. Regulatory agencies are aware of the risks and have taken or are considering appropriate regulatory actions for most alkaloids. These vary from setting limits for the presence of a compound in feed, foods and beverages, trying to define safe upper limits, advising on a strategy aiming at restrictions in use, informing the public to be cautious or taking specific plant varieties from the market. For some alkaloids known to be present in the modern food chain, e.g., piperine, nicotine, theobromine, theophylline and tropane alkaloids risks coming from the human food chain are considered to be low if not negligible. Remarkably, for many alkaloids that are known constituents of the modern food chain and of possible concern, tolerable daily intake values have so far not been defined. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies

PubMed Central

Meng, Ian D; Dodick, David; Ossipov, Michael H; Porreca, Frank

2017-01-01

Introduction Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates. Literature review Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol. Conclusions Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined. PMID:21444643

Changing Patterns of Fungal Toxins in Crops: Challenges for Analysts.

PubMed

Miller, J David

2016-07-01

This short review discusses the need to manage climate-driven expansion of old toxins in new geographic areas (e.g., aflatoxin or fumonisin in corn in historically cooler areas, and ergot where rainfall and cropping patterns have changed). In addition, a renewed consideration of the toxins that can occur in feed sources used in cool-season dairy areas is needed (e.g., silage and distillers dry grains with solubles). A separate issue concerns genetic changes that are occurring in the species that cause Fusarium head blight/Gibberella ear rot. Small differences in climate appear to determine the distribution of the two dominant populations (native to the new world and from Asia). The chemotype that produces deoxynivalenol via the monoacetate at the 3 position results in the accumulation of somewhat more deoxynivalenol than the native population, which involves the monoacetate at the 15 position. There are also genetic changes occurring that have resulted in populations that produce different metabolites. Similarly, an increase in the area where Aspergillus flavus can thrive and the discovery of the sexual stage of this fungus have raised the potential of genetic change accelerated by climate. To address all these issues, new methods and increased availability of reference standards, as well as training and awareness, will be required.

Mycotoxins: toxicity, carcinogenicity, and the influence of various nutritional conditions*

PubMed Central

Newberne, Paul M.

1974-01-01

Toxicologic diseases of man and animals, associated with molds growing on foods, have been recognized for centuries. Only in recent years, however, have these mycotoxicoses received the attention of many laboratories and skilled scientists around the world in a broad inter-disciplinary effort. This review covers the literature on mycotoxicoses but centers on those about which most is known, particularly the diseases associated with metabolites elaborated by some strains of Aspergilli, Penicillia, Fusaria, Stachybotrys, and Claviceps. The ubiquitous nature of the aflatoxins, toxic metabolites produced by Aspergillus flavus, make them important to public health, especially since it is now known that certain areas of endemic liver disease coincide with consumption of aflatoxins and, often, malnutrition. The older disease of ergotism, the scourge of Europe for centuries, is considered in detail. Alimentary toxic aleukia, which has caused enormous suffering in Russian human and animal populations, is better understood as a result of relatively recent experimental investigations. Stachybotryotoxicosis, a disease previously considered to be of significance only to man has now been identified in domestic animals. Finally, Japanese studies have clearly revealed the hepatotoxicity of certain metabolites of Penicillium molds. Factors that influence susceptibility to mycotoxins and the hazards they present to man are also reviewed. ImagesFIGURE 2. PMID:4620330

The histidine kinase CpHK2 has impact on spore germination, oxidative stress and fungicide resistance, and virulence of the ergot fungus Claviceps purpurea.

PubMed

Nathues, Eva; Jörgens, Cordula; Lorenz, Nicole; Tudzynski, Paul

2007-09-01

SUMMARY Histidine kinases are important mediators for adaptation of bacteria and plants to environmental signals. Genome analyses of filamentous fungi have revealed the presence of a high number of potential hybrid histidine kinase (HK)-encoding genes; the role of most of these potential sensors is so far unclear, though some members of the class III histidine kinases were shown to be involved in osmostress responses. Here we present a functional analysis of cphk2, a histidine kinase-encoding gene in the biotrophic grass pathogen Claviceps purpurea. The putative product of cphk2 (CpHK2) was shown to group within family X of fungal HKs and it had high homology to the oxidative stress sensors SpMAK2/3 of Schizosaccharomyces pombe. Analysis of a cphk2 deletion mutant indicated that this histidine kinase is involved in spore germination, sensitivity to oxidative stress and fungicide resistance. In addition, virulence of the Dcphk2 mutant on rye was significantly reduced compared with the wild-type strain, even if the conidial titre was adjusted to the lower germination rate. This is the first report of a role for a class X histidine kinase in a filamentous fungus.

Transsphenoidal microsurgery in the treatment of acromegaly and gigantism.

PubMed

Arafah, B U; Brodkey, J S; Kaufman, B; Velasco, M; Manni, A; Pearson, O H

1980-03-01

Twenty-five patients with acromegaly and 3 patients with gigantism underwent transsphenoidal microsurgery in an attempt to remove the tumor and preserve normal pituitary function whenever possible. An adenoma was identified and removed in 27 of 28 patients. Evaluation 3--6 months postoperatively revealed a GH level less than 5 ng/ml in 29 patients, 5--10 ng/ml in 4 patients and 11--29 ng/ml in 4 other patients. Dynamics of GH secretion were normal in 11 patients who had normal pituitary function and are considered cured. Two patients with low or undetectable GH levels are also considered cured at the expense of being hypopituitary. Three of 7 patients with normal basal GH levels but abnormal dynamics of GH secretion relapsed within 1 yr. Eleven of the 13 patients considered cured did not have extrasellar extension, while 14 of the 15 patients not cured had extrasellar extension. Five patients who were not cured with surgery received radiation therapy. Three patients were treated with an ergot derivative, Lergotrile mesylate, after surgery and radiation therapy failed to normalize GH levels. Transsphenoidal microsurgery is an optimal form of therapy for patients with acromegaly or gigantism, especially those with no extrasellar extension. Dynamics of GH secretion are very useful in evaluating the completeness of adenoma removal.

Engaging One Health for Non-Communicable Diseases in Africa: Perspective for Mycotoxins

PubMed Central

Ladeira, Carina; Frazzoli, Chiara; Orisakwe, Orish Ebere

2017-01-01

The role of mycotoxins—e.g., aflatoxins, ochratoxins, trichothecenes, zearalenone, fumonisins, tremorgenic toxins, and ergot alkaloids—has been recognized in the etiology of a number of diseases. In many African countries, the public health impact of chronic (indoor) and/or repeated (dietary) mycotoxin exposure is largely ignored hitherto, with impact on human health, food security, and export of African agricultural food products. Notwithstanding, African scientific research reached milestones that, when linked to findings gained by the international scientific community, make the design and implementation of science-driven governance schemes feasible. Starting from Nigeria as leading African Country, this article (i) overviews available data on mycotoxins exposure in Africa; (ii) discusses new food safety issues, such as the environment–feed–food chain and toxic exposures of food producing animals in risk assessment and management; (iii) identifies milestones for mycotoxins risk management already reached in West Africa; and (iv) points out preliminary operationalization aspects for shielding communities from direct (on health) and indirect (on trade, economies, and livelihoods) effects of mycotoxins. An African science-driven engaging of scientific knowledge by development actors is expected therefore. In particular, One health/One prevention is suggested, as it proved to be a strategic and sustainable development framework. PMID:29085817

Neural control of salivary glands in ixodid ticks.

PubMed

Šimo, Ladislav; Zitňan, Dušan; Park, Yoonseong

2012-04-01

Studies of tick salivary glands (SGs) and their components have produced a number of interesting discoveries over the last four decades. However, the precise neural and physiological mechanisms controlling SG secretion remain enigmatic. Major studies of SG control have identified and characterized many pharmacological and biological compounds that activate salivary secretion, including dopamine (DA), octopamine, γ-aminobutyric acid (GABA), ergot alkaloids, pilocarpine (PC), and their pharmacological relatives. Specifically, DA has shown the most robust activities in various tick species, and its effect on downstream actions in the SGs has been extensively studied. Our recent work on a SG dopamine receptor has aided new interpretations of previous pharmacological studies and provided new concepts for SG control mechanisms. Furthermore, our recent studies have suggested that multiple neuropeptides are involved in SG control. Myoinhibitory peptide (MIP) and SIFamide have been identified in the neural projections reaching the basal cells of acini types II and III. Pigment-dispersing factor (PDF)-immunoreactive neural projections reach type II acini, and RFamide- and tachykinin-immunoreactive projections reach the SG ducts, but the chemical nature of the latter three immunoreactive substances are unidentified yet. Here, we briefly review previous pharmacological studies and provide a revised summary of SG control mechanisms in ticks. Copyright © 2011 Elsevier Ltd. All rights reserved.

Acute migraine medication adherence, migraine disability and patient satisfaction: A naturalistic daily diary study.

PubMed

Seng, Elizabeth K; Robbins, Matthew S; Nicholson, Robert A

2017-09-01

Objective To examine the influence of acute migraine medication adherence on migraine disability and acute medication satisfaction. Methods Adults with migraine completed three months of daily electronic diaries assessing headache symptoms, acute medication taken, acute medication satisfaction, and daily migraine disability. Repeated measures mixed-effects models examined the effect of initial medication type [migraine-specific medication (MSM) vs. over-the-counter analgesic (OTC) vs. an opiate/barbiturate], the severity of pain at dosing, and their interaction with daily migraine disability and satisfaction with acute medication. Results Participants (N = 337; 92.5% female; 91.1% Caucasian, non-Hispanic; 84.0% with episodic migraine) recorded 29,722 diary days. Participants took acute medication on 96.5% of 8090 migraine days. MSM was most frequently taken first (58%), followed by OTC (29.9%) and an opiate/barbiturate (12.1%). Acute medication was most frequently taken when pain was mild (41.2%), followed by moderate (37.7%) and severe pain (11.4%). Initially dosing with MSM while pain was mild was associated with the lowest daily disability [medication × pain at dosing F (4, 6336.12) = 58.73, p < .001] and highest acute medication satisfaction [medication × pain at dosing F (4, 3867.36) = 24.00, p < .001]. Conclusion Using an MSM (triptan or ergot) first was associated with the lowest migraine disability and highest acute medication satisfaction.

New appendix criteria open for a broader concept of chronic migraine.

PubMed

Olesen, J; Bousser, M-G; Diener, H-C; Dodick, D; First, M; Goadsby, P J; Göbel, H; Lainez, M J A; Lance, J W; Lipton, R B; Nappi, G; Sakai, F; Schoenen, J; Silberstein, S D; Steiner, T J

2006-06-01

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.

Links between Genetic Groups, Indole Alkaloid Profiles and Ecology within the Grass-Parasitic Claviceps purpurea Species Complex.

PubMed

Negård, Mariell; Uhlig, Silvio; Kauserud, Håvard; Andersen, Tom; Høiland, Klaus; Vrålstad, Trude

2015-04-28

The grass parasitic fungus Claviceps purpurea sensu lato produces sclerotia with toxic indole alkaloids. It constitutes several genetic groups with divergent habitat preferences that recently were delimited into separate proposed species. We aimed to 1) analyze genetic variation of C. purpurea sensu lato in Norway, 2) characterize the associated indole alkaloid profiles, and 3) explore relationships between genetics, alkaloid chemistry and ecology. Approximately 600 sclerotia from 14 different grass species were subjected to various analyses including DNA sequencing and HPLC-MS. Molecular results, supported by chemical and ecological data, revealed one new genetic group (G4) in addition to two of the three known; G1 (C. purpurea sensu stricto) and G2 (C. humidiphila). G3 (C. spartinae) was not found. G4, which was apparently con-specific with the recently described C. arundinis sp. nov, was predominantly found in very wet habitats on Molinia caerulea and infrequently in saline habitats on Leymus arenarius. Its indole-diterpene profile resembled G2, while its ergot alkaloid profile differed from G2 in high amounts of ergosedmam. In contrast to G1, indole-diterpenes were consistently present in G2 and G4. Our study supports and complements the newly proposed species delimitation of the C. purpurea complex, but challenges some species characteristics including host spectrum, habitat preferences and sclerotial floating ability.

Links between Genetic Groups, Indole Alkaloid Profiles and Ecology within the Grass-Parasitic Claviceps purpurea Species Complex

PubMed Central

Negård, Mariell; Uhlig, Silvio; Kauserud, Håvard; Andersen, Tom; Høiland, Klaus; Vrålstad, Trude

2015-01-01

The grass parasitic fungus Claviceps purpurea sensu lato produces sclerotia with toxic indole alkaloids. It constitutes several genetic groups with divergent habitat preferences that recently were delimited into separate proposed species. We aimed to 1) analyze genetic variation of C. purpurea sensu lato in Norway, 2) characterize the associated indole alkaloid profiles, and 3) explore relationships between genetics, alkaloid chemistry and ecology. Approximately 600 sclerotia from 14 different grass species were subjected to various analyses including DNA sequencing and HPLC-MS. Molecular results, supported by chemical and ecological data, revealed one new genetic group (G4) in addition to two of the three known; G1 (C. purpurea sensu stricto) and G2 (C. humidiphila). G3 (C. spartinae) was not found. G4, which was apparently con-specific with the recently described C. arundinis sp. nov, was predominantly found in very wet habitats on Molinia caerulea and infrequently in saline habitats on Leymus arenarius. Its indole-diterpene profile resembled G2, while its ergot alkaloid profile differed from G2 in high amounts of ergosedmam. In contrast to G1, indole-diterpenes were consistently present in G2 and G4. Our study supports and complements the newly proposed species delimitation of the C. purpurea complex, but challenges some species characteristics including host spectrum, habitat preferences and sclerotial floating ability. PMID:25928134

Drugs in breast milk.

PubMed

Hervada, A R; Feit, E; Sagraves, R

1978-09-01

The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

Experimentally determined soil organic matter-water sorption coefficients for different classes of natural toxins and comparison with estimated numbers.

PubMed

Schenzel, Judith; Goss, Kai-Uwe; Schwarzenbach, René P; Bucheli, Thomas D; Droge, Steven T J

2012-06-05

Although natural toxins, such as mycotoxins or phytoestrogens are widely studied and were recently identified as micropollutants in the environment, many of their environmentally relevant physicochemical properties have not yet been determined. Here, the sorption affinity to Pahokee peat, a model sorbent for soil organic matter, was investigated for 29 mycotoxins and two phytoestrogens. Sorption coefficients (K(oc)) were determined with a dynamic HPLC-based column method using a fully aqueous mobile phase with 5 mM CaCl(2) at pH 4.5. Sorption coefficients varied from less than 10(0.7) L/kg(oc) (e.g., all type B trichothecenes) to 10(4.0) L/kg(oc) (positively charged ergot alkaloids). For the neutral compounds the experimental sorption data set was compared with predicted sorption coefficients using various models, based on molecular fragment approaches (EPISuite's KOCWIN or SPARC), poly parameter linear free energy relationship (pp-LFER) in combination with predicted descriptors, and quantum-chemical based software (COSMOtherm)). None of the available models was able to adequately predict absolute K(oc) numbers and relative differences in sorption affinity for the whole set of neutral toxins, largely because mycotoxins exhibit highly complex structures. Hence, at present, for such compounds fast and consistent experimental techniques for determining sorption coefficients, as the one used in this study, are required.

Pregnancy-related acute myocardial infarction in Japan: a review of epidemiology, etiology and treatment from case reports.

PubMed

Satoh, Hiroshi; Sano, Makoto; Suwa, Kenichiro; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Hayashi, Hideharu

2013-01-01

Pregnancy-related acute myocardial infarction (AMI) is uncommon, but can result in maternal and/or fetal death. This study retrospectively reviews pregnancy-related AMI reported from medical institutions in Japan. We electronically or manually searched the literature for reports of pregnancy-related AMI between 1981 and 2011. In total, 62 patients were described and the numbers increased in accordance with the rising average age of the mothers. AMI occurred frequently in women aged 30-34 years (mean age, 33), in the third trimester and postpartum (n=11 and n=28, respectively). The prevalence of conventional risk factors was relatively low (n=21). On the other hand, 29 patients had obstetric and/or non-obstetric complications, and 24 received medication. Only 8 AMI were caused by atherosclerosis, while coronary dissection, thrombus and spasm were the cause in 14, 9 and 12 cases, respectively. All patients with atherosclerosis had conventional risk factors, and some patients with spasm had a history of smoking. Medication with ergot derivatives was associated mostly with spasm, whereas ritodrine was potentially related to dissection. The prevalence of pregnancy-related AMI in Japan seems lower than in Western countries, and the etiology differs considerably. However, as the trend of later childbearing continues, more pregnant women have more risk factors, complications, and require medication. Cardiologists and obstetricians must consider the increased risk of AMI.

Nicergoline in mild to moderate dementia. A multicenter, double-blind, placebo-controlled study.

PubMed

Battaglia, A; Bruni, G; Ardia, A; Sacchetti, G

1989-04-01

In view of some controversies still existing about the real efficacy of ergot derivatives in the management of dementia, a double-blind, randomized, parallel group trial extending up to 6 months was carried out to compare the effects of nicergoline, 60 mg daily, and placebo in 315 patients suffering from mild to moderate dementia. Clinical evaluation was performed by the SCAG scale. The trial, which included a 1-month placebo run-in period, showed that both placebo and nicergoline were associated with some degree of improvement. The effect of nicergoline, however, was significantly greater and more sustained, steadily increasing with time. In particular, the difference between nicergoline and placebo in mean total SCAG score was 5.5 at 3 months (95% confidence interval: 3.6-7.4) and increased to 9.8 at 6 months (95% confidence interval: 7.8-11.8). A comparison of nicergoline versus placebo in the frequencies of changes in each item of the SCAG showed also a significant difference at 6 months, the percent of patients displaying an improvement by at least 2 points ranging from 13.5 (bothersome) to 30.2 (disorientation) in nicergoline group, against 4.1 (self-care) to 14.3 (fatigue) in placebo group. The safety of nicergoline, as judged by hemodynamic changes and drug-related adverse reactions, was quite satisfactory.

Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia.

PubMed

Asai, S; Zhao, H; Yamashita, A; Jike, T; Kunimatsu, T; Nagata, T; Kohno, T; Ishikawa, K

1999-11-03

Whereas a 2-3 degrees C decrease in intraischemic brain temperature can be neuroprotective, mild brain hyperthermia significantly worsens outcome. Our previous study suggested that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu](e)) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of Glu. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu](e) in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells. In the present study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid derivative, showed minimal inhibition of the [Glu](e) elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthermia. Moreover, the nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e., activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia.

