The running down phenomenon in temporal lobe epilepsy.
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Cerebral Cortex↗
Biomedical subjects
T Rasmussen
Publications and source records attributed to T Rasmussen.
Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.
Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients.
Animals↗
Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.
Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.
Animals↗
Redox components and structure of the respiratory NADH:ubiquinone oxidoreductase (complex I).
The proton-pumping NADH:ubiquinone oxidoreductase is the first complex in the respiratory chains of many purple bacteria and of mitochondria of most eucaryotes. The bacterial complex consists of 14 different subunits. The mitochondrial complex contains at least 29 additional proteins that do not directly participate in electron transfer and proton translocation. We analysed electron micrographs of isolated and negatively stained complex I particles from Escherichia coli and Neurospora crassa and obtained three-dimensional models of both complexes at medium resolution. Both have the same L-shaped overall structure with a peripheral arm protruding into the aqueous phase and a membrane arm extending into the membrane. The two arms of the bacterial complex are only slightly shorter than those of the mitochondrial complex although the protein mass of the former is only half of that of the latter. The presence of a novel redox group in the membrane arm of the complex is discussed. This group has been detected in the N. crassa complex by means of UV-visible spectroscopy. After reduction with an excess of NADH and reoxidation by the lactate dehydrogenase reaction, a reduced-minus-oxidized difference spectrum was obtained that cannot be attributed to the known cofactors flavin mononucleotide (FMN) and the FeS clusters N1, N2, N3 and N4. Due to its positive midpoint potential the novel group is believed to transfer electrons from the FeS clusters to ubiquinone. Its role in proton translocation is discussed.
Computer Simulation↗
Search for novel redox groups in mitochondrial NADH:ubiquinone oxidoreductase (complex I) by diode array UV/VIS spectroscopy.
The proton-translocating NADH:ubiquinone oxidoreductase of mitochondria (complex I) is a large L-shaped multisubunit complex. The peripheral matrix arm contains one FMN and a number of iron-sulfur (FeS) clusters and is involved in NADH oxidation and electron transfer to the membrane intrinsic arm. There, following a yet unknown mechanism, the redox-driven proton translocation and the ubiquinone reduction take place. Redox groups that would be able to link electron transfer with proton translocation have not been found so far in the membrane arm. We searched for such groups in complex I isolated from Neurospora crassa. Under anaerobic conditions, the preparation was analyzed in different redox states by means of UV/VIS and EPR spectroscopy. Absorption bands in the UV/VIS redox difference spectra were found which cannot be attributed to the FMN or the EPR detectable FeS clusters. The existence of two novel groups is postulated and their possible locations in the electron pathway and their roles in proton translocation are discussed.
Electron Spin Resonance Spectroscopy↗
Identification and characterisation of malignant cells using RT-PCR on single flow-sorted cells.
In an attempt to optimise stem cell graft evaluation we have developed a method of quantifying the number of cells in a phenotypically defined population of cells, expressing a gene of interest by combining an RT-PCR method working on whole single cells with flow cytometry. The clinical potential is illustrated by two examples. First, the phenotypes of clonal cells in the bone marrow (BM) of a patient with multiple myeloma (MM), were determined by sorting cells phenotypically defined by their expression of surface antigens and then performing RT-PCR on the individual sorted cells using the rearranged immunoglobulin heavy chain (IgH) gene as clonal marker. All plasma cells with the phenotype CD38++/CD45RA- expressed the clonal marker, whereas it could not be detected in plasma cells with the phenotype CD38++/CD45RA+. A minor population of clonal cells with the CD38+/CD45RA- phenotype was found. Second, the number of committed (CD34+/CD38+) and non-committed (CD34+/CD38-) stem cells, expressing the chimeric fusion gene p210 BCR/ABL in the autograft from a patient with chronic myeloid leukemia (CML), was determined. The number of cells expressing BCR/ABL mRNA was nearly equal in the CD34+/CD38+ and CD34+/CD38- compartment (8.1 and 8.5%). The method presented can easily be applied to determine the phenotype of malignant cells, where a unique mRNA species exist. Furthermore, the method allows one to predict the outcome of antibody mediated purging experiment.