High Density Single Nucleotide Polymorphism (SNP) Mapping and Quantitative Trait Loci (QTL) Analysis in a Biparental Spring Triticale Population Localized Major and Minor Effect Fusarium Head Blight Resistance and Associated Traits QTL

PubMed Central

Dhariwal, Raman; Fedak, George; Dion, Yves; Pozniak, Curtis; Laroche, André; Eudes, François; Randhawa, Harpinder Singh

2018-01-01

Triticale (xTriticosecale Wittmack) is an important feed crop which suffers severe yield, grade and end-use quality losses due to Fusarium head blight (FHB). Development of resistant triticale cultivars is hindered by lack of effective genetic resistance sources. To dissect FHB resistance, a doubled haploid spring triticale population produced from the cross TMP16315/AC Ultima using a microspore culture method, was phenotyped for FHB incidence, severity, visual rating index (VRI), deoxynivalenol (DON) and some associated traits (ergot, grain protein content, test weight, yield, plant height and lodging) followed by single nucleotide polymorphism (SNP) genotyping. A high-density map consisting of 5274 SNPs, mapped on all 21 chromosomes with a map density of 0.48 cM/SNP, was constructed. Together, 17 major quantitative trait loci were identified for FHB on chromosomes 1A, 2B, 3A, 4A, 4R, 5A, 5R and 6B; two of incidence loci (on 2B and 5R) also co-located with loci for severity and VRI, and two other loci of VRI (on 1A and 4R) with DON accumulation. Major and minor loci were also identified for all other traits in addition to many epistasis loci. This study provides new insight into the genetic basis of FHB resistance and their association with other traits in triticale. PMID:29304028

Selective labeling of serotonin receptors by d-[3H]lysergic acid diethylamide in calf caudate.

PubMed Central

Whitaker, P M; Seeman, P

1978-01-01

Since it was known that d-lysergic acid diethylamide (LSD) affected catecholaminergic as well as serotoninergic neurons, the objective in this study was to enhance the selectivity of [3H]LSD binding to serotonin receptors in vitro by using crude homogenates of calf caudate. In the presence of a combination of 50 nM each of phentolamine (added to preclude the binding of [3H]LSD to alpha-adrenoceptors), apomorphine, and spiperone (added to preclude the binding of [3H]LSD to dopamine receptors), it was found by Scatchard analysis that the total number of [3H]LSD sites went down to 300 fmol/mg, compared to 1100 fmol/mg in the absence of the catecholamine-blocking drugs. The IC50 values (concentrations to inhibit binding by 50%) for various drugs were tested on the binding of [3H]LSD in the presence of 50 nM each of apomorphine (A), phentolamine (P) and spiperone (S). With this combination, the IC50 for serotonin was 35 nM (compared to 1000 nM without it), indicating that [3H]LSD had become considerably more selectively displaceable by serotonin under these conditions whereas the effects of norepinephrine and dopamine on [3H]LSD binding were eliminated. Various ergots had approximately equal IC50 values against [3H]serotonin and [3H]LSD but tryptamines were much more selective against [3H]serotonin; the data may indicate the existence of the two types of serotonin receptors. PMID:32537

Neuropsychiatric phenomena in the medieval text Cantigas de Santa Maria.

PubMed

Gondim, Francisco De Assis Aquino; Griesbach, Sarah H; Thomas, Florian P

2015-05-12

To discuss the neuropsychiatric phenomena described in Cantigas de Santa Maria (Canticles of St. Mary [CSM]). CSM is a collection of 427 canticles composed in Galician-Portuguese between 1252 and 1284 at the Court of King Alfonso X the Wise of Spain (1221-1284). The canticles (of which 9 are repeated) include devotional and liturgical poems and 353 narrative stories consisting mainly of depictions of Marian miracles. Most are set to music and many are illustrated. We reviewed the canticles for description of miracles and other neuropsychiatric phenomena. Two neurologists reached a consensus about the descriptions. Of the 353 miracles, 279 medically relevant facts (from 187 canticles) and 25 instances of resurrection were reported. Possible neuropsychiatric conditions were described in 98 canticles. Physicians were mentioned in 16 narratives. The most common neurologic conditions detailed were blindness (n = 17), dystonia, weakness, and deformities (n = 20). Other common conditions included psychosis (n = 15), speech disorder/deaf-mutism (n = 12), infections (n = 15), sexual dysfunction/infertility/obstetrical-gynecologic issues (n = 18), head trauma (n = 5), ergotism/St. Anthony's fire (n = 7), and others. There were 9 instances of prodromic mystical experiences/hallucinations heralding death. While limited by retrospection and interpretation of neuropsychiatric phenomena in the medieval context, these short accounts are among the first descriptions of neuropsychiatric conditions in early Portuguese/Galician. They reflect how medieval societies used rational and irrational approaches to understand occurrences in their lives. © 2015 American Academy of Neurology.

Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs.

PubMed

Ramírez Rosas, Martha B; Labruijere, Sieneke; Villalón, Carlos M; Maassen Vandenbrink, Antoinette

2013-08-01

The introduction of the triptans (5-hydroxytryptamine (5-HT)1B/1D receptor agonists) was a great improvement in the acute treatment of migraine. However, shortcomings of the triptans have prompted research on novel serotonergic targets for the treatment of migraine. In this review the different types of antimigraine drugs acting at 5-HT receptors, their discovery and development are discussed. The first specific antimigraine drugs were the ergot alkaloids, consisting of ergotamine, dihydroergotamine and methysergide, which are agonists at 5-HT receptors, but can also bind α-adrenoceptors and dopamine receptors. In the 1990s, the triptans became available on the market. They are 5-HT1B/1D receptor agonists, showing fewer side effects due to their receptor specificity. In the last years, compounds that bind specifically to 5-HT1D, 5-HT1F and 5-HT7 receptors have been explored for their antimigraine potential. Furthermore, the serotonergic system seems to act in tight connection with the glutamatergic as well as the CGRP-ergic systems, which may open novel therapeutic avenues. Although the triptans are very effective in treating migraine attacks, their shortcomings have stimulated the search for novel drugs. Currently, the focus is on 5-HT1F receptor agonists, which seem devoid of vascular side effects. Moreover, novel compounds that affect multiple transmitter and/or neuropeptide systems that are involved in migraine could be of therapeutic relevance.

[Simulation training in the management of obstetric emergencies. A review of the literature].

PubMed

Bogne, V; Kirkpatrick, C; Englert, Y

2014-01-01

To assess the value of simulation based training in the management of obstetric emergencies. A search by keywords: obstetrics, gynecology, simulation, drills, emergency training restricted to randomized trials led to a selection of eight articles. Shoulder dystocia simulation unmasked deficiencies in performing Mc Robert maneuver in nearly 20% of doctors in training as well as ineffective and potentially harmful maneuver such as pressure on the uterine fundus. Delivery of the impacted shoulder improved from 42.9% to 83.3% after simulation training leading to a shorter head to body delivery interval. In postpartum haemorrhage simulation, lack of knowledge on prostaglandins and alkaloids of ergot, delay to transfer the patient to the operating room (82% of cases) and a poor communication between different professionals were identified. Post simulation improvement was seen in knowledge, technical skills, team spirit and structured communication. In severe preeclampsia simulation, mistakes such as injection of undiluted magnesium sulphate, caesarean section on an unstable patient were identified and reduced by 75%. Management of magnesium sulphate toxicity was also improved after simulation training. This review confirms the potential of simulation in training health professionals on management of obstetrics emergencies. Although the integration of this training modality into the curriculum of health care professionals in obstetrics and gynaecology seems beneficial, questions on the cost, the minimum standard of facilities, type of mannequins, human resources and frequency of drills required to achieve the learning objectives remain unanswered.

The Epipolythiodiketopiperazine Gene Cluster in Claviceps purpurea: Dysfunctional Cytochrome P450 Enzyme Prevents Formation of the Previously Unknown Clapurines.

PubMed

Dopstadt, Julian; Neubauer, Lisa; Tudzynski, Paul; Humpf, Hans-Ulrich

2016-01-01

Claviceps purpurea is an important food contaminant and well known for the production of the toxic ergot alkaloids. Apart from that, little is known about its secondary metabolism and not all toxic substances going along with the food contamination with Claviceps are known yet. We explored the metabolite profile of a gene cluster in C. purpurea with a high homology to gene clusters, which are responsible for the formation of epipolythiodiketopiperazine (ETP) toxins in other fungi. By overexpressing the transcription factor, we were able to activate the cluster in the standard C. purpurea strain 20.1. Although all necessary genes for the formation of the characteristic disulfide bridge were expressed in the overexpression mutants, the fungus did not produce any ETPs. Isolation of pathway intermediates showed that the common biosynthetic pathway stops after the first steps. Our results demonstrate that hydroxylation of the diketopiperazine backbone is the critical step during the ETP biosynthesis. Due to a dysfunctional enzyme, the fungus is not able to produce toxic ETPs. Instead, the pathway end-products are new unusual metabolites with a unique nitrogen-sulfur bond. By heterologous expression of the Leptosphaeria maculans cytochrome P450 encoding gene sirC, we were able to identify the end-products of the ETP cluster in C. purpurea. The thioclapurines are so far unknown ETPs, which might contribute to the toxicity of other C. purpurea strains with a potentially intact ETP cluster.

The Epipolythiodiketopiperazine Gene Cluster in Claviceps purpurea: Dysfunctional Cytochrome P450 Enzyme Prevents Formation of the Previously Unknown Clapurines

PubMed Central

Tudzynski, Paul; Humpf, Hans-Ulrich

2016-01-01

Claviceps purpurea is an important food contaminant and well known for the production of the toxic ergot alkaloids. Apart from that, little is known about its secondary metabolism and not all toxic substances going along with the food contamination with Claviceps are known yet. We explored the metabolite profile of a gene cluster in C. purpurea with a high homology to gene clusters, which are responsible for the formation of epipolythiodiketopiperazine (ETP) toxins in other fungi. By overexpressing the transcription factor, we were able to activate the cluster in the standard C. purpurea strain 20.1. Although all necessary genes for the formation of the characteristic disulfide bridge were expressed in the overexpression mutants, the fungus did not produce any ETPs. Isolation of pathway intermediates showed that the common biosynthetic pathway stops after the first steps. Our results demonstrate that hydroxylation of the diketopiperazine backbone is the critical step during the ETP biosynthesis. Due to a dysfunctional enzyme, the fungus is not able to produce toxic ETPs. Instead, the pathway end-products are new unusual metabolites with a unique nitrogen-sulfur bond. By heterologous expression of the Leptosphaeria maculans cytochrome P450 encoding gene sirC, we were able to identify the end-products of the ETP cluster in C. purpurea. The thioclapurines are so far unknown ETPs, which might contribute to the toxicity of other C. purpurea strains with a potentially intact ETP cluster. PMID:27390873

Molecular characterization of the NADPH oxidase complex in the ergot fungus Claviceps purpurea: CpNox2 and CpPls1 are important for a balanced host-pathogen interaction.

PubMed

Schürmann, Janine; Buttermann, Dagmar; Herrmann, Andrea; Giesbert, Sabine; Tudzynski, Paul

2013-10-01

Reactive oxygen species producing NADPH oxidase (Nox) complexes are involved in defense reactions in animals and plants while they trigger infection-related processes in pathogenic fungi. Knowledge about the composition and localization of these complexes in fungi is limited; potential components identified thus far include two to three catalytical subunits, a regulatory subunit (NoxR), the GTPase Rac, the scaffold protein Bem1, and a tetraspanin-like membrane protein (Pls1). We showed that, in the biotrophic grass-pathogen Claviceps purpurea, the catalytical subunit CpNox1 is important for infection. Here, we present identification of major Nox complex partners and a functional analysis of CpNox2 and the tetraspanin CpPls1. We show that, as in other fungi, Nox complexes are important for formation of sclerotia; CpRac is, indeed, a complex partner because it interacts with CpNoxR, and CpNox1/2 and CpPls1 are associated with the endoplasmatic reticulum. However, unlike in all other fungi, Δcppls1 is more similar to Δcpnox1 than to Δcpnox2, and CpNox2 is not essential for infection. In contrast, Δcpnox2 shows even more pronounced disease symptoms, indicating that Cpnox2 controls the infection process and moderates damage to the host. These data confirm that fungal Nox complexes have acquired specific functions dependent of the lifestyle of the pathogen.

An oleate hydroxylase from the fungus Claviceps purpurea: cloning, functional analysis, and expression in Arabidopsis.

PubMed

Meesapyodsuk, Dauenpen; Qiu, Xiao

2008-07-01

Claviceps purpurea, a fungal pathogen responsible for ergot diseases in many agriculturally important cereal crops, produces high levels of ricinoleic acid (12-hydroxyoctadec-cis-9-enoic acid) in its sclerotia. It has been believed for many years that the biosynthesis of this fatty acid in C. purpurea involves a hydration process with linoleic acid as the substrate. Using degenerate polymerase chain reaction, we cloned a gene from the sclerotia encoding an enzyme (CpFAH) that has high sequence similarity to the C. purpurea oleate desaturase, but only low similarity to plant oleate hydroxylases. Functional analysis of CpFAH in yeast (Saccharomyces cerevisiae) indicated it acted predominantly as a hydroxylase, introducing hydroxyl groups at the 12-position of oleic acid and palmitoleic acid. As well, it showed Delta(12) desaturase activities on 16C and 18C monounsaturated fatty acids and, to a much lesser extent, omega(3) desaturase activities on ricinoleic acid. Heterologous expression of CpFAH under the guidance of a seed-specific promoter in Arabidopsis (Arabidopsis thaliana) wild-type and mutant (fad2/fae1) plants resulted in the accumulation of relatively higher levels of hydroxyl fatty acids in seeds. These data indicate that the biosynthesis of ricinoleic acid in C. purpurea is catalyzed by the fungal desaturase-like hydroxylase, and CpFAH, the first Delta(12) oleate hydroxylase of nonplant origin, is a good candidate for the transgenic production of hydroxyl fatty acids in oilseed crops.

Dihydroergocryptine: a pseudo-irreversible alpha-adrenergic antagonist in the guinea pig vas deferens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilberding, C.A.; Marks, B.H.

1981-03-01

The ergot alkaloid, dihydroergocryptine, exhibits some of the characteristics of a competitive alpha-adrenergic antagonist. Dihydroergocryptine physiological antagonism is surmountable by high concentrations of alpha-adrenergic agonists and (/sup 3/H)-dihydroergocryptine readily binds and dissociates from crude membranes with the characteristics expected of an alpha-adrenoreceptor ligand. However, during physiological studies, dihydroergocryptine antagonism is not readily reversible by washing. To explain this apparently paradoxical behavior of dihydroergocryptine, the characteristic of (/sup 3/H)-dihydroergocryptine accumulation and efflux in the guinea pig vas deferens were studied. Vas deferens segments accumulated 0.99 pmol (/sup 3/H)-dihydroergocryptine/mg protein. Most of the radioligand was extractable by acid-ethanol. About 5-6% of themore » radioligand remained bound to extracted tissue residues and appeared to be associated with crude membrane fractions prepared from vas deferens segments. Kinetic analysis of (/sup 3/H)-dihydroergocryptine efflux from vas deferens segments indicated the presence of three compartments of radioligand in this tissue. A large compartment of (/sup 3/H)-dihydroergocryptine emptied slowly and may represent radioligand accumulated into the intracellular space. (/sup 3/H)-Dihydroergocryptine also was released from a compartment which exhibited the size and kinetics characteristic of alpha-adrenoreceptor sites on guinea pig vas deferens crude membranes. A small compartment of (/sup 3/H)-dihydroergocryptine was nonexchangeable and nonextractable by acid-ethanol; this nonextractable radioligand may be bound covalently to membrane sites and/or other tissue components.« less

Physiological Effects of Ergot Alkaloid and Indole-Diterpene Consumption on Sheep under Hot and Thermoneutral Ambient Temperature Conditions.

PubMed

Henry, Michelle L E; Kemp, Stuart; Dunshea, Frank R; Leury, Brian J

2016-06-02

A controlled feeding study was undertaken to determine the physiological and production effects of consuming perennial ryegrass alkaloids (fed via seed) under extreme heat in sheep. Twenty-four Merino ewe weaners (6 months; initial BW 30.8 ± 1.0 kg) were selected and the treatment period lasted 21 days following a 14 day acclimatisation period. Two levels of two factors were used. The first factor was alkaloid, fed at a nil (NilAlk) or moderate level (Alk; 80 μg/kg LW ergovaline and 20.5 μg/kg·LW lolitrem B). The second factor was ambient temperature applied at two levels; thermoneutral (TN; constant 21-22 °C) or heat (Heat; 9:00 AM-5:00 PM at 38 °C; 5:00 PM-9:00 AM at 21-22 °C), resulting in four treatments, NilAlk TN, NilAlk Heat, Alk TN and Alk Heat. Alkaloid consumption reduced dry matter intake ( p = 0.008), and tended to reduce liveweight ( p = 0.07). Rectal temperature and respiration rate were increased by both alkaloid and heat ( p < 0.05 for all). Respiration rate increased to severe levels when alkaloid and heat were combined, indicating the short term effects which may be occurring in perennial ryegrass toxicosis (PRGT) areas during severe weather conditions, a novel finding. When alkaloid ingestion and heat were administered separately, similar physiological responses occurred, indicating alkaloid ingestion causes a similar heat stress response to 38 °C heat.

Indoor mold, toxigenic fungi, and Stachybotrys chartarum: infectious disease perspective.

PubMed

Kuhn, D M; Ghannoum, M A

2003-01-01

Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. This has caused concern regarding health effects of moldy indoor environments and has resulted in many studies of moisture- and mold-damaged buildings. Recently, there have been reports of severe illness as a result of indoor mold exposure, particularly due to Stachybotrys chartarum. While many authors describe a direct relationship between fungal contamination and illness, close examination of the literature reveals a confusing picture. Here, we review the evidence regarding indoor mold exposure and mycotoxicosis, with an emphasis on S. chartarum. We also examine possible end-organ effects, including pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage reports in detail, since they provided important impetus for concerns about Stachybotrys. Some valid concerns exist regarding the relationship between indoor mold exposure and human disease. Review of the literature reveals certain fungus-disease associations in humans, including ergotism (Claviceps species), alimentary toxic aleukia (Fusarium), and liver disease (Aspergillys). While many papers suggest a similar relationship between Stachybotrys and human disease, the studies nearly uniformly suffer from significant methodological flaws, making their findings inconclusive. As a result, we have not found well-substantiated supportive evidence of serious illness due to Stachybotrys exposure in the contemporary environment. To address issues of indoor mold-related illness, there is an urgent need for studies using objective markers of illness, relevant animal models, proper epidemiologic techniques, and examination of confounding factors.

Indoor Mold, Toxigenic Fungi, and Stachybotrys chartarum: Infectious Disease Perspective

PubMed Central

Kuhn, D. M.; Ghannoum, M. A.

2003-01-01

Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. This has caused concern regarding health effects of moldy indoor environments and has resulted in many studies of moisture- and mold-damaged buildings. Recently, there have been reports of severe illness as a result of indoor mold exposure, particularly due to Stachybotrys chartarum. While many authors describe a direct relationship between fungal contamination and illness, close examination of the literature reveals a confusing picture. Here, we review the evidence regarding indoor mold exposure and mycotoxicosis, with an emphasis on S. chartarum. We also examine possible end-organ effects, including pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage reports in detail, since they provided important impetus for concerns about Stachybotrys. Some valid concerns exist regarding the relationship between indoor mold exposure and human disease. Review of the literature reveals certain fungus-disease associations in humans, including ergotism (Claviceps species), alimentary toxic aleukia (Fusarium), and liver disease (Aspergillys). While many papers suggest a similar relationship between Stachybotrys and human disease, the studies nearly uniformly suffer from significant methodological flaws, making their findings inconclusive. As a result, we have not found well-substantiated supportive evidence of serious illness due to Stachybotrys exposure in the contemporary environment. To address issues of indoor mold-related illness, there is an urgent need for studies using objective markers of illness, relevant animal models, proper epidemiologic techniques, and examination of confounding factors. PMID:12525430

Rotigotine, a dopamine receptor agonist, increased BDNF protein levels in the rat cortex and hippocampus.

PubMed

Adachi, Naoki; Yoshimura, Aya; Chiba, Shuichi; Ogawa, Shintaro; Kunugi, Hiroshi

2018-01-01

Brain-derived neurotrophic factor (BDNF) critically controls the fate and function of the neuronal network and has received much attention as a target of many brain diseases. Dopaminergic system dysfunction has also been implicated in a variety of neuropsychiatric diseases. Rotigotine, a non-ergot dopamine receptor agonist, is used in the treatment of Parkinson's disease and restless legs syndrome. To investigate the effects of rotigotine on neuronal functions both in vivo and in vitro, rats and primary cortical neurons were administered rotigotine, and the mRNA and protein expression levels of BDNF, its receptor TrkB and downstream signaling molecules, and synaptic proteins were determined. We found that BDNF protein was increased in the cortex and hippocampus of rats after 7days of rotigotine treatment. In contrast, BDNF mRNAs were reduced 6h after rotigotine treatment in cultured neurons presumably through the transient suppression of neuronal activity. We identified differential expression of D1, D2, and D3 receptors in the rat brain and cultured neurons. The observed increase in the expression of BDNF protein in the cortex and hippocampus after subchronic administration of rotigotine suggests that it may exert its medical effect in part through improving BDNF function in the brain. In addition, our results highlight the complex relationships between rotigotine and BDNF expression, which depend on the brain region, time course, and dose of the drug. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Transdermal rotigotine in advanced Parkinson's disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Nomoto, Masahiro; Mizuno, Yoshikuni; Kondo, Tomoyoshi; Hasegawa, Kazuko; Murata, Miho; Takeuchi, Masahiro; Ikeda, Junji; Tomida, Takayuki; Hattori, Nobutaka

2014-10-01

Rotigotine, a non-ergot dopamine receptor agonist, offers potential for continuous dopaminergic stimulation that could avoid the fluctuations observed with traditional treatments. We conducted a randomized, double-blind, placebo-controlled trial in Japanese patients with advanced Parkinson's disease (PD) to investigate the efficacy and safety of rotigotine. Inclusion criteria included the presence of motor complications, such as wearing off, on-off, delayed-on/no-on, any circumstances that could interfere with levodopa dose escalation because of side effects, or declining levodopa efficacy. The enrolled patients received once-daily applications of rotigotine transdermal patches or matched placebo patches. A total of 174 patients were randomly assigned to rotigotine (87 patients) or placebo (87 patients). The full analysis set included 172 patients (86 for the rotigotine group and 86 for the placebo group). The maximum maintenance dose of rotigotine was set at 16 mg/24 h. The changes in unified PD rating scale Part III scores from baseline to the end of the trial were -10.1 ± 9.0 (mean ± standard deviation) in the rotigotine group and -4.4 ± 7.4 in the placebo group (p < 0.001). There was a significantly greater reduction in the off-time (p = 0.014) in the rotigotine group. Rotigotine was well tolerated, with serious adverse events being reported in only three patients in each group. Rotigotine at doses of up to 16 mg/24 h is efficacious and safe in Japanese patients with advanced PD.

Endophytic Fungi in Indigenous Australasian Grasses Associated with Toxicity to Livestock

PubMed Central

Miles, Christopher O.; di Menna, Margaret E.; Jacobs, Surrey W. L.; Garthwaite, Ian; Lane, Geoffrey A.; Prestidge, Ron A.; Marshall, Sergio L.; Wilkinson, Heather H.; Schardl, Christopher L.; Ball, Olivier J.-P.; Latch, Garrick C. M.

1998-01-01

Grazing of Echinopogon spp. by livestock in Australia has caused symptoms similar to those of perennial ryegrass staggers. We observed an endophytic fungus in the intercellular spaces of the leaves and seeds of New Zealand and Australian specimens of Echinopogon ovatus. Culture of surface-sterilized seeds from New Zealand specimens yielded a slow-growing fungus. An examination in which immunoblotting and an enzyme-linked immunosorbent assay (ELISA) were used indicated that E. ovatus plants from Australia and New Zealand were infected with fungi serologically related to Neotyphodium lolii (the endophyte of perennial ryegrass) and other Epichloe and Neotyphodium spp. endophytic in pooid grasses. No lolitrems (the indole–diterpenoids implicated as the causative agents of perennial ryegrass staggers), peramine analogs, or ergot alkaloids were detected in the infected specimens by high-performance liquid chromatography or ELISA. However, in endophyte-infected E. ovatus plants from New Zealand, analogs of the indole–diterpenoid paxilline (thought to be a biosynthetic precursor of the lolitrems and related tremorgens) were detected by ELISA, and N-formylloline was detected by gas chromatography. Endophyte-free specimens of New Zealand E. ovatus did not contain detectable paxilline analogs or lolines and were more palatable than infected specimens to adults of the pasture pest Listronotus bonariensis (Argentine stem weevil). Hyphae similar to those of the E. ovatus endophyte were also found in herbarium specimens of Echinopogon nutans var. major, Echinopogon intermedius, Echinopogon caespitosus, and Echinopogon cheeli. This appears to be the first time that an endophytic Neotyphodium species has been identified in grasses endemic to New Zealand or Australia. PMID:9464398

Faces of a changing climate: semi-quantitative multi-mycotoxin analysis of grain grown in exceptional climatic conditions in Norway.

PubMed

Uhlig, Silvio; Eriksen, Gunnar Sundstøl; Hofgaard, Ingerd Skow; Krska, Rudolf; Beltrán, Eduardo; Sulyok, Michael

2013-09-27

Recent climatological research predicts a significantly wetter climate in Southern Norway as a result of global warming. Thus, the country has already experienced unusually wet summer seasons in the last three years (2010-2012). The aim of this pilot study was to apply an existing multi-analyte LC-MS/MS method for the semi-quantitative determination of 320 fungal and bacterial metabolites in Norwegian cereal grain samples from the 2011 growing season. Such knowledge could provide important information for future survey and research programmes in Norway. The method includes all regulated and well-known mycotoxins such as aflatoxins, trichothecenes, ochratoxin A, fumonisins and zearalenone. In addition, a wide range of less studied compounds are included in the method, e.g., Alternaria toxins, ergot alkaloids and other metabolites produced by fungal species within Fusarium, Penicillium and Aspergillus. Altogether, 46 metabolites, all of fungal origin, were detected in the 76 barley, oats and wheat samples. The analyses confirmed the high prevalence and relatively high concentrations of type-A and -B trichothecenes (e.g., deoxynivalenol up to 7230 µg/kg, HT-2 toxin up to 333 µg/kg). Zearalenone was also among the major mycotoxins detected (maximum concentration 1670 µg/kg). Notably, several other Fusarium metabolites such as culmorin, 2-amino-14,16-dimethyloctadecan-3-ol and avenacein Y were co-occurring. Furthermore, the most prevalent Alternaria toxin was alternariol with a maximum concentration of 449 µg/kg. A number of Penicillium and Aspergillus metabolites were also detected in the samples, e.g., sterigmatocystin in concentrations up to 20 µg/kg.

Endocrine and respiratory responses to ergotamine in Brahman and Hereford steers.

PubMed

Browning, Richard; Thompson, Frederick N

2002-06-01

Ergot alkaloids are considered causative agents of fescue toxicosis, a syndrome experienced by cattle consuming tall fescue (Festuca arundinacea) infected with the fungal endophyte Neotyphodium coenophialum. One sign of fescue toxicosis in cattle is severe hyperthermia. This study assessed hormonal responses to ergotamine in heat-sensitive and heat-tolerant cattle. Seven Hereford (heat-sensitive, Bos taurus) and 7 Brahman (heat-tolerant, Bos indicus) steers on a fescue-free diet received ergotamine tartrate iv. Blood was sampled every 15 min for 2 h before and 4 h after dosing for determination of circulating hormonal changes. Respiration rates were recorded hourly. Ambient temperature and relative humidity averaged 31C and 48%, respectively, during sampling. A breed x time interaction existed (p < 0.01) for plasma prolactin, LH, insulin, glucagon, cortisol, triiodothyronine and glucose concentrations. The breed x time interaction tended to affect (p = 0.14) growth hormone and influenced (p < 0.01) respiration rates. Ergotamine reduced (p < 0.01) plasma LH and increased (p < 0.01) growth hormone concentrations in Brahman. Both breeds responded to ergotamine with increased (p < 0.01) plasma cortisol, glucagon, and glucose and reduced (p < 0.01) insulin concentrations. The magnitude of response for cortisol, insulin, and glucose were greater for the Brahman. Ergotamine increased (p < 0.01) plasma triiodothyronine and respiration rates in Hereford, whereas these traits were unaltered in Brahman. Acute ergotamine exposure generally resulted in similar effects on Brahman and Hereford steers. The triiodothyronine and respiratory comparisons revealed modified responses in Brahman that suggest a potential benefit of using heat-tolerant genetics to reduce the adverse effects of fescue toxicosis in cattle.

Efficacy and safety of rotigotine in elderly patients with Parkinson's disease in comparison with the non-elderly: a post hoc analysis of randomized, double-blind, placebo-controlled trials.

PubMed

Nomoto, Masahiro; Iwaki, Hirotaka; Kondo, Hiroyuki; Sakurai, Masaya

2018-02-01

Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo-controlled trials performed in Japan to clarify the difference of anti-parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, significantly improved in both elderly and non-elderly patients. Regarding safety, the incidence of total adverse event tended to be lower in elderly patients than non-elderly patients, although it was not significant. No difference was observed in maintenance dosage of rotigotine between the two groups. In conclusion, the improvement in motor symptoms and frequency of adverse events were shown to be similar in elderly and non-elderly patients with rotigotine-levodopa combination therapy. Further, there was no major difference in maintenance dosage of rotigotine between the age groups. These results suggest good tolerability of rotigotine among elderly patients.

Transgene × Environment Interactions in Genetically Modified Wheat

PubMed Central

Zeller, Simon L.; Kalinina, Olena; Brunner, Susanne; Keller, Beat; Schmid, Bernhard

2010-01-01

Background The introduction of transgenes into plants may cause unintended phenotypic effects which could have an impact on the plant itself and the environment. Little is published in the scientific literature about the interrelation of environmental factors and possible unintended effects in genetically modified (GM) plants. Methods and Findings We studied transgenic bread wheat Triticum aestivum lines expressing the wheat Pm3b gene against the fungus powdery mildew Blumeria graminis f.sp. tritici. Four independent offspring pairs, each consisting of a GM line and its corresponding non-GM control line, were grown under different soil nutrient conditions and with and without fungicide treatment in the glasshouse. Furthermore, we performed a field experiment with a similar design to validate our glasshouse results. The transgene increased the resistance to powdery mildew in all environments. However, GM plants reacted sensitive to fungicide spraying in the glasshouse. Without fungicide treatment, in the glasshouse GM lines had increased vegetative biomass and seed number and a twofold yield compared with control lines. In the field these results were reversed. Fertilization generally increased GM/control differences in the glasshouse but not in the field. Two of four GM lines showed up to 56% yield reduction and a 40-fold increase of infection with ergot disease Claviceps purpurea compared with their control lines in the field experiment; one GM line was very similar to its control. Conclusions Our results demonstrate that, depending on the insertion event, a particular transgene can have large effects on the entire phenotype of a plant and that these effects can sometimes be reversed when plants are moved from the glasshouse to the field. However, it remains unclear which mechanisms underlie these effects and how they may affect concepts in molecular plant breeding and plant evolutionary ecology. PMID:20635001

Transgene x environment interactions in genetically modified wheat.

PubMed

Zeller, Simon L; Kalinina, Olena; Brunner, Susanne; Keller, Beat; Schmid, Bernhard

2010-07-12

The introduction of transgenes into plants may cause unintended phenotypic effects which could have an impact on the plant itself and the environment. Little is published in the scientific literature about the interrelation of environmental factors and possible unintended effects in genetically modified (GM) plants. We studied transgenic bread wheat Triticum aestivum lines expressing the wheat Pm3b gene against the fungus powdery mildew Blumeria graminis f.sp. tritici. Four independent offspring pairs, each consisting of a GM line and its corresponding non-GM control line, were grown under different soil nutrient conditions and with and without fungicide treatment in the glasshouse. Furthermore, we performed a field experiment with a similar design to validate our glasshouse results. The transgene increased the resistance to powdery mildew in all environments. However, GM plants reacted sensitive to fungicide spraying in the glasshouse. Without fungicide treatment, in the glasshouse GM lines had increased vegetative biomass and seed number and a twofold yield compared with control lines. In the field these results were reversed. Fertilization generally increased GM/control differences in the glasshouse but not in the field. Two of four GM lines showed up to 56% yield reduction and a 40-fold increase of infection with ergot disease Claviceps purpurea compared with their control lines in the field experiment; one GM line was very similar to its control. Our results demonstrate that, depending on the insertion event, a particular transgene can have large effects on the entire phenotype of a plant and that these effects can sometimes be reversed when plants are moved from the glasshouse to the field. However, it remains unclear which mechanisms underlie these effects and how they may affect concepts in molecular plant breeding and plant evolutionary ecology.

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study.

PubMed

Pinter, M M; Pogarell, O; Oertel, W H

1999-04-01

Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.

Analysis of lysergic acid amide in human serum and urine after ingestion of Argyreia nervosa seeds.

PubMed

Paulke, Alexander; Kremer, Christian; Wunder, Cora; Toennes, Stefan W

2012-08-01

The ergot alkaloid lysergic acid amide (LSA) is a secondary plant constituent in a number of plants, but it is mainly present in considerable amounts in Convolvulaceae, like Argyreia nervosa. Due to its close structural similarity to lysergic acid diethylamide, LSA is considered as psychedelic and therefore promoted as so-called "legal high" in various internet forums. During a human behavioral study with orally administered seeds of A. nervosa, blood and urine samples were obtained. The present study describes the validation of a sensitive and robust high performance liquid chromatography method with fluorescence detection, which was applied to the study samples. The limit of detection (LOD) and lower limit of quantification in human serum were 0.05 and 0.17 ng/mL, respectively, and in urine, the LOD was 0.15 ng/mL. Intra- and interday precision and accuracy were below 15 % relative standard deviation with a bias better than ±15 %. No conversion of LSA to its epimer iso-LSA was noted during analyses. The LSA concentrations in the authentic human serum samples were in the range of 0.66 to 3.15 ng/mL approximately 2 h after ingestion. In urine, LSA could be found 1-24 h after ingestion; after 48 h, no LSA could be detected. The LSA epimer iso-LSA was also detected in serum and urine in varying ratios. In conclusion, LSA serum levels in the low nanogram per milliliter range correlated with severe vegetative adverse effects (nausea, weakness, fatigue, tremor, blood pressure elevation) and a psychosis-like state, which led to study termination.

The diversity and distribution of fungi on residential surfaces.

PubMed

Adams, Rachel I; Miletto, Marzia; Taylor, John W; Bruns, Thomas D

2013-01-01

The predominant hypothesis regarding the composition of microbial assemblages in indoor environments is that fungal assemblages are structured by outdoor air with a moderate contribution by surface growth, whereas indoor bacterial assemblages represent a mixture of bacteria entered from outdoor air, shed by building inhabitants, and grown on surfaces. To test the fungal aspect of this hypothesis, we sampled fungi from three surface types likely to support growth and therefore possible contributors of fungi to indoor air: drains in kitchens and bathrooms, sills beneath condensation-prone windows, and skin of human inhabitants. Sampling was done in replicated units of a university-housing complex without reported mold problems, and sequences were analyzed using both QIIME and the new UPARSE approach to OTU-binning, to the same result. Surfaces demonstrated a mycological profile similar to that of outdoor air from the same locality, and assemblages clustered by surface type. "Weedy" genera typical of indoor air, such as Cladosporium and Cryptococcus, were abundant on sills, as were a diverse set of fungi of likely outdoor origin. Drains supported more depauperate assemblages than the other surfaces and contained thermotolerant genera such as Exophiala, Candida, and Fusarium. Most surprising was the composition detected on residents' foreheads. In addition to harboring Malassezia, a known human commensal, skin also possessed a surprising richness of non-resident fungi, including plant pathogens such as ergot (Claviceps purperea). Overall, fungal richness across indoor surfaces was high, but based on known autecologies, most of these fungi were unlikely to be growing on surfaces. We conclude that while some endogenous fungal growth on typical household surfaces does occur, particularly on drains and skin, all residential surfaces appear - to varying degrees - to be passive collectors of airborne fungi of putative outdoor origin, a view of the origins of the indoor microbiome quite different from bacteria.

Synchronicity of pollination and inoculation with Claviceps africana and its effects on pollen-pistil compatibility and seed production in sorghum.

PubMed

Cisneros-López, Ma Eugenia; Mendoza-Onofre, Leopoldo E; González-Hernández, Víctor A; Zavaleta-Mancera, H Araceli; Mora-Aguilera, Gustavo; Hernández-Martínez, Miguel; Córdova-Téllez, Leobigildo

2010-04-01

Sorghum ergot (caused by Claviceps africana) is a disease that affects sorghum seed development and yield. The interaction between pollen tube growth and hyphal development determines whether ovaries will be fertilized or colonized. Thus their respective deposition times on the stigma are critical. The effect of the time interval between pollination and inoculation on stigma receptivity and seed production was measured under field conditions in the male-sterile line A9 at Montecillo, State of México (2240m altitude). Pollination and inoculation treatments, from simultaneous application to 2 and 4h difference, were imposed when all stigmas on the panicle had emerged. Control panicles were either only pollinated or only inoculated. Eighteen hours later, pollen grains that adhered to, and germinated within the stigma, pollen tubes in the style and ovary, and fertilized pistils were counted. Pistils showing some disease expression (germinated spores, mycelium growth, or tissue necrosis) at 18, 48, and 72h were recorded. The number of diseased florets was registered at the dough growth stage, while number of seeds, grain yield and 100-seeds weight was measured at the physiological maturity. The pathogen applied in a water suspension of macro and secondary conidia caused a decrease in stigma receptivity; the greatest decrease (40-60%) occurred when the pollen and the inoculum were deposited almost simultaneously, regardless of which was deposited first. The route of the pollen tube was also the route for fungal infection. On average, treatments first inoculated had 60% more diseased florets and 36% less grain yield, 30% fewer seeds and seed size decreased 8%, than those first pollinated. Copyright © 2010 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Candyflipping and Other Combinations: Identifying Drug–Drug Combinations from an Online Forum

PubMed Central

Chary, Michael; Yi, David; Manini, Alex F.

2018-01-01

Novel psychoactive substances (NPS) refer to synthetic compounds or derivatives of more widely known substances of abuse that have emerged over the last two decades. Case reports suggest that users combine substances to achieve desired psychotropic experiences while reducing dysphoria and unpleasant somatic effects. However, the pattern of combining NPS has not been studied on a large scale. Here, we show that posts discussing NPS describe combining nootropics with sedative-hypnotics and stimulants with plant hallucinogens or psychiatric medications. Discussions that mention sedative-hypnotics most commonly also mention hallucinogens and stimulants. We analyzed 20 years of publicly available posts from Lycaeum, an Internet forum dedicated to sharing information about psychoactive substance use. We used techniques from natural language processing and machine learning to identify NPS and correlate patterns of co-mentions of substances across posts. We found that conversations mentioning synthetic hallucinogens tended to divide into those mentioning hallucinogens derived from amphetamine and those derived from ergot. Conversations that mentioned synthetic hallucinogens tended not to mention plant hallucinogens. Conversations that mention bath salts commonly mention sedative-hypnotics or nootropics while more canonical stimulants are discussed with plant hallucinogens and psychiatric medications. All types of substances are frequently compared to MDMA, DMT, cocaine, or atropine when trying to describe their effects. Our results provide the largest analysis to date of online descriptions of patterns of polysubstance use and further demonstrate the utility of social media in learning about trends in substance use. We anticipate this work to lead to a more detailed analysis of the knowledge contained online about the patterns of usage and effects of novel psychoactive substances. PMID:29760666

Art and dystonia.

PubMed

Garcia-Ruiz, Pedro J; Slawek, Jaroslaw; Sitek, Emilia J; Martinez Castrillo, Juan Carlos

2015-09-15

Dystonia has a recent history in medicine. Focal dystonia was described in the 19th century by classic authors including Gowers, whilst generalized dystonia was described at the turn of the century. However, it is possible to find precise descriptions of dystonia in art, centuries before the medical definition. We have reviewed several pieces of art (sculpture, painting and literature) across the history that might represent descriptions of dystonia, from ancient period to nowadays. In classic times, the first reference to abnormal postures can be tracked back to the new Empire of Egypt (equinus foot), not to mention some recently described examples of dystonia from the Moche sculptures in Peru or Veracruz culture from Mexico. In Middle Ages it is possible to find many examples of sculptures in European cathedrals representing peasants with dramatic, presumably dystonic postures that coexist with amputation of limbs. This unique combination of dystonia and limb amputation probably represents ergotism. The painters Brueghel, Ribera and Velazquez also represented figures with postures likely to be dystonic. Literature is also a source of precise pre-neurological descriptions, especially during the 19th century. In David Copperfield, Dickens depicts characters with generalized dystonia (Uriah Heep), cervical dystonia (Mr. Sharp) and spasmodic dysphonia (Mr Creakle). Finally, even in modern Art (19th and 20th centuries), there are dramatic descriptions of abnormal postures that are likely to be dystonic, such as painful cervical dystonia (Brancusi), cervical dystonia with sensory trick (Modigliani) and upper limb dystonia (Wyspianski). However some postures presented in works of art may simply be a form of artistic expression and only bear unintentional resemblance to the dystonic postures. Art may be a source of neurological information, and that includes primary and secondary dystonia. Copyright © 2015 Elsevier B.V. All rights reserved.

[Plant-microbe symbioses as an evolutionary continuum].

PubMed

Provorov, N A

2009-01-01

In spite of enormous taxonomic, structural and functional diversity of plant-microbe interactions, they are characterized by a historical succession which allows us to consider different forms of symbioses as the components of an evolutionary continuum. Their ancestral form is represented by arbuscular mycorrhiza (AM) which originated at the outset of terrestrial flora evolution and constituted a key factor for the land colonization by plants. In the course of AM evolution the plant acquired a basal set of genes for regulating the performance of microbes which colonize the root tissues. Later, these genes were repeatedly reorganized to meet the involvement of novel mutualistic symbionts (N2-fixing bacteria, ectomycorrhizal fungi, endophytes and epiphytes) and pathogens into the symbiotic interactions. Form the microbial side, the evolutionary succession of mutualism and antagonism is restricted to the defensive symbioses formed by plants with the ergot fungi, Clavibacter, Bacillus and Pseudomonas bacteria. Involvement of the similar systems for symbiotic interactions may be related to convergent evolution in the distant microorganisms (adaptation to the conservative host defense/regulatory factors), to molecular mimicry (imitation of the mechanisms of interaction used by the more ancient symbionts) or to the horizontal gene transfer. The hypotheses of the successive substitution of symbionts is suggested to address the relationships between AM and N2-fixing nodular symbioses in dicotyledons plants. AM formation is considered as a source of preadaptations responsible for the substitution of glomalean fungi which occupied the plant symbiotic compartments by the actinomycetes Frankia (in Rosid I plants) which were exchanged for the more competitive root nodule bacteria (in legumes). The development of nutritional symbioses with microbes is considered as an ancestral function of plant roots which were later supplemented or substituted with the function of assimilating the soil nutrients.

[Inter- and intraindividual pharmacokinetic variations in the treatment of Parkinson's disease].

PubMed

Nomoto, Masahiro; Nakatsuka, Akiko; Nagai, Masahiro; Yabe, Hayato; Moritoyo, Takashi; Moritoyo, Hiroyoko; Nisikawa, Noriko

2005-11-01

In the treatment of Parkinson's disease, levodopa, DCI, MAO-B inhibitor, COMT inhibitors, dopamine receptor agonists, amantadine, anticholinergics have been applied and new drugs are being developed. Levodopa is still the golden standard in the treatment of Parkinson's disease. The study on levodopa bioavailability showed 3-4 times differences in individual patients. Drug-food interactions are prominent in levodopa. Low protein food increased levodopa bioavailability and improved no ON or delayed ON in the treatment of Parkinson's disease. Vitamine C or magnesium did not alter the bioavailability of levodopa. The bioavailability of levodopa between the levodopa/carbidioa (100/12.5) group and the levodopa/benserazide (100/25) group was studied in patients with Parkinson's disease by population PK study. C(max) of levodopa in levodeopa/benserazide group was twice as high as in levodopa/carbidopa group. Domperidone, a dopamine receptor antagonist applied as an antiemetic inceases vowel movement. The effect of domperidone on levodopa bioavailability was studied, and the combination of domperidone with levodopa increased AUC of levodopa. Clarythromycin or grape fruit juice inhibits both of CYP3A4 and P-glycoprotein which work on metabolism and absorption of drugs. Coadministration of clarythromycin with ergot alkaloids such as cabergoline or bromocriptine increased the AUC up to 2-3 times. Amantadine is excreted through kidney without being metabolized and renal function is the most important factor in the blood concentration of amantadine. In elder women with the body weight of 50 kg or less, creatinine clearance is less than 50 ml/min even though the serum creatinine is within the normal range. Selegiline is metabolized through CYP2D6 and 3A4. Coadministration of qunidine, cimetidine, maclorides, antifungals, grape fruit juice increase the bioavailability of selegiline and may augment the antiparkinsonian effect.

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans.

PubMed

Böttiger, Y; Dostert, P; Benedetti, M S; Bani, M; Fiorentini, F; Casati, M; Poggesti, I; Alm, C; Alvan, G; Bertilsson, L

1996-12-01

1. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3. After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4. The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l-1 and AUC (0, th) 144 nmol l-1h, mean MDL Cmax 183 nmol l-1 and AUC 2627 nmol l-1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l-1 and AUC 10512 nmol l-1h, MDL concentrations below limit of quantitation). 5. We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans

PubMed Central

BÖTTIGER, Y.; DOSTERT, P.; STROLIN BENEDETTI, M.; BANI, M.; FIORENTINI, F.; CASATI, M.; POGGESTI, I.; ALM, C.; ALVAN, G.; BERTILSSON, L.

1996-01-01

1Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l−1 and AUC (0, th) 144 nmol l−1h, mean MDL Cmax 183 nmol l−1 and AUC 2627 nmol l−1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l−1 and AUC 10512 nmol l−1h, MDL concentrations below limit of quantitation). 5We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism. PMID:8971425

Effects of nicergoline on rabbit electroretinogram during recovery after ischaemia in light and dark.

PubMed

Blasco, G; Traversa, U; Drago, F

1997-11-01

Nicergoline is an ergot alkaloid derivative acting as a neuroprotective agent. In the present investigation, b-wave time-course recovery profiles under both light- and dark-adapted conditions, were studied in order to evaluate the possible effectiveness of nicergoline in the protection of the rabbit retina. Retinal ischaemia was induced by bilateral occlusion of common carotid artery in male rabbit of the Dutch strain. Groups of animals were subjected to 15-, 30- and 60-min periods of ischaemia under pentobarbital anaesthesia. Electroretinogram recordings were simultaneously obtained from both eyes, using, as the stimulus, the brightest flash from a stimulator positioned 15 cm in front of each eye. The treatment with nicergoline, administered immediately before the carotid occlusion, induced a significant protection only when the ischaemia seemed to cause retinal damage that the reperfusion alone was not able to recover completely. Nicergoline did not modify the recovery rate after 15-min or 30-min light-adapted and 15-min dark-adapted ischaemia; in these conditions the controls showed a full recovery. After 30-min dark-adapted ischaemia, the maximum recovery of the controls was 82%, and nicergoline significantly improved b-wave amplitude at all time points of reperfusion up to the complete recovery. Rabbit retina was irreversibly damaged by a 60-min ischaemia. In these conditions nicergoline significantly increased the percentage of b-wave recovery both in light- and dark-adapted ERG. Nicergoline, probably on the basis of its metabolic actions, seems to be effective in severe conditions of hypoxia and is more potent in dark than in light-adapted conditions. Its effectiveness in these experimental conditions could be justified by the different oxygen consumption of the photoreceptors in light and dark and the different sensitivity of cones and rods to the ischaemia.

The Diversity and Distribution of Fungi on Residential Surfaces

PubMed Central

Adams, Rachel I.; Miletto, Marzia; Taylor, John W.; Bruns, Thomas D.

2013-01-01

The predominant hypothesis regarding the composition of microbial assemblages in indoor environments is that fungal assemblages are structured by outdoor air with a moderate contribution by surface growth, whereas indoor bacterial assemblages represent a mixture of bacteria entered from outdoor air, shed by building inhabitants, and grown on surfaces. To test the fungal aspect of this hypothesis, we sampled fungi from three surface types likely to support growth and therefore possible contributors of fungi to indoor air: drains in kitchens and bathrooms, sills beneath condensation-prone windows, and skin of human inhabitants. Sampling was done in replicated units of a university-housing complex without reported mold problems, and sequences were analyzed using both QIIME and the new UPARSE approach to OTU-binning, to the same result. Surfaces demonstrated a mycological profile similar to that of outdoor air from the same locality, and assemblages clustered by surface type. “Weedy” genera typical of indoor air, such as Cladosporium and Cryptococcus, were abundant on sills, as were a diverse set of fungi of likely outdoor origin. Drains supported more depauperate assemblages than the other surfaces and contained thermotolerant genera such as Exophiala, Candida, and Fusarium. Most surprising was the composition detected on residents’ foreheads. In addition to harboring Malassezia, a known human commensal, skin also possessed a surprising richness of non-resident fungi, including plant pathogens such as ergot (Claviceps purperea). Overall, fungal richness across indoor surfaces was high, but based on known autecologies, most of these fungi were unlikely to be growing on surfaces. We conclude that while some endogenous fungal growth on typical household surfaces does occur, particularly on drains and skin, all residential surfaces appear – to varying degrees – to be passive collectors of airborne fungi of putative outdoor origin, a view of the origins of the indoor microbiome quite different from bacteria. PMID:24223861

Presence of Multiple Mycotoxins and Other Fungal Metabolites in Native Grasses from a Wetland Ecosystem in Argentina Intended for Grazing Cattle

PubMed Central

Nichea, María J.; Palacios, Sofia A.; Chiacchiera, Stella M.; Sulyok, Michael; Krska, Rudolf; Chulze, Sofia N.; Torres, Adriana M.; Ramirez, María L.

2015-01-01

The aim of this study was to evaluate the occurrence of several fungal metabolites, including mycotoxins in natural grasses (Poaceae) intended for grazing cattle. A total number of 72 and 77 different metabolites were detected on 106 and 69 grass samples collected during 2011 and 2014, respectively. A total of 60 metabolites were found across both years. Among the few mycotoxins considered toxic for ruminants, no samples of natural grasses were contaminated with aflatoxins, ochratoxin A, ergot alkaloids, and gliotoxin, among others. However, we were able to detect important metabolites (toxic to ruminants) such as type A trichothecenes, mainly T-2 toxin and HT-2 toxin (up to 5000 µg/kg each), and zearalenone (up to 2000 µg/kg), all at very high frequencies and levels. Other fungal metabolites that were found to be prevalent were other Fusarium metabolites like beauvericin, equisetin and aurofusarin, metabolites produced by Alternaria spp., sterigmatocystin and its precursors and anthrachinone derivatives. It is important to point out that the profile of common metabolites was shared during both years of sampling, and also that the occurrence of important metabolites is not a sporadic event. Considering that this area of temperate grassland is used for grazing cattle all year long due to the richness in palatable grasses (Poaceae), the present work represents a starting point for further studies on the occurrence of multi-mycotoxins in natural grasses in order to have a complete picture of the extent of cattle exposure. Also, the present study shows that the presence of zeranol in urine of beef cattle may not be a consequence of illegal use of this banned substance, but the product of the natural occurrence of zearalenone and α-zearalenol in natural grasses intended for cattle feeding. PMID:26308052

Antigenotoxic Studies of Different Substances to Reduce the DNA Damage Induced by Aflatoxin B1 and Ochratoxin A

PubMed Central

Madrigal-Santillán, Eduardo; Morales-González, José A.; Vargas-Mendoza, Nancy; Reyes-Ramírez, Patricia; Cruz-Jaime, Sandra; Sumaya-Martínez, Teresa; Pérez-Pastén, Ricardo; Madrigal-Bujaidar, Eduardo

2010-01-01

Mycotoxins are produced mainly by the mycelial structure of filamentous fungi, or more specifically, molds. These secondary metabolites are synthesized during the end of the exponential growth phase and appear to have no biochemical significance in fungal growth and development. The contamination of foods and feeds with mycotoxins is a significant problem for the adverse effects on humans, animals, and crops that result in illnesses and economic losses. The toxic effect of the ingestion of mycotoxins in humans and animals depends on a number of factors including intake levels, duration of exposure, toxin species, mechanisms of action, metabolism, and defense mechanisms. In general, the consumption of contaminated food and feed with mycotoxin induces to neurotoxic, immunosuppressive, teratogenic, mutagenic, and carcinogenic effect in humans and/or animals. The most significant mycotoxins in terms of public health and agronomic perspective include the aflatoxins, ochratoxin A (OTA), trichothecenes, fumonisins, patulin, and the ergot alkaloids. Due to the detrimental effects of these mycotoxins, several strategies have been developed in order to reduce the risk of exposure. These include the degradation, destruction, inactivation or removal of mycotoxins through chemical, physical and biological methods. However, the results obtained with these methods have not been optimal, because they may change the organoleptic characteristics and nutritional values of food. Another alternative strategy to prevent or reduce the toxic effects of mycotoxins is by applying antimutagenic agents. These substances act according to several extra- or intracellular mechanisms, their main goal being to avoid the interaction of mycotoxins with DNA; as a consequence of their action, these agents would inhibit mutagenesis and carcinogenesis. This article reviews the main strategies used to control AFB1 and ochratoxin A and contains an analysis of some antigenotoxic substances that reduce the DNA damage caused by these mycotoxins. PMID:22069607

Initiating and optimizing acute therapy for migraine: the role of patient-centered stratified care.

PubMed

Diamond, Merle; Cady, Roger

2005-03-01

Migraine is a chronic, intermittently disabling condition that affects physical, mental, and social aspects of health-related quality of life. Because patients seeking assistance with migraine most often present to primary care providers, these healthcare professionals play critical roles in the diagnosis and treatment process. A comprehensive migraine management plan involves a partnership between the patient and healthcare professional where treatment goals and strategies are established. Elements of such a plan should include preventive strategies to reduce the frequency and effects of future attacks as well as the use of acute treatments to address the immediate need for relief during an attack. Approaches to prevention include education, lifestyle modification, and, often, appropriate medication. Many medications have been used for acute treatment. Nonspecific agents include nonsteroidal anti-inflammatory drugs (NSAIDs), single or combination analgesics (sometimes including antiemetics or caffeine), and narcotics. Migraine-specific medications include ergot alkaloids and triptans (5-hydroxytryptamine(1B/1D) agonists). Various professional organizations have created guidelines to help providers in choosing appropriate management interventions. Clinical approaches to the patient with migraine include step care, whereby all patients begin on a simple or nonspecific treatment, stepping up to the next level of therapy if treatment is unsuccessful; or stratified care, whereby first-line therapy is tailored to the severity of the patient's pattern of headache. Studies have demonstrated that for more disabled headache patients, the stratified-care approach results in more robust headache response with less disability and greater cost-effectiveness than step care. Patient satisfaction studies demonstrate that the use of migraine-specific abortive medications (triptans) is associated with a higher satisfaction rate than over-the-counter preparations, NSAIDs, and analgesic combinations. Patients who initially reported satisfaction with the latter medications also reported a preference for triptan therapy. Healthcare professionals can assist patients, not only by choosing the most appropriate medication but also by assessing whether the level of benefit the patient is currently receiving could be improved.

The Dancing Manias: Psychogenic Illness as a Social Phenomenon.

PubMed

Lanska, Douglas J

2018-01-01

The dancing mania erupted in the 14th century in the wake of the Black Death, and recurred for centuries in central Europe - particularly Germany, the Netherlands, and Belgium - finally abating in the early 17th century. The term "dancing mania" was derived from "choreomania," a concatenation of choros (dance) and mania (madness). A variant, tarantism, was prevalent in southern Italy from the 15th to the 17th centuries, and was attributed at the time to bites from the tarantula spider. Affected individuals participated in continuous, prolonged, erratic, often frenzied and sometimes erotic, dancing. In the 14th century, the dancing mania was linked to a corruption of the festival of St. John's Day by ancient pagan customs, but by the 16th century it was commonly considered an ordeal sent by a saint, or a punishment from God for people's sins. Consequently, during outbreaks in the 14th and 15th centuries, the dancing mania was considered an issue for magistrates and priests, not physicians, even though the disorder proved intractable to decrees and exorcisms. However, in the 16th century Paracelsus discounted the idea that the saints caused or interceded in the cure of the dancing mania; he instead suggested a psychogenic or malingered etiology, and this reformulation brought the dancing mania within the purview of physicians. Paracelsus advocated various mystical, psychological, and pharmacological approaches, depending on the presumptive etiologic factors with individual patients. Only music provided any relief for tarantism. Later authors suggested that the dancing mania was a mass stress-induced psychosis, a mass psychogenic illness, a culturally determined form of ritualized behavior, a manifestation of religious ecstasy, or even the result of food poisoning caused by the toxic and psychoactive chemical products of ergot fungi. In reality, dancing manias did not have a single cause, but component causes likely included psychogenic illness, malingering, and ritualized behaviors. © 2018 S. Karger AG, Basel.

Contamination with ergot bodies (Claviceps purpurea sensu lato) of two horse pastures in Northern Germany.

PubMed

Aboling, S; Drotleff, A M; Cappai, M G; Kamphues, J

2016-11-01

Because the occurrence of Claviceps in European pastures may have been overlooked to cause serious health problem for grazing animals, we documented the degree of Claviceps contamination in two horse pastures and estimated whether the horses could have ingested a critical quantity of alkaloids. We counted the Claviceps sclerotia and determined alkaloid levels using high performance liquid chromatography with fluorescence detection. Depending on the location, the number of sclerotia varied from 0.09 to 0.19 per square meter (central area) and from 0.23 to 55.8 per square meter (border strips). Alkaloid levels in individual sclerotia also varied in different genera of grasses, ranging from 0.98 ± 0.17 μg/kg in Agrostis sp. to 25.82 ± 9.73 μg/kg in Dactylis sp., equivalent to 0.98 μg/kg and 7.26 mg/kg. Sclerotia from Dactylis contained high levels of ergosine (0.209 % ± 0.100 %) and ergocristine (0.374 % ± 0.070 %). Depending on the localization in pastures, alkaloid levels in forage (dry matter, DM) ranged from 16.1 to 45.4 μg/kg in central areas and from 23.9 to 722 μg/kg in border strips. The amount of alkaloids that a horse could have ingested depended on its daily DM uptake, which was higher in the central areas (5.85 kg/day) than in the border strips (2.73 or 0.78 kg/day). In the central areas, this amount of alkaloids ranged from 94.2 to 265.9 μg/day; and in the border strips, from 65.3 (in 2.73 kg DM/day) to as much as 563.8 μg/day (in 0.78 kg DM/day). All these amounts are higher than the European averages for alkaloids ingested by horses via feedstuffs.

Cross-talk of the biotrophic pathogen Claviceps purpurea and its host Secale cereale.

PubMed

Oeser, Birgitt; Kind, Sabine; Schurack, Selma; Schmutzer, Thomas; Tudzynski, Paul; Hinsch, Janine

2017-04-04

The economically important Ergot fungus Claviceps purpurea is an interesting biotrophic model system because of its strict organ specificity (grass ovaries) and the lack of any detectable plant defense reactions. Though several virulence factors were identified, the exact infection mechanisms are unknown, e.g. how the fungus masks its attack and if the host detects the infection at all. We present a first dual transcriptome analysis using an RNA-Seq approach. We studied both, fungal and plant gene expression in young ovaries infected by the wild-type and two virulence-attenuated mutants. We can show that the plant recognizes the fungus, since defense related genes are upregulated, especially several phytohormone genes. We present a survey of in planta expressed fungal genes, among them several confirmed virulence genes. Interestingly, the set of most highly expressed genes includes a high proportion of genes encoding putative effectors, small secreted proteins which might be involved in masking the fungal attack or interfering with host defense reactions. As known from several other phytopathogens, the C. purpurea genome contains more than 400 of such genes, many of them clustered and probably highly redundant. Since the lack of effective defense reactions in spite of recognition of the fungus could very well be achieved by effectors, we started a functional analysis of some of the most highly expressed candidates. However, the redundancy of the system made the identification of a drastic effect of a single gene most unlikely. We can show that at least one candidate accumulates in the plant apoplast. Deletion of some candidates led to a reduced virulence of C. purpurea on rye, indicating a role of the respective proteins during the infection process. We show for the first time that- despite the absence of effective plant defense reactions- the biotrophic pathogen C. purpurea is detected by its host. This points to a role of effectors in modulation of the effective plant response. Indeed, several putative effector genes are among the highest expressed genes in planta.

A Concise History of Mycotoxin Research.

PubMed

Pitt, John I; Miller, J David

2017-08-23

Toxigenic fungi and mycotoxins entered human food supplies about the time when mankind first began to cultivate crops and to store them from one season to the next, perhaps 10,000 years ago. The storage of cereals probably initiated the transition by mankind from hunter-gatherer to cultivator, at the same time providing a vast new ecological niche for fungi pathogenic on grain crops or saprophytic on harvested grain, many of which produced mycotoxins. Grains have always been the major source of mycotoxins in the diet of man and his domestic animals. In the historical context, ergotism from Claviceps purpurea in rye has been known probably for more than 2000 years and caused the deaths of many thousands of people in Europe in the last millennium. Known in Japan since the 17th century, acute cardiac beriberi associated with the consumption of moldy rice was found to be due to citreoviridin produced by Penicillium citreonigrum. This toxin was believed to be only of historic importance until its reemergence in Brazil a few years ago. Other Penicillium toxins, including ochratoxin A, once considered to be a possible cause of Balkan endemic nephropathy, are treated in a historical context. The role of Fusarium toxins in human and animal health, especially T-2 toxin in alimentary toxic aleukia in Russia in the 1940s and fumonisins in equine leucoencephalomalasia, is set out in some detail. Finally, this paper documents the story of the research that led to our current understanding of the formation of aflatoxins in grains and nuts, due to the growth of Aspergillus flavus and its role, in synergy with the hepatitis B virus, in human liver cancer. During a period of climate change and greatly reduced crop diversity on a global basis, researchers tasked with monitoring the food system need to be aware of fungal toxins that might have been rare in their working careers that can reappear.

Fungi producing significant mycotoxins.

PubMed

2012-01-01

Mycotoxins are secondary metabolites of microfungi that are known to cause sickness or death in humans or animals. Although many such toxic metabolites are known, it is generally agreed that only a few are significant in causing disease: aflatoxins, fumonisins, ochratoxin A, deoxynivalenol, zearalenone, and ergot alkaloids. These toxins are produced by just a few species from the common genera Aspergillus, Penicillium, Fusarium, and Claviceps. All Aspergillus and Penicillium species either are commensals, growing in crops without obvious signs of pathogenicity, or invade crops after harvest and produce toxins during drying and storage. In contrast, the important Fusarium and Claviceps species infect crops before harvest. The most important Aspergillus species, occurring in warmer climates, are A. flavus and A. parasiticus, which produce aflatoxins in maize, groundnuts, tree nuts, and, less frequently, other commodities. The main ochratoxin A producers, A. ochraceus and A. carbonarius, commonly occur in grapes, dried vine fruits, wine, and coffee. Penicillium verrucosum also produces ochratoxin A but occurs only in cool temperate climates, where it infects small grains. F. verticillioides is ubiquitous in maize, with an endophytic nature, and produces fumonisins, which are generally more prevalent when crops are under drought stress or suffer excessive insect damage. It has recently been shown that Aspergillus niger also produces fumonisins, and several commodities may be affected. F. graminearum, which is the major producer of deoxynivalenol and zearalenone, is pathogenic on maize, wheat, and barley and produces these toxins whenever it infects these grains before harvest. Also included is a short section on Claviceps purpurea, which produces sclerotia among the seeds in grasses, including wheat, barley, and triticale. The main thrust of the chapter contains information on the identification of these fungi and their morphological characteristics, as well as factors influencing their growth and the various susceptible commodities that are contaminated. Finally, decision trees are included to assist the user in making informed choices about the likely mycotoxins present in the various crops.

Effect of autogenic training on drug consumption in patients with primary headache: an 8-month follow-up study.

PubMed

Zsombok, Terezia; Juhasz, Gabriella; Budavari, Agota; Vitrai, Jozsef; Bagdy, Gyorgy

2003-03-01

To examine the effects of Schultz-type autogenic training on headache-related drug consumption and headache frequency in patients with migraine, tension-type, or mixed (migraine plus tension-type) headache over an 8-month period. Behavioral treatments often are used alone or adjunctively for different types of headache. There are, however, only a few studies that have compared the efficacy and durability of the same treatment in different types of primary headache, and the effects of treatment on headache-related drug consumption rarely have been assessed even in these studies. Twenty-five women with primary headache (11 with mixed headache, 8 with migraine, and 6 with tension-type headache) were evaluated via an open-label, self-controlled, 8-month, follow-up study design. After an initial 4 months of observation, patients began learning Schultz-type autogenic training as modified for patients with headache. They practiced autogenic training on a regular basis for 4 months. Based on data from headache diaries and daily medication records, headache frequencies and the amounts of analgesics, "migraine-specific" drugs (ergots and triptans), and anxiolytics taken by the patients were compared in the three subgroups over the 8-month period. Results.-From the first month of implementation of autogenic training, headache frequencies were significantly reduced in patients with tension-type and mixed headache. Significant reduction in frequency was achieved in patients with migraine only from the third month of autogenic training. Decreases in headache frequencies were accompanied by decreases in consumption of migraine drugs and analgesics resulting in significant correlations among these parameters. Reduction in consumption of anxiolytic drugs was more rapid and robust in patients with tension-type headache compared to patients with migraine, and this outcome failed to show any correlation with change in headache frequency. Schultz-type autogenic training is an effective therapeutic approach that may lead to a reduction in both headache frequency and the use of headache medication.

[Seasonal and periodic rhythms of infectious diseases (author's transl)].

PubMed

Knorr, M; Schadewaldt, H

1979-03-01

The causes of epidemics are plainly not the pathogens alone as was initially assumed by Koch's school, predisposition and constitution of the population proved to be equally important. Ever since ancient times problems linked with the "constitutio epidemica" have been topical; the "physis", the "natura hominis" and the invironment of man play an increasingly important role in the symptomatology of disease, as can be gathered from such early documents as the "Corpus hippocraticum". Fracastoro distinguished between contagious and non-contagious epidemics. The casual organisms were considered to be miasmas -- noxious emanations -- or "contagia" i.e. likewise toxic substances. Questions concerning the origin of these miasmas turned attention to the environment (air, soil, water) and even led to astrological medicine. Not until the Renaissance were attempts made to differentiate the usual global words for epidemic, such as "loimos", "lues" and "pestis" with the result that a symptom was used more and more to designate a disease. For example, the symptom fever led to the designation "three-day fever" or "four-day fever", "typhus fever". This terminology made a differential diagnosis difficult to establish, thwarted selection measures to check epidemics and the medical world was thus helpless in explaining the causal agents and the phenomena of epidemics. This is illustrated by some epidemiological examples (ergotism, scurvy, yellow fever, English sweat, diphtheria and malaria). In this connection the "morbus novus", the transformation of the pathogen and the change of the pathogen is discussed. Many questions still left unanswered regarding the seasonal incidence, the fluctuation and disappearance of epidemics over decades or even centuries lead more frequently to sociomedical considerations with respect to the victims of epidemics, their predisposition, constitution and environment exposure term "hospital gangrene" with the modern term "hospitalism", we are not dealing with a transformation but a change of the pathogen. The impressive effects produced by antibiotics resulted in carelessness and along with the unprecedented advances in medicine and engineering we forgot to bear in mind that almost all great steps forward have an adverse side. Hygiene and practical medicine have only made a modest beginning in establishing the contact which should indeed be a matter of course in the hospital.

Field testing of the ICHD-3β and expert opinion criteria for chronic migraine.

PubMed

Jiang, Huahua; Deng, Yong; Zhang, Yixin; Jin, Jieli; Kong, Xueying; Zhu, Qiuwen; Wang, Kuiyun; Zhou, Jiying

2016-12-01

Chronic headache (CrH) occurs commonly in the population, and chronic migraine (CM) accounts for much of the CrH. Diagnostic criteria for CM remain controversial, and this could lead to undertreatment of CM. The purpose of this study was to analyze the clinical profiles of CM and to field test the International Classification of Headache Disorders-3β criteria (ICHD-3β) and Expert Opinion criteria (EO) for CM application. We retrospectively reviewed the medical records of CrH patients in our headache clinic during the period. Eligible patients were selected from CrH population based on Silberstein and Lipton criteria (S-L) for CM, and meanwhile fulfilled with migraine days at least 8 days/month. Then we evaluated the characteristics of clinic profiles and outcomes between patients diagnosed CM using ICHD-3β and EO criteria. Field tested the CM criteria Of ICHD-3β and EO. In a total of 710 CrH patients , 261 (36.8 %) were recruited with CM based on both S-L criteria and fulfilled at least 8 migraine days/month. Be understandable, all the 261 patients met the EO criteria, and only 185 (70.9 %) met ICHD-3β for CM. For the 76 patients who met EO but not ICHD-3β, 70 had atypical migraine attacks (probable migraine, PM), and another 6 had typical migraine attacks but less than a total history of 5 attacks. Although 173 (66.3 %) were concurrent with medication overuse, just one patient overused triptans and none used ergot agents. Clinical features were not significantly different between the ICHD-3β and EO criteria groups (P > 0.05), and neither were outcomes of prophylaxis (P = 0.966). Total migraine prophylaxis effectiveness was 73 %. Migraine-specific analgesics are rarely used in China, permitting patients with PM to avail themselves of "migraine days" is a reasonable accommodation for this difficult condition. In our hands, use of the new EO criteria for diagnosis of CM increases the sensitivity and maintains the specificity of decision making, and therefore should be adopted in CM management practice.

Type II diacylglycerol acyltransferase from Claviceps purpurea with ricinoleic acid, a hydroxyl fatty acid of industrial importance, as preferred substrate.

PubMed

Mavraganis, Ioannis; Meesapyodsuk, Dauenpen; Vrinten, Patricia; Smith, Mark; Qiu, Xiao

2010-02-01

Claviceps purpurea, the fungal pathogen that causes the cereal disease ergot, produces glycerides that contain high levels of ricinoleic acid [(R)-12-hydroxyoctadec-cis-9-enoic acid] in its sclerotia. Recently, a fatty acid hydroxylase (C. purpurea FAH [CpFAH]) involved in the biosynthesis of ricinoleic acid was identified from this fungus (D. Meesapyodsuk and X. Qiu, Plant Physiol. 147:1325-1333, 2008). Here, we describe the cloning and biochemical characterization of a C. purpurea type II diacylglycerol acyltransferase (CpDGAT2) involved in the assembly of ricinoleic acid into triglycerides. The CpDGAT2 gene was cloned by degenerate RT-PCR (reverse transcription-PCR). The expression of this gene restored the in vivo synthesis of triacylglycerol (TAG) in the quadruple mutant strain Saccharomyces cerevisiae H1246, in which all four TAG biosynthesis genes (DGA1, LRO1, ARE1, and ARE2) are disrupted. In vitro enzymatic assays using microsomal preparations from the transformed yeast strain indicated that CpDGAT2 prefers ricinoleic acid as an acyl donor over linoleic acid, oleic acid, or linolenic acid, and it prefers 1,2-dioleoyl-sn-glycerol over 1,2-dipalmitoyl-sn-glycerol as an acyl acceptor. The coexpression of CpFAH with CpDGAT2 in yeast resulted in an increased accumulation of ricinoleic acid compared to the coexpression of CpFAH with the native yeast DGAT2 (S. cerevisiae DGA1 [ScDGA1]) or the expression of CpFAH alone. Northern blot analysis indicated that CpFAH is expressed solely in sclerotium cells, with no transcripts of this gene being detected in mycelium or conidial cells. CpDGAT2 was more widely expressed among the cell types examined, although expression was low in conidiospores. The high expression of CpDGAT2 and CpFAH in sclerotium cells, where high levels of ricinoleate glycerides accumulate, provided further evidence supporting the roles of CpDGAT2 and CpFAH as key enzymes for the synthesis and assembly of ricinoleic acid in C. purpurea.

Ergovaline Stability in Tall Fescue Based on Sample Handling and Storage Methods

NASA Astrophysics Data System (ADS)

Lea, Krista; Smith, Lori; Gaskill, Cynthia; Coleman, Robert; Smith, S.

2014-09-01

Ergovaline is an ergot alkaloid produced by the endophyte Neotyphodium coenophialum (Morgan-Jones and Gams) found in tall fescue (Schedonorus arundinacea (Schreb.) Dumort.) and blamed for a multitude of livestock disorders. Ergovaline is known to be unstable and affected by many variables. The objective of this study was to determine the effect of sample handling and storage on the stability of ergovaline in tall fescue samples. Fresh tall fescue was collected from a horse farm in central Kentucky at three harvest dates and transported on ice to the University of Kentucky Veterinary Diagnostic Laboratory. Plant material was frozen in liquid nitrogen, milled and mixed before being allocated into different sub-samples. Three sub-samples were assigned to each of 14 sample handling or storage treatments. Sample handling included increased heat and UV light to simulate transportation in a vehicle and on ice in a cooler per standard transportation recommendations. Storage conditions included storage at 22oC, 5oC and -20oC for up to 28 days. Each sub-sample was then analyzed for ergovaline concentration using HPLC with fluorescence detection and this experiment was repeated for each harvest date. Sub-samples exposed to UV light and heat lost a significant fraction of ergovaline in 2 hours, while sub-samples stored on ice in a cooler showed no change in ergovaline in 2 hours. All sub-samples stored at 22oC, 5oC and -20oC lost a significant fraction of ergovaline in the first 24 hours of storage. There was little change in ergovaline in the freezer (-20oC) after the first 24 hours up to 28 days of storage but intermittent losses were observed at 22oC and 5oC. To obtain results that most closely represent levels in the field, all samples should be transported on ice to the laboratory immediately after harvest for same day analysis. If immediate testing is not possible, samples should be stored at -20oC until analysis.

Ruminal tryptophan-utilizing bacteria degrade ergovaline from tall fescue seed extract.

PubMed

Harlow, B E; Goodman, J P; Lynn, B C; Flythe, M D; Ji, H; Aiken, G E

2017-02-01

The objectives of this study were to evaluate degradation of ergovaline in a tall fescue [ (Schreb.) Darbysh.] seed extract by rumen microbiota ex vivo and to identify specific bacteria capable of ergovaline degradation in vitro. Rumen cell suspensions were prepared by harvesting rumen fluid from fistulated wether goats ( = 3), straining, and differential centrifugation. Suspensions were dispensed into anaerobic tubes with added Trypticase with or without extract (∼10 μg kg ergovaline). Suspensions were incubated for 48 h at 39°C. Samples were collected at 0, 24, and 48 h for ergovaline analysis and enumeration of hyper-ammonia producing (HAB) and tryptophan-utilizing bacteria. Ergovaline values were analyzed by repeated measures using the mixed procedure of SAS. Enumeration data were log transformed for statistical analysis. When suspensions were incubated with extract, 11 to 15% of ergovaline disappearance was observed over 48 h ( = 0.02). After 24 h, suspensions with added extract had 10-fold less HAB than controls ( = 0.04), but treatments were similar by 48 h ( = 1.00). However, after 24 h and 48 h, suspensions with extract had 10-fold more tryptophan-utilizing bacteria ( < 0.01) that were later isolated and identified by their 16S RNA gene sequence as . The isolates and other known rumen pure cultures ( JB1, B159, HD4, B, F, MD1, SR) were evaluated for the ability to degrade ergovaline in vitro. Pure culture cell suspensions were incubated as described above and samples were taken at 0 and 48 h for ergovaline analysis. Data were analyzed using the ANOVA procedure of SAS. All HAB, including the isolates, tested degraded ergovaline (54 to 75%; < 0.05). B14 was also able to degrade ergovaline but to a lesser capacity (12%; < 0.05), but all other bacteria tested did not degrade ergovaline. The results of this study indicate which rumen bacteria may play an important role in ergovaline degradation and that microbiological strategies for controlling their activity could have ramifications for fescue toxicosis and other forms of ergotism in ruminants.

Effects of endophyte-infected tall fescue on indicators of thermal status and growth in Hereford and Senepol steers.

PubMed

Browning, R

2004-02-01

Poor growth often occurs in cattle consuming ergot alkaloids associated with endophyte-infected (EI) tall fescue. Hyperthermia may contribute significantly to poor growth resulting from fescue toxicosis. This study examined indicators of thermal status and growth in Hereford (n = 30; heat-sensitive Bos taurus; H) and Senepol (n = 28; heat-tolerant Bos taurus; S) steers fed EI tall fescue (TF) or orchardgrass (OG) in 2 x 2 factorial experiments. Respiration rates, daytime shade use, tail skin temperatures, and body weights were measured during the summer and fall of 2000 (Exp. 1) and 2001 (Exp. 2). Experimental diets consisted of hay and seed for 12 wk in 2000, hay for 6 wk during the summer of 2001, and hay plus seed for 6 wk during the fall of 2001. In Exp. 1, EI tall fescue increased (P < 0.01) respiration rates, shade use, and skin temperatures in both breeds. Breed x diet affected (P < 0.01) 12-wk ADG in Exp. 1. Growth rate was lower for H-TF (262 g/d) than for S-TF, S-OG, and H-OG (475, 497, and 524 g/d, respectively). In Exp. 2, Senepol had lower (P < 0.01) respiration rates, shade use, and skin temperatures compared with Hereford, but diet did not alter (P > 0.14) these indicator traits in either breed. Breed x diet affected (P < 0.01) summer growth rates. Growth rate was lower for H-TF (88 g/d) than for H-OG, S-TF, and S-OG (508, 555, and 566 g/d, respectively). Adding seed to the diets in Exp. 2 decreased (P < 0.01) ADG for both breeds on TF during the fall. Thermal status indicator traits in Senepol and Hereford steers were similarly altered by TF; however, only Hereford showed consistently poor growth. Senepol showed resilience in their capacity for growth under conditions of fescue toxicosis. Senepol influence may enhance cattle performance in production systems that use EI tall fescue as the base forage.

[50 years of the Institute for Research in Pharmacy and Biochemistry].

PubMed

Trcka, V

2003-05-01

After the nationalization of pharmaceutical industry and establishment of the United Pharmaceutical Enterprises in 1946, the Research and Control Institute (VKU) was established in Prague in 1947 to support the development of research, manufacture, and control of drugs. After other measures of nationalization and unification of research, in 1951 the research sections of the VKU and the pharmaceutical sections of the Research Institute of CCHZ were fused to form the Research Institute for Pharmacy and Biochemistry (VUFB). The section the VUFB taking care of the quality of production was transformed into the Pharmaceutical Control Institute (KUF). Each of the institutes had its own farm for breeding experimental animals outside Prague. In 1958, KUF was transformed into the Research Institute of Medicinal Plants (VULERO) and later, in 1960, into the Research Institute of Natural Substances (VUPL), which eventually fused with VUFB in 1967. During the years of increasing activities of VUFB, a chemical pilot plant was established in Olomouc, and a department of clinical pharmacology in Plzen. Research activities of VUFB were aimed to search for original drugs and to develop non-proprietary medicines in the field of the central and vegetative nervous systems, blood circulation, inflammatory processes, microbial infections, carcinostatic drugs, etc. In natural substances, the greatest attention was paid to ergot alkaloids, but the extent of research also included the constituents of the poppy, periwinkle, and other plants. An important part of the programme was also the breeding and cultivation of selected medicinal plants. The results of research were continuously published in both inland and foreign scholarly journals and at conferences and congresses. Every year, usually more than 100 papers were published and 40-50 for patents applications were submitted. The activity of the Institute resulted in the production of 30 original substances which were introduced into therapeutic practice. Twenty of them are still commonly prescribed. Some of these original substances got into foreign markets, particularly Prothiaden and Trimepranol represented important exports. In addition, 83 non-proprietary drugs were introduced into the inland market.

An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

PubMed

Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

2015-04-01

This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D₃/D₂/D₁ dopamine receptor agonist in the treatment of PD and RLS.

PS2-5: Prevalence of Migraine in a Diverse Community – Electronic Methods for Migraine Ascertainment in a Large Integrated Health Plan

PubMed Central

Pressman, Alice; Jacobson, Alice; Avins, Andy

2013-01-01

Background/Aims Migraine, a common neurological disorder, is among the top 20 causes of disability worldwide. One-year prevalence of migraine in the US is estimated to range from 8–15%, with women affected at approximately three times the rate of men. Current methods for migraine ascertainment from headache clinics and surveys are costly, affected by clinic-ascertainment bias, and do not work in situations where patient contact is not feasible. With the growing use of electronic medical records (EMR), new methods must be developed for identifying and tracking migraine prevalence over time. We sought to develop an EMR algorithm, to identify migraine, and to characterize its prevalence in Kaiser Permanente Northern California (KPNC). Methods From EMRs of all KPNC members, we collected all outpatient migraine diagnoses (ICD9 code 346.xx) and migraine-specific prescriptions (ergots, triptans, and acetaminophen with caffeine) for 2006–2010. We chart-reviewed a random sample to develop an electronic Migraine Probability Algorithm (score 0–100). We tested the algorithm in a second independent chart review. Using membership data, we calculated prevalences by age, race, and gender. Results We identified 313,174 KPNC members with evidence of migraine - 233,620 women and 79,554 men. The 5-year period-prevalence of migraine among KPNC adults was 17.1% for women and 5.9% for men. Among children, rates did not differ by gender (<2%) until the age of 10, when prevalences were higher - 5.8% for girls and 3.5% for boys. For women, prevalence peaked at ages 25–29. In contrast, males experienced flat prevalence with age (range 5%–6%). Overall, Whites had higher prevalence than Asians, but Blacks did not differ appreciably. Conclusions We used EMR data to capture migraine diagnoses and show prevalence patterns similar to those reported in the literature. Prevalence of diagnosed migraine in KPNC was 2.5–3 times higher in women than men; migraine peaked with age in women, but remained flat for men; and prevalence of migraine among Asian adults was roughly 2/3 that of Whites. These methods for ascertainment of migraine are inexpensive and easy to implement and have applications and implications that extend well to other institutions and debilitating pain conditions.

Effects of fescue type and sampling date on the ruminal disappearance kinetics of autumn-stockpiled tall fescue.

PubMed

Flores, R; Coblentz, W K; Ogden, R K; Coffey, K P; Looper, M L; West, C P; Rosenkrans, C F

2007-06-01

Two tall fescue (Festuca arundinacea Schreb.) forages, one an experimental host plant/endophyte association containing a novel endophyte (HM4) that produces low or nil concentrations of ergot alkaloids, and the other a typical association of Kentucky 31 tall fescue and the wild-type endophyte (Neotyphodium coenophialum; E+), were autumn-stockpiled following late-summer clipping and fertilization with 56 kg/ha of N to assess the nutritive value and ruminal disappearance kinetics of autumn-stockpiled tall fescue forages. Beginning on December 4, 2003, sixteen 361 +/- 56.4-kg replacement dairy heifers were stratified by weight and breeding and assigned to one of four 1.6-ha pastures (2 each of E+ and HM4) that were strip-grazed throughout the winter. Pastures were sampled before grazing was initiated (December 4), each time heifers were allowed access to a fresh strip (December 26, January 15, and February 4), and when the study was terminated (February 26). For fiber components, there were no interactions between fescue type and sampling date for either pregrazed or postgrazed forages. Over sampling dates, neutral detergent fiber (NDF; 56.5 to 67.8%), acid detergent fiber (27.7 to 34.9%), hemicellulose (28.8 to 34.0%), cellulose (25.0 to 28.1%), and lignin (3.61 to 10.05%) varied with sampling date, but patterns were almost exclusively curvilinear with time. Ruminal disappearance rate of dry matter (DM) was not affected by any treatment factor (overall mean for both pregrazed and postgrazed forages = 0.050 h(- 1)); similar responses were observed for NDF disappearance (overall mean = 0.048 h(- 1)). Interactions of fescue type and sampling date were observed for both pregrazed and postgrazed forages with respect to effective ruminal disappearance of DM; however, estimates were relatively high for all forages (overall mean = 64.0%). Effective disappearance of NDF was relatively extensive for all forages (overall mean = 55.4% of NDF). Based on the results of this trial, the endophyte status of stockpiled tall fescue forages had little practical effect on forage nutritive value and kinetics of ruminal DM or NDF disappearance. Overall, autumn-stockpiled tall fescue forages would appear to be a legitimate and lower cost alternative to harvested forages, and appear to possess suitable nutritional characteristics for developing dairy heifers in the Ozark Highlands.

Medication overuse headache: withdrawal and prophylactic therapeutic regimen.

PubMed

Trucco, Marco; Meineri, Piero; Ruiz, Luigi; Gionco, Maurizio

2010-06-01

Medication overuse headache (MOH) is a secondary headache, whose diagnostic criteria were settled by the Second Edition of the International Classification of Headache Disorders and its subsequent revisions. Its diagnosis and treatment represent a growing problem worldwide and a challenge for headache specialists. The aim of this study was to evaluate the efficacy of a therapeutic regimen for withdrawal of the overused drug and prophylaxis of headache in a population of patients suffering from MOH in 8 hospitals of Piemonte - Liguria - Valle d'Aosta. Seventy patients, 58 females (82.9%) and 12 males (17.1%), mean age at observation 51.04 +/- 12.59 years, affected by MOH following International Headache Society diagnostic revised criteria were treated as inpatients (n = 40) or in Day Hospital (n = 30). Headache Index (HI) and Daily Drug Intake (DDI) were used for evaluating the severity of headache and medication overuse. The patients were treated by abrupt discontinuation of the overused drug and by a therapeutic protocol including i.v. hydration, dexhamethasone, metoclopramide, and benzodiazepines for 7-15 days. Prophylactic medication was started at the beginning of therapeutic protocol. Patients underwent follow-up controls 1, 3, and 6 months after discharge. The initial diagnosis was MOH in all patients included in the study. The overused medications were simple analgesics in 18 cases (25.7%), combination analgesics in 26 cases (37.1%), triptans alone in 9 cases (12.9%), or in combination with analgesics in 13 cases (18.6%), and ergot derivatives (in combination) in 4 cases (5.7%). We collected data from 59 patients at first follow-up (1 month), 56 after 3 months, and 42 after 6 months. Mean HI was 0.92 at admission, 0.19 at discharge, 0.35 after 30 days, 0.39 after 3 months, and 0.42 after 6 months. Mean DDI was 2.72 at admission, 0.22 at discharge, 0.31 after 1 month, 0.38 after 3 months, and 0.47 after 6 months. These results proved to be highly statistically significant. The protocol was generally effective, safe, and well-tolerated. The results tend to remain stable with time, and seem to be encouraging about long-term use of this therapeutic protocol on a larger number of patients suffering from MOH.

Integrating bermudagrass into tall fescue-based pasture systems for stocker cattle.

PubMed

Kallenbach, R L; Crawford, R J; Massie, M D; Kerley, M S; Bailey, N J

2012-01-01

The daily BW gain of stocker steers grazing tall fescue [Lolium arundinaceum (Schreb.) S.J. Darbysh. = Schedonorus arundinaceus (Schreb.) Dumort.]-based pastures typically declines during summer. To avoid these declines, in part to mitigate the effects of tall fescue toxicosis, it is commonly advised to move cattle to warm-season forage during this period. A 3-yr (2006, 2007, and 2008) grazing study was conducted to evaluate the effect of replacing 25% of the area of a tall fescue/clover (81% endophyte-infected) pasture system with "Ozark" bermudagrass [Cynodon dactylon (L.) Pers.] overseeded with clover (Trifolium spp.) to provide summer grazing for stocker steers (TF+BERM). The TF+BERM treatment was compared with a grazing system in which tall fescue/clover (TF) pastures were the only type of forage available for grazing. Our objective was to determine if replacement of 25% of the land area in a fescue system with bermudagrass would increase annual beef production compared with a system based solely on tall fescue. The study was conducted at the Southwest Research and Education Center of the University of Missouri near Mt. Vernon. Each treatment was rotationally stocked with 5 steers (248 ± 19.3 kg) on 1.7 ha. Fertilizer applications were applied at rates recommended for each respective forage species. Total forage production, BW gain per hectare, and season-long ADG of steers was greater (P < 0.06) for TF+BERM than for TF in 2006, but none of these measures differed (P > 0.19) in 2007 or 2008. In vitro true digestibility of pastures was greater (P = 0.01) for TF (84.4%, SEM = 0.64%) compared with TF+BERM (80.6%, SEM = 0.79%), even in summer. The decreased in vitro true digestibility of the bermudagrass pastures likely negated any benefit that animals in TF+BERM had in avoiding the ergot-like alkaloids associated with endophyte-infected tall fescue. Renovating 25% of the pasture system to bermudagrass provided some benefit to the system in years when summertime precipitation was limited (2006) but provided no value in wetter years (2007 and 2008). Although renovating endophyte-infected tall fescue pastures to a warm-season forage is a widely used practice to mitigate tall fescue toxicosis, the benefits of this practice are limited if forage quality of the warm season component is poor.

LC-MS/MS multi-method for mycotoxins after single extraction, with validation data for peanut, pistachio, wheat, maize, cornflakes, raisins and figs.

PubMed

Spanjer, Martien C; Rensen, Peter M; Scholten, Jos M

2008-04-01

Mycotoxin analysis is usually carried out by high performance liquid chromatography after immunoaffinity column cleanup or in enzyme-linked immunosorbent assay tests. These methods normally involve determination of single compounds only. EU legislation already exists for the aflatoxins, ochratoxin A and patulin in food, and legislation will come into force for deoxynivalenol, zearalenone and the fumonisins in 2007. To enforce the various legal limits, it would be preferable to determine all mycotoxins by routine analysis in different types of matrices in one single extract. This would also be advantageous for HACCP control purposes. For this reason, a multi-method was developed with which 33 mycotoxins in various products could be analysed simultaneously. The mycotoxins were extracted with an acetonitrile/water mixture, diluted with water and then directly injected into a LC-MS/MS system. The mycotoxins were separated by reversed-phase HPLC and detected using an electrospray ionisation interface (ESI) and tandem MS, using MRM in the positive ion mode, to increase specificity for quality control. The following mycotoxins could be analysed in a single 30-min run: Aflatoxins B1, B2, G1 and G2, ochratoxin A, deoxynivalenol, zearalenone, T-2 toxin, HT-2 toxin, alpha-zearalenol, alpha-zearalanol, beta-zearalanol, sterigmatocystin, cyclopiazonic acid, penicillic acid, fumonisins B1, B2 and B3, diacetoxyscirpenol, 3- and 15-acetyl-deoxynivalenol, zearalanone, ergotamin, ergocornin, ergocristin, alpha-ergocryptin, citrinin, roquefortin C, fusarenone X, nivalenol, mycophenolic acid, alternariol and alternariol monomethyl ether. The limit of quantification for the aflatoxins and ochratoxin A was 1.0 microg kg(-1) and for deoxynivalenol 50 microg kg(-1). The quantification limits for the other mycotoxins were in the range 10-200 microg kg(-1). The matrix effect and validation data are presented for between 13 and 24 mycotoxins in peanuts, pistachios, wheat, maize, cornflakes, raisins and figs. The method has been compared with the official EU method for the determination of aflatoxins in food and relevant FAPAS rounds. The multi-mycotoxin method has been proven by the detection of more than one mycotoxin in maize, buckwheat, figs and nuts. The LC-MS/MS technique has also been applied to baby food, which is subject to lower limits for aflatoxin B1 and ochratoxin A, ergot alkaloids in naturally contaminated rye and freeze-dried silage samples.

Hair Transplantation in Migraine Headache Patients.

PubMed

Ors, Safvet

2017-09-01

Migraine headache is a primary neurologic disease affecting millions of people worldwide. As a consequence, quality of life is diminished, productivity suffers (through loss of work force), and treatment costs are substantial. The occurrence rate in the general population is quite high, with women accounting for 3 of every 4 cases. Between January 2011 and May 2012, a total of 221 patients received hair transplants. Another 590 patients underwent hair transplantation between June 2012 and December 2016. Initially (first interval), patients were not questioned on migraine headaches in preoperative visits, but questioning was regularly done thereafter. Overall, 150 patients given transplants in the first period were surveyed by phone regarding preoperative migraine headaches. Aside from the 1 incidental discovery, no other instances of migraine emerged. Headache origins were occipital-frontal in 2 patients, occipital-temporal in 2 patients, and occipital-temporal-frontal in the 2 others. Donor/receiver areas in hair transplantation and migraine trigger zones shared locations. Headache frequencies ranged from 4 to 8 days per month (average, 6 days), and pain scores were 5-8 (10 being highest). Duration of pain was 3-5 hours (average, 4 hours). All six patients had used various medications, such as triptans, ergot, and nonsteroidal anti-inflammatory drugs, before hair transplantation. The 1 female patient was a 32-year-old seeking treatment for alopecia, with a 6-year history of migraine headaches. The male patients presenting with androgenetic alopecia (grade 4-5 by Norwood classification) had 6- to 20-year migrainous histories. After hair transplantation, each migraine sufferer was checked once in the first month and then once every 3 months. Those who could not appear in person after the first year were evaluated by phone every 3 months. Migraine headaches had ceased in all 6 patients, none of whom used medical treatments for migraines thereafter. The postoperative improvement each patient experienced was dramatic ( P < 0.001). Overall, the mean intensity of headaches declined from 6.6 ± 1.47 to 0, on an analog scale of 1-10 ( P < 0.001); and mean headache frequency was reduced from 5.83 ± 1.03/month to 0/month ( P < 0.001). Likewise, the migraine pain index fell from a mean of 149.33 ± 19.21/month to mean of 0/month ( P < 0.001). This report details 6 patients who experienced abatement of migraine headache symptoms following hair transplantation. The positive effects of hair transplantation on migraine headache and potential mechanisms of action are also discussed.

Édouard Manet's Tabes Dorsalis: From Painful Ataxia to Phantom Limb.

PubMed

Bogousslavsky, Julien; Tatu, Laurent

2016-01-01

Édouard Manet (1832-1883) is considered the 'father' of Impressionism and even of XXth century modern art. Manet's genius involved getting away from the classical narrative or historical topics and replacing them by the banality of daily life. Technically, he erased volumes into flat two-dimensional coloured planes, and distorted conventional perspective with often gross brushstrokes intentionally giving an 'unfinished' aspect to the work. It is little known that Manet had a very painful second part of his life, due to excruciating limb and chest pains, which developed in parallel with proprioceptive ataxia and gait imbalance. Manet always remained discreet about his private life, and we mainly know that his future wife was his family piano teacher, with whom he had a liaison already at age 17. Later, the great but platonic passion of his life was the painter Berthe Morisot (1841-1895), who got married to Manet's brother Eugène. In fact, we do not know whether he had any mistress at all, although he had several elegant 'flirts' in the mundane and artistic milieu. Thus, while Manet's progressive painful ataxia from age 40 yields little doubt on its tabetic origin, how he contracted syphilis at least 15-20 years before will probably remain a mystery. It is fascinating that Manet's daily struggle against pain and poor coordination may have led his art to become one of the most significant of modern times, opening the way to XXth century avant-gardes, along with another victim of syphilis, Paul Gauguin (1848-1903). Manet never showed any sign of General Paresis, and like his contemporary the writer Alphonse Daudet, his clinical picture remained dominated by paroxysmal pain and walking impairment. Difficult hand coordination made him quit watercolor painting, and during the last 2 years of his life, he had to focus on small format oil works, whose subject was nearly limited to modest bunches of fresh flowers, now often considered to be his maturity masterpieces. Having become bedridden, he had to be amputated of one leg, which was developing gangrene probably associated with ergot overuse. While he died shortly thereafter, we have some witness anecdotes suggesting that he experienced a phantom limb: when Claude Monet (1840-1926) visited him and sat down on his bed, Manet violently shouted at him that he was just sitting on his (absent) leg, which provoked terrible pains. With its facts and mysteries, the subtle interaction between Manet's illness and his work output remains one of the most intriguing stories in neurology of art. © 2016 S. Karger AG, Basel.

Pharmacokinetics and effect of food after oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with Parkinson's disease.

PubMed

Hattori, N; Hasegawa, K; Sakamoto, T

2012-10-01

Ropinirole hydrochloride, a dopamine receptor agonist with a non-ergot alkaloid structure, is highly selective for the dopamine D(2) /D(3) receptors. This study was conducted to evaluate the steady-state pharmacokinetics, safety and efficacy after repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with Parkinson's disease (PD). This was a multicenter, open-label, uncontrolled study. The total duration of participation in the study ranged from 56 to 63 weeks. In the study, the plasma concentrations of ropinirole, its major metabolite SK&F104557 (N-depropyl ropinirole) and another metabolite SK&F89124 (ropinirole hydroxylated at the seventh position of the indole ring) were assessed. Safety based on adverse events, haematology, biochemistry, urinalysis and electrocardiography (ECG) (standard 12-lead ECG) were evaluated, and vital signs (blood pressure/pulse rate) were measured. Efficacy based on the Japanese version of Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (motor) and II [activities of daily living (ADL)] as well as tolerability was evaluated. After repeated oral administration of prolonged-release tablets of ropinirole hydrochloride in Japanese patients with PD, ropinirole, SK&F104557 and low levels of SK&F89124 were detected in plasma. The trough concentrations of ropinirole and the two metabolites increased in proportion to the dose when ropinirole hydrochloride prolonged-release tablets were administered at doses ranging from 2 to 16 mg/day. The plasma exposure to ropinirole and its two metabolites after intake of normal diet was comparable to that in the fasting state. The most common adverse events (10% or more) were somnolence, nausea, constipation, hallucination and nasopharyngitis. Most adverse events were mild or moderate in severity, and with no death. During the treatment period, serious adverse events were reported in five patients. Efficacy analysis (LOCF) at the final endpoint up to week 16 demonstrated a mean (SD) change from baseline in the Japanese UPDRS III (motor) and II (ADL) scores of -11·3 (8·21) and -3·9 (3·22), respectively, and thereafter remained at similar levels until week 52. After administration of prolonged-release tablets of ropinirole hydrochloride in the absence of L-dopa preparations in Japanese patients with PD, the plasma pharmacokinetics of ropinirole and its metabolites was linear and not affected by food. Compared with the immediate-release (IR) tablet, the prolonged-release tablet can be administered to Japanese patients with PD at a reduced daily dose frequency and adjusted to the maintenance dose after fewer dose changes with a smaller diurnal variation in the plasma ropinirole concentration. © 2012 Blackwell Publishing Ltd.

Alterations in serotonin receptor-induced contractility of bovine lateral saphenous vein in cattle grazing endophyte-infected tall fescue.

PubMed

Klotz, J L; Brown, K R; Xue, Y; Matthews, J C; Boling, J A; Burris, W R; Bush, L P; Strickland, J R

2012-02-01

As part of a 2-yr study documenting the physiologic impact of grazing endophyte-infected tall fescue on growing cattle, 2 experiments were conducted to characterize and evaluate effects of grazing 2 levels of toxic endophyte-infected tall fescue pastures on vascular contractility and serotonin receptors. Experiment 1 examined vasoconstrictive activities of 5-hydroxytryptamine (5HT), α-methylserotonin (ME5HT; a 5HT(2) receptor agonist), d-lysergic acid (LSA), and ergovaline (ERV) on lateral saphenous veins collected from steers immediately removed from a high-endophyte-infected tall fescue pasture (HE) or a low-endophyte-infected mixed-grass (LE) pasture. Using the same pastures, Exp. 2 evaluated effects of grazing 2 levels of toxic endophyte-infected tall fescue on vasoconstrictive activities of (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), BW 723C86 (BW7), CGS-12066A (CGS), and 5-carboxamidotryptamine hemiethanolate maleate (5CT), agonists for 5HT(2A),( 2B), 5HT(1B), and 5HT(7) receptors, respectively. One-half of the steers in Exp. 2 were slaughtered immediately after removal from pasture, and the other one-half were fed finishing diets for >91 d before slaughter. For Exp. 1, maximal contractile intensities were greater (P < 0.05) for steers grazing LE pastures than HE pastures for 5HT (73.3 vs. 48.9 ± 2.1%), ME5HT (52.7 vs. 24.9 ± 1.5%), and ERV (65.7 vs. 49.1 ± 2.6%). Onset of contractile response did not differ for 5HT (P = 0.26) and ERV (P = 0.93), but onset of ME5HT contraction was not initiated (P < 0.05) in HE steers until 10(-4) compared with 10(-5) M in LE-grazing steers. For Exp. 2, maximal contractile intensities achieved with DOI were 35% less (P < 0.05), whereas those achieved with 5CT were 37% greater (P < 0.05), in steers grazing HE pastures. Contractile response to CGS did not differ between pasture groups, and there was an absence of contractile response to BW7 in both groups. There were no differences between endophyte content in contractile responses after animals were finished for >91 d. Experiment 1 demonstrated that grazing of HE pastures for 89 to 105 d induces functional alterations in blood vessels, as evidenced by reduced contractile capacity and altered serotonergic receptor activity. Experiment 2 demonstrated that grazing HE pastures alters vascular responses, which may be mediated through altered serotonin receptor activities, and these alterations may be ameliorated by the removal of ergot alkaloid exposure as demonstrated by the absence of differences in finished steers.

Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.

PubMed

Baron, Eric P; Lucas, Philippe; Eades, Joshua; Hogue, Olivia

2018-05-24

Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine. Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 "Yes" responses, 20% (n = 102) giving 2 "Yes" responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with "OG Shark" the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2-59.5%), most commonly opiates/opioids (40.5-72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%). Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with "OG Shark", a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes β-caryophyllene and β-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.

Interaction between a tannin-containing legume and endophyte-infected tall fescue seed on lambs' feeding behavior and physiology.

PubMed

Villalba, J J; Spackman, C; Goff, B M; Klotz, J L; Griggs, T; MacAdam, J W

2016-02-01

It was hypothesized that a tannin-rich legume such as sainfoin attenuates the negative postingestive effects of ergot alkaloids in tall fescue. Thirty-two 4-mo-old lambs were individually penned and randomly assigned to a 2 × 2 factorial arrangement with 2 legume species, sainfoin (SAN; 2.9% condensed tannins) or cicer milkvetch (CIC; without tannins) and a mixed ration containing tall fescue seed (50:30:20 seed:beet pulp:alfalfa) with 2 levels of endophyte infection (endophyte-infected tall fescue seed [E+; 3,150 ug/L ergovaline] or endophyte-free tall fescue seed [E-]). For a 10-d baseline period, half of the lambs were fed SAN and half were fed CIC and all lambs had ad libitum amounts of E-. In an ensuing 10-d experimental period, the protocol was the same except half of the lambs fed SAN or CIC received E+ instead of E-. Subsequently, all lambs could choose between their respective legume and seed-containing ration and between E+ and E-. Finally, an in vitro radial diffusion assay was conducted to determine whether tannins isolated from SAN would bind to alkaloids isolated from E+. All groups consumed similar amounts of E- during baseline period ( > 0.10), but lambs ate more E- than E+ during the experimental period ( < 0.05) and lambs offered SAN ate more E+ than lambs offered CIC ( < 0.05). Groups fed E- during the baseline and experimental periods had similar rectal temperatures ( > 0.10), but lambs fed E+ had lower rectal temperatures per gram of feed ingested when supplemented with SAN than with CIC ( < 0.05). Lambs fed E+ had greater concentrations of hemoglobin and more red blood cells than lambs fed E- ( < 0.05), but plasmatic concentrations of cortisol and prolactin did not differ among treatments ( > 0.10). All lambs preferred their treatment ration over their treatment legume, but lambs in the SAN and E+ treatment ate more legume + ration than lambs in the CIC and E+ (CIC-E+; < 0.05) treatment. All lambs preferred E- over E+, but lambs in the CIC-E+ treatment ate the least amount of E+ ( < 0.05). Binding of isolated SAN tannins to protein was reduced by the E+ isolate ( < 0.05), suggesting a tannin-alkaloid complexation but only from tannins extracted from SAN fed early in the experimental period. In summary, SAN supplementation increased intake of and preference for E+ and reduced rectal temperatures relative to CIC supplementation. Our results suggest that these effects were mediated by the condensed tannins in SAN through alkaloid inactivation, an interaction that declined with plant maturity.

Nicergoline in senile dementia of Alzheimer type and multi-infarct dementia: a double-blind, placebo-controlled, clinical and EEG/ERP mapping study.

PubMed

Saletu, B; Paulus, E; Linzmayer, L; Anderer, P; Semlitsch, H V; Grünberger, J; Wicke, L; Neuhold, A; Podreka, I

1995-02-01

In a double-blind, placebo-controlled study on the therapeutic efficacy and central effects of nicergoline, an ergot alkaloid with metabolic, antithrombotic and vasoactive action, 112 patients with mild to moderate dementia, diagnosed according to DSM III-R criteria (MMS 13-25), living in pensioners' homes, were included. Fifty-six were subdiagnosed as senile dementia of the Alzheimer type (SDAT), 56 as multiinfarct dementia (MID), based on computed tomography and Hachinski scores (< or = 49 SDAT, > or = 7 MID). They received, after 2 weeks' run-in period (placebo), randomized for 8 weeks either 2 x 30 mg nicergoline (NIC) or 2 x 1 placebo (PLAC) orally. The four subgroups (SDAT/NIC. SDAT/PLAC, MID/NIC, MID/PLAC; 4 x 28 patients) were comparable in regard to age and sex. Only four, four, four and two patients of the respective groups did not finish the study for minor reasons. Confirmatory statistical analysis demonstrated in the target variable-the Clinical Global Impression (CGI)-a significant superiority of Global Impression (CGI)-a significant superiority of NIC over PLAC in both the SDAT and MID groups. Global improvement (CGI item 2) was seen in both nicergoline subgroups (3 and 3), while no changes occurred under placebo (4 and 4, respectively). The responder versus non-responder ratio was in the SDAT/NIC group 16/8, versus 8/16 in the SDAT/PLAC group (chi 2 = 4.1, P = 0.04); in the MID/NIC group 17/7, versus 7/19 in the MID/PLAC group (chi 2 = 7.96, P < 0.005). Furthermore, there was a significant improvement of the Mini-Mental State and the SCAG score in both the MID and SDAT group after 8 weeks of nicergoline, which was significantly superior to the minimal improvement or no change in placebo-treated SDAT and MID patients. EEG mapping demonstrated in NIC-treated SDAT and MID patients a significant decrease in delta and theta, increase in alpha 2 and beta activity and an acceleration of the centroid of the total power spectrum as compared with pretreatment, while opposite changes occurred in PLAC-treated SDAT and MID patients. The differences between PLAC and NIC reached the level of statistical significance. Event-related potential (ERP) recordings demonstrated a significantly shortened P300 latency under NIC treatment in both SDAT and MID patients, while there was a trend towards lengthening under PLAC. Thus, nicergoline improved vigilance and information processing at the neurophysiological level, which leads at the behavioural level to clinical improvement both in degenerative and vascular dementia.

From bench to bedside: An overview of rotigotine for the treatment of restless legs syndrome.

PubMed

Bogan, Richard K

2014-03-01

Restless legs syndrome (RLS) is a common chronic neurologic disorder. Symptoms are most prevalent during the evening and at night, although daytime symptoms may emerge as the disease progresses. Dopamine agonists are currently considered first-line therapy for moderate to severe idiopathic RLS. Most dopamine agonists have short half-lives and are administered in the evening, shortly before the onset of RLS symptoms. Rotigotine is a non-ergot dopamine receptor agonist that has been specifically developed as a transdermal patch to provide continuous drug delivery over a 24-hour period. This review details the development of rotigotine, from the preclinical studies that established its pharmacokinetic profile to large-scale clinical trials in patients with RLS. Placebo-controlled trials that demonstrated the efficacy and tolerability of rotigotine are discussed, in addition to open-label studies that investigated long-term therapy. Studies were identified by a PubMed search using the key word rotigotine in conjunction with restless legs syndrome and by reviewing reference lists of retrieved publications. All clinical trials of rotigotine in RLS published before September 2013 were included. Preclinical studies have established activity of rotigotine as a dopamine receptor agonist, and pharmacokinetic data have shown that transdermal delivery maintains stable plasma levels over 24 hours. Rotigotine has demonstrated efficacy in improving moderate to severe RLS symptoms in randomized, placebo-controlled trials, based on scores on the International RLS Study Group rating scale, the RLS-6 scale, and the Clinical Global Impression-Severity subscale. Results of an open-label extension study suggest that efficacy may be maintained for up to 5 years. A polysomnographic study demonstrated an improvement in periodic limb movement index with rotigotine, and subjective assessments have suggested beneficial effects in terms of amelioration of sleep disturbances. Premature discontinuations from rotigotine treatment have ranged from 8% to 38% in studies of 6 weeks to 12 months in duration; 57% of patients discontinued prematurely during a 5-year study. In each trial, adverse events were typical of dopaminergic stimulation and use of a transdermal patch. The most common adverse events were application-site reactions, with a reported prevalence ranging from 17% (1-month sleep laboratory trial) to 58% (5-year open-label extension study). Clinically significant augmentation was recorded in 39 of 295 patients (13%) receiving rotigotine during the 5-year study, of whom 15 (5%) were receiving a dose within the US Food and Drug Administration-approved range of 1 to 3 mg/24 h. Findings from clinical studies have suggested that rotigotine is efficacious in improving RLS symptoms and is generally well-tolerated. The risk of developing clinically significant augmentation appears to be low. As such, rotigotine represents an important addition for RLS treatment. Copyright © 2014 The Authors. Published by EM Inc USA.. All rights reserved.

Cardiovascular Events, Conditions, and Procedures Among People With Episodic Migraine in the US Population: Results from the American Migraine Prevalence and Prevention (AMPP) Study.

PubMed

Buse, Dawn C; Reed, Michael L; Fanning, Kristina M; Kurth, Tobias; Lipton, Richard B

2017-01-01

Though migraine, particularly migraine with aura, is a cardiovascular (CV) risk factor, the scope and distribution of cardiovascular disease in representative samples of people with migraine are not known. This is important because many widely used acute migraine treatments, including triptans, ergot alkaloids, and nonsteroidal anti-inflammatory drugs, carry precautions, warnings, or contraindications for use in persons with CV disease. To assess the scope and distribution of cardiovascular events, conditions, and procedures in persons with episodic migraine in a representative sample of the US population, using data from the American Migraine Prevalence and Prevention (AMPP) Study. Eligible subjects completed the 2009 AMPP survey, met ICHD-3beta criteria for migraine, and had a headache frequency of less than 15 days per month (episodic migraine). A survey on cardiovascular events (ie, myocardial infarction), conditions (ie, angina), and procedures (ie, carotid endarterectomy) was adopted from the Women's Health Study and the Physician's Health Studies. Cardiovascular events and conditions were defined by participant reports of having both experienced and received a physician diagnosis for a particular event or condition. The distribution of CV events, conditions, and procedures was summarized for the entire migraine sample and in groups defined by gender and age (22-39, 40-59, and ≥60). To assess the numbers of persons with episodic migraine in the US, we applied age and gender stratified estimates of migraine prevalence to the 2015 Census data. To estimate the number of cardiovascular events, conditions, and procedures in the US migraine population, we applied age and gender stratified event rates to the number of persons with episodic migraine in each stratum. The 2009 AMPP Study survey was returned by 11,792 study participants out of 16,983 (64.9% response rate), including 6723 individuals who met study criteria for episodic migraine (5227 women and 1496 men). Among 22-39 year olds with episodic migraine, 3.4% reported having received a physician diagnosis of CV events or conditions and 1.1% reported undergoing CV related procedures. Among 40-59 year olds, 10.2% reported having received a physician diagnosis of CV events or conditions and 3.5% reported CV related procedures. For those age 60 or older, 22.3% reported CV events or conditions and 8.8% reported CV procedures. Prevalence of events, conditions, and procedures was higher in men than women and also in older age groups. However, the absolute number of CV events, procedures, and conditions was greater for women than men due to the higher population prevalence of episodic migraine in women. We projected that 2.0 million women and 665,000 men in the US had episodic migraine and a history of one or more CV event, condition, or procedure. By age group, it is estimated that 579,000 among those aged 22-39, 1.37 million of those aged 40-59, and 696,000 of those 60 and older with episodic migraine have ever had at least one CV event, procedure, or condition. Based on these analyses, we estimate that there are roughly 2.6 million people with episodic migraine aged 22 and older in the US with one or more prior CV event, condition, or procedure. For this group, cardiovascular contraindications to many migraine-specific acute migraine therapies may make treatment challenging. © 2016 American Headache Society.

Active versus expectant management for women in the third stage of labour

PubMed Central

Begley, Cecily M; Gyte, Gillian ML; Devane, Declan; McGuire, William; Weeks, Andrew

2014-01-01

Background Active management of the third stage of labour involves giving a prophylactic uterotonic, early cord clamping and controlled cord traction to deliver the placenta. With expectant management, signs of placental separation are awaited and the placenta is delivered spontaneously. Active management was introduced to try to reduce haemorrhage, a major contributor to maternal mortality in low-income countries. Objectives To compare the effectiveness of active versus expectant management of the third stage of labour. Search methods We searched the Cochrane Pregnancy and Childbirth Group Trials Register (15 February 2011). Selection criteria Randomised and quasi-randomised controlled trials comparing active versus expectant management of the third stage of labour. Data collection and analysis Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Main results We included seven studies (involving 8247 women), all undertaken in hospitals, six in high-income countries and one in a low-income country. Four studies compared active versus expectant management, and three compared active versus a mixture of managements. We used random-effects in the analyses because of clinical heterogeneity. There was an absence of high quality evidence for our primary outcomes. The evidence suggested that for women at mixed levels of risk of bleeding, active management showed a reduction in the average risk of maternal primary haemorrhage at time of birth (more than 1000 mL) (average risk ratio (RR) 0.34, 95% confidence interval (CI) 0.14 to 0.87, three studies, 4636 women) and of maternal haemoglobin (Hb) less than 9 g/dL following birth (average RR 0.50, 95% CI 0.30 to 0.83, two studies, 1572 women). We also found no difference in the incidence in admission of infants to neonatal units (average RR 0.81, 95% CI 0.60 to 1.11, two studies, 3207 women) nor in the incidence of infant jaundice requiring treatment (0.96, 95% CI 0.55 to 1.68, two studies, 3142 women). There were no data on our other primary outcomes of very severe postpartum haemorrhage (PPH) at the time of birth (more than 2500 mL), maternal mortality, or neonatal polycythaemia needing treatment. Active management also showed a significant decrease in primary blood loss greater than 500 mL, and mean maternal blood loss at birth, maternal blood transfusion and therapeutic uterotonics during the third stage or within the first 24 hours, or both and significant increases in maternal diastolic blood pressure, vomiting after birth, after-pains, use of analgesia from birth up to discharge from the labour ward and more women returning to hospital with bleeding (outcome not pre-specified). There was also a decrease in the baby’s birthweight with active management, reflecting the lower blood volume from interference with placental transfusion. In the subgroup of women at low risk of excessive bleeding, there were similar findings, except there was no significant difference identified between groups for severe haemorrhage or maternal Hb less than 9 g/dL (at 24 to 72 hours). Hypertension and interference with placental transfusion might be avoided by using modifications to the active management package, e.g. omitting ergot and deferring cord clamping, but we have no direct evidence of this here. Authors’ conclusions Although there is a lack of high quality evidence, active management of the third stage reduced the risk of haemorrhage greater than 1000 mL at the time of birth in a population of women at mixed risk of excessive bleeding, but adverse effects were identified. Women should be given information on the benefits and harms of both methods to support informed choice. Given the concerns about early cord clamping and the potential adverse effects of some uterotonics, it is critical now to look at the individual components of third-stage management. Data are also required from low-income countries. PMID:22071837

Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study.

PubMed

Oertel, Wolfgang; Trenkwalder, Claudia; Beneš, Heike; Ferini-Strambi, Luigi; Högl, Birgit; Poewe, Werner; Stiasny-Kolster, Karin; Fichtner, Andreas; Schollmayer, Erwin; Kohnen, Ralf; García-Borreguero, Diego

2011-08-01

Safety and efficacy of non-ergot dopamine agonists for the treatment of idiopathic restless legs syndrome have been shown in short-term trials. We did a prospective open-label extension of a 6-week, double-blind randomised trial to assess the safety, tolerability, and efficacy of rotigotine transdermal patch for up to 5 years in patients with restless legs syndrome. Patients (aged 18-75 years) with moderate-to-severe idiopathic restless legs syndrome were treated with once-daily rotigotine transdermal patch in 33 centres in Austria, Germany, and Spain between July 31, 2003, and April 15, 2009. The dose was titrated in weekly increments (up to 4 weeks) from 0·5 mg/24 h to a maximum of 4 mg/24 h, and was followed by up to 5 years of maintenance at the optimum dose. Primary safety outcomes included occurrence of adverse events and dropouts. Efficacy assessments were secondary and included the International Restless Legs Syndrome study group severity rating scale (IRLS). Augmentation of symptoms was assessed by means of standard diagnostic criteria and was confirmed by an international expert panel. All patients who received at least one dose of study drug were included in assessments. This study is registered with ClinicalTrials.gov, number NCT00498186. 295 patients entered the open-label study, of whom 126 (43%) completed 5 years of follow-up. 169 (57%) patients discontinued treatment, 89 (30%) because of adverse events and 31 (11%) because of lack of efficacy. 70 patients (24%) discontinued during year 1 of maintenance. The most common adverse events were application site reactions, which occurred in 37% (106/290) of patients in year 1, 17% (38/220) of patients in year 2, 14% (27/191) of patients in year 3, and in less than 6% of patients during year 4 (8/159) and year 5 (8/147). 56 patients (19%) discontinued because of application site reactions. Mean rotigotine dose was 2·43 mg/24 h (SD 1·21) after initial titration and 3·09 mg/24 h (1·07) at the end of maintenance. Of 89 patients who discontinued because of adverse events, 28 (31%) were on 4 mg/24 h rotigotine. Mean IRLS score of patients entering the open-label study was 27·8 (SD 5·9) at baseline of the double-blind trial. In patients who completed the maintenance period, mean IRLS score was reduced from a baseline score of 27·7 (SD 6·0) by a mean of 18·7 points (SD 9·5) to a score of 9·0 (SD 9·2) at the end of maintenance. 39% (48/123) of patients who completed the trial were classified as symptom free according to the IRLS. Clinically significant augmentation was recorded in 39 patients (13%), of whom 15 (5%) were receiving a dose of rotigotine within the range approved by the European Medicines Agency (EMA; 1-3 mg/24 h) and 24 (8%) were receiving 4 mg/24 h rotigotine. Rotigotine transdermal patch is generally well tolerated after 1 year and provides sustained efficacy for patients with moderate-to-severe restless legs syndrome at a stable dose for up to 5 years. Thus, rotigotine transdermal patch is an appropriate long-term treatment option for moderate-to-severe restless legs syndrome, a disorder that often requires lifelong treatment. UCB BioSciences, on behalf of Schwarz Pharma, Ireland. Copyright © 2011 Elsevier Ltd. All rights reserved.

Quantum mechanics in complex systems

NASA Astrophysics Data System (ADS)

Hoehn, Ross Douglas

This document should be considered in its separation; there are three distinct topics contained within and three distinct chapters within the body of works. In a similar fashion, this abstract should be considered in three parts. Firstly, we explored the existence of multiply-charged atomic ions by having developed a new set of dimensional scaling equations as well as a series of relativistic augmentations to the standard dimensional scaling procedure and to the self-consistent field calculations. Secondly, we propose a novel method of predicting drug efficacy in hopes to facilitate the discovery of new small molecule therapeutics by modeling the agonist-protein system as being similar to the process of Inelastic Electron Tunneling Spectroscopy. Finally, we facilitate the instruction in basic quantum mechanical topics through the use of quantum games; this method of approach allows for the generation of exercises with the intent of conveying the fundamental concepts within a first year quantum mechanics classroom. Furthermore, no to be mentioned within the body of the text, yet presented in appendix form, certain works modeling the proliferation of cells types within the confines of man-made lattices for the purpose of facilitating artificial vascular transplants. In Chapter 2, we present a theoretical framework which describes multiply-charged atomic ions, their stability within super-intense laser fields, also lay corrections to the systems due to relativistic effects. Dimensional scaling calculations with relativistic corrections for systems: H, H-, H 2-, He, He-, He2-, He3- within super-intense laser fields were completed. Also completed were three-dimensional self consistent field calculations to verify the dimensionally scaled quantities. With the aforementioned methods the system's ability to stably bind 'additional' electrons through the development of multiple isolated regions of high potential energy leading to nodes of high electron density is shown. These nodes are spaced far enough from each other to minimized the electronic repulsion of the electrons, while still providing adequate enough attraction so as to bind the excess elections into orbitals. We have found that even with relativistic considerations these species are stably bound within the field. It was also found that performing the dimensional scaling calculations for systems within the confines of laser fields to be a much simpler and more cost-effective method than the supporting D=3 SCF method. The dimensional scaling method is general and can be extended to include relativistic corrections to describe the stability of simple molecular systems in super-intense laser fields. Chapter 3, we delineate the model, and aspects therein, of inelastic electron tunneling and map this model to the protein environment. G protein-coupled receptors (GPCRs) constitute a large family of receptors that sense molecules outside of a cell and activate signal transduction pathways inside the cell. Modeling how an agonist activates such a receptor is important for understanding a wide variety of physiological processes and it is of tremendous value for pharmacology and drug design. Inelastic electron tunneling spectroscopy (IETS) has been proposed as the mechanism by which olfactory GPCRs are activated by an encapsulated agonist. In this note we apply this notion to GPCRs within the mammalian nervous system using ab initio quantum chemical modeling. We found that non-endogenous agonists of the serotonin receptor share a singular IET spectral aspect both amongst each other and with the serotonin molecule: a peak that scales in intensity with the known agonist activities. We propose an experiential validation of this model by utilizing lysergic acid dimethylamide (DAM-57), an ergot derivative, and its isotopologues in which hydrogen atoms are replaced by deuterium. If validated our theory may provide new avenues for guided drug design and better in silico prediction of efficacies. Our final chapter, explores methods which may be explored to assist in the early instruction in quantum mechanics. The learning of quantum mechanics is contingent upon an understanding of the physical significance of the mathematics that one must perform. Concepts such as normalization, superposition, interference, probability amplitude and entanglement can prove challenging for the beginning student. This paper outlines several class exercises that use a non-classical version of tic-tac-toe to instruct several topics in an undergraduate quantum mechanics course. Quantum tic-tac-toe (QTTT) is a quantum analogue of classical tic-tac-toe (CTTT) benefiting from the use of superposition in movement, qualitative (and later quantitative) displays of entanglement and state collapse due to observation. QTTT can be used for the benefit of the students understanding in several other topics with the aid of proper discussion.

Miscellaneous treatments for antipsychotic-induced tardive dyskinesia.

PubMed

Soares-Weiser, Karla; Rathbone, John; Ogawa, Yusuke; Shinohara, Kiyomi; Bergman, Hanna

2018-03-19

Antipsychotic (neuroleptic) medication is used extensively to treat people with chronic mental illnesses. Its use, however, is associated with adverse effects, including movement disorders such as tardive dyskinesia (TD) - a problem often seen as repetitive involuntary movements around the mouth and face. This review, one in a series examining the treatment of TD, covers miscellaneous treatments not covered elsewhere. To determine whether drugs, hormone-, dietary-, or herb-supplements not covered in other Cochrane reviews on TD treatments, surgical interventions, electroconvulsive therapy, and mind-body therapies were effective and safe for people with antipsychotic-induced TD. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials including trial registers (16 July 2015 and 26 April 2017), inspected references of all identified studies for further trials and contacted authors of trials for additional information. We included reports if they were randomised controlled trials (RCTs) dealing with people with antipsychotic-induced TD and schizophrenia or other chronic mental illnesses who remained on their antipsychotic medication and had been randomly allocated to the interventions listed above versus placebo, no intervention, or any other intervention. We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CIs). We assumed that people who left early had no improvement. We assessed risk of bias and created 'Summary of findings' tables using GRADE. We included 31 RCTs of 24 interventions with 1278 participants; 22 of these trials were newly included in this 2017 update. Five trials are awaiting classification and seven trials are ongoing. All participants were adults with chronic psychiatric disorders, mostly schizophrenia, and antipsychotic-induced TD. Studies were primarily of short (three to six6 weeks) duration with small samples size (10 to 157 participants), and most (61%) were published more than 20 years ago. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment, generation of the sequence, and blinding.Nineteen of the 31 included studies reported on the primary outcome 'No clinically important improvement in TD symptoms'. Two studies found moderate-quality evidence of a benefit of the intervention compared with placebo: valbenazine (RR 0.63, 95% CI 0.46 to 0.86, 1 RCT, n = 92) and extract of Ginkgo biloba (RR 0.88, 95% CI 0.81 to 0.96, 1 RCT, n = 157), respectively. However, due to small sample sizes we cannot be certain of these effects.We consider the results for the remaining interventions to be inconclusive: Low- to very low-quality evidence of a benefit was found for buspirone (RR 0.53, 95% CI 0.33 to 0.84, 1 RCT, n = 42), dihydrogenated ergot alkaloids (RR 0.45, 95% CI 0.21 to 0.97, 1 RCT, n = 28), hypnosis or relaxation, (RR 0.45, 95% CI 0.21 to 0.94, 1 study, n = 15), pemoline (RR 0.48, 95% CI 0.29 to 0.77, 1 RCT, n = 46), promethazine (RR 0.24, 95% CI 0.11 to 0.55, 1 RCT, n = 34), insulin (RR 0.52, 95% CI 0.29 to 0.96, 1 RCT, n = 20), branched chain amino acids (RR 0.79, 95% CI 0.63 to 1.00, 1 RCT, n = 52), and isocarboxazid (RR 0.24, 95% CI 0.08 to 0.71, 1 RCT, n = 20). There was low- to very low-certainty evidence of no difference between intervention and placebo or no treatment for the following interventions: melatonin (RR 0.89, 95% CI 0.71 to 1.12, 2 RCTs, n = 32), lithium (RR 1.59, 95% CI 0.79 to 3.23, 1 RCT, n = 11), ritanserin (RR 1.00, 95% CI 0.70 to 1.43, 1 RCT, n = 10), selegiline (RR 1.37, 95% CI 0.96 to 1.94, 1 RCT, n = 33), oestrogen (RR 1.18, 95% CI 0.76 to 1.83, 1 RCT, n = 12), and gamma-linolenic acid (RR 1.00, 95% CI 0.69 to 1.45, 1 RCT, n = 16).None of the included studies reported on the other primary outcome, 'no clinically significant extrapyramidal adverse effects'. This review has found that the use of valbenazine or extract of Ginkgo biloba may be effective in relieving the symptoms of tardive dyskinesia. However, since only one RCT has investigated each one of these compounds, we are awaiting results from ongoing trials to confirm these results. Results for the remaining interventions covered in this review must be considered inconclusive and these compounds probably should only be used within the context of a well-designed evaluative study.

Efficacy of nicergoline in dementia and other age associated forms of cognitive impairment.

PubMed

Fioravanti, M; Flicker, L

2001-01-01

Nicergoline is an ergot derivative currently in use in over fifty countries for more than three decades, for the treatment of cognitive, affective, and behavioral disorders of older people. It was initially considered as a vasoactive drug and mainly prescribed for cerebrovascular disorders. Recent findings suggest other actions which has provided a rationale for the use of nicergoline for the treatment of various forms of dementia, including Alzheimer's Disease. To determine whether there is evidence of efficacy of nicergoline in the treatment of dementia and other age-associated forms of cognitive decline,and to assess the safety and tolerability of the drug. 1. Electronic databases search. The Cochrane Controlled Trials Register (which contains citations from the MEDLINE, EMBASE, Psych LIT, and hand searches of geriatric, dementia, psychogeriatric journals, and conference abstracts) was searched using the following terms: 'Nicergoline', 'Sermion'. 2. Reference search. The reference lists of all obtained studies was checked. 3. Pharmaceutical company Pharmacia & Upjohn, owners of the rights to produce and market nicergoline in various different countries, was asked to provide data and reports of clinical trials. In case of unavailability of numerical data in published studies, the authors of each paper, were asked for any published or unpublished data. - All unconfounded, double-blind, randomized, placebo-controlled, published and unpublished trials were sought. Non-randomized trials were excluded. Open trials were considered for inclusion if patients were randomized to the different treatment groups. - All patients diagnosed as having dementia or other cognitive disorder defined according to classification criteria accepted at the time of each study. - Nicergoline given at any dose for more than one day with placebo control. Type of outcome variables: 1. Cognitive function (as measured by psychometric tests). 2. Clinical impression (such as CIBIC or other clinical global measures of change). 3. Functional performance including dependency. 4. Behavioural disturbance. 5. Safety and acceptability as measured by the incidence of adverse effects (including side-effects) leading to withdrawal. 6. Death 7. Effect on carer 8. Use of services 9. Quality of life. A comprehensive search of the international literature and the producing company archives has been performed to identify all possible sources of data for this review. Only those trials fulfilling the inclusion criteria of belonging to either category A or B of allocation concealment, as defined by the Cochrane Organisation, were examined for data extraction by one reviewer. If there was doubt then the other reviewer was consulted. Data availability restricted analyses to 'completers' analyses for the outcome measures. Outcomes able to be assessed included: Behaviour, Cognition, Clinical Judgment, Tolerability, EEG. The Sandoz Clinical Assessment Geriatric Scale (SCAG) was the outcome used in the largest number of patients (814 patients). The results from these studies were homogeneous in nature despite including patients observed for periods of time ranging from 2 months to 12 months. There was a difference in favour of the active treatment in reducing the behavioural symptoms described by this scale, -5.18 points [-8.03, -2.33]. This scale has a maximum of 133 points. The therapeutic effects of nicergoline seem to be evident by 2 months of treatment and maintained for 6 months. In general other behavioural outcome measures which include the GRS, the IADL, and the MACC and were episodically used in few studies, failed to demonstrate statistically significant results although there was a trend favouring treatment. Cognitive assessment has been performed in a moderate number of patients with the MMSE (261 patients) and the ADAS-Cog (342 patients). No significant heterogeneity was found for these trials, despite the trials extending over periods of treatment of 3 to 12 months. There was a difference between treatment and control groups on the MMSE favouring nicergoline treatment. At 12 months the effect size was 2.86 [0.98, 4.74] The effect size for the ADAS-Cog, used exclusively with Alzheimer's disease patients, did not reveal a significant benefit. At 12 months the trend favoured treatment (-1.64 [-4.62, 1.34]). The other results from various cognitive measures tended to favour nicergoline but this was based on a small number of cases. The clinical impression of change obtained from a total of 921 patients was homogeneous across the studies, despite reflecting changes over periods of time ranging from 2 to 12 months. The Peto odd ratio for improvement in the subjects treated with nicergoline over these varying time periods was 3.33 [2.50, 4.43]. Tolerability assessed in 1427 patients was homogeneous across all studies and demonstrated a mildly increased risk of adverse events on treatment, OR 1.51[1.10, 2.07]. The clinical studies on nicergoline were carried out with diverse criteria and modalities of evaluation. Despite this, the 14 studies included in this review, have presented generally consistent results. Results of this meta-analysis provide some evidence of positive effects of nicergoline on cognition and behaviour and these effects are supported by an effect on clinical global impression. There was some evidence that there were increased risk of adverse effects associated with nicergoline. These results were obtained on older patients with mild to moderate cognitive and behavioural impairment of various clinical origins, including chronic cerebrovascular disorders and Alzheimer's dementia. The few studies specifically performed on patients with Alzheimer's disease were performed with too few people to give a definitive answer to the questions concerning the use of nicergoline for this form of dementia. This drug has not been evaluated using current diagnostic categories such as MCI or in association with therapeutic agents of different nature such as cholinesterase or antioxidant drugs.