DNA Primers↗
Electrocorticography and outcome in frontal lobe epilepsy.
The prognostic significance of epileptiform activity (EA) recorded at electrocorticography (ECOG) was examined in a group of 60 consecutive non-tumoral patients with intractable frontal lobe epilepsy (FLE). Pre-excision EA was documented as absent, focal (one gyrus), regional (two gyri), lobar (3 gyri) or multilobar (frontal + temporal gyri). Post-excision EA was documented as absent, restricted to the resection border, or recorded distant to the resection border, and was quantitated by spike frequency. Pre-excision EA from < or = 2 gyri and absence of post-resection EA correlated with Class I or II (Engel classification) outcome while pre-excision EA from > or = 3 gyri and persistent post-resection EA, especially distant to the resection border, correlated with Class III or IV outcome (P < 0.001). A significant correlation between poorer outcomes and increased abundance of distant post-resection EA was observed (P < 0.001). EA restricted to the resection border was not significantly correlated with outcome. Presence of a circumscribed lesion correlated with Class I outcome (P < 0.01) and absence of pathological abnormality correlated with Class IV outcome (P < 0.05). Neither side nor extent of surgical excision correlated with outcome. EA recorded at ECOG is of prognostic significance in FLE. A lobar or multilobar distribution of pre-excision EA and persistent post-excision EA distant to the resection border, especially when abundant, are highly unfavorable prognostic indicators. In contrast, a restricted distribution of pre-excision EA and absence of post-resection EA both herald a favorable outcome.
Adolescent↗
Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice.
The nicotinic compounds (-)-cytisine, (-)-lobeline, (+/-)-epibatidine, (S)-3methyl-5-(1-methyl-2-pyrrolidinyl)isoaxzole (ABT-418), (-)-nicotine, and cocaine were compared in an acute self-administration model using drug-naive mice that could self-administer intravenous infusions contingent on nose poking (fixed ratio 1 with no time out). Although the nose pokes of yoked control mice were unaffected by unit dose, inverted U-shaped unit dose response curves were seen with cocaine (up to 0.26 mg/kg/infusion), nicotine (up to 0.175 mg/kg/infusion), cytisine (up to 0.125 mg/kg/infusion), and lobeline (up to 1.25 mg/kg/infusion) in mice receiving infusions contingent upon nose poke responses. Epibatidine (up to 1.25 microg/kg/infusion) and ABT-418 (up to 0.125 mg/kg/infusion) failed to exhibit inverted U-shaped unit dose response curves. The present studies demonstrate that cytisine and lobeline, but not ABT-418 or epibatidine, were self-administered by drug-naive mice in a manner similar to cocaine and nicotine. These findings are discussed in terms of potency and selectivity at the alpha4beta2 nicotinic acetylcholine receptor subunit combination.
Animals↗
CD34+ subset and tumor cell quantitation by flow cytometry--step toward quality assessment of autografts in B cell malignancies.
To day it is possible to predict the probability of fast engraftment based on a very simple flow cytometry standard analysis of CD34+ cells as documented by the 28 laboratories within the NSCL-G. However, the risk for delayed platelet engraftment still needs to be predicted in clinical practice for patients receiving less than 10 x 10(6) CD34+ cells/kg. Here we present data from our center supporting that identification by double staining of uncommitted (CD34+/CD38-) and lineage specific (CD34+/CD61+) progenitors may allow us to predict patients at high risk for prolonged platelet recovery. Following high dose therapy more than 30% of patients with haematological malignancies do suffer from disease recurrence within the first 3-6 months following high dose therapy. Today there are strong indications that such patients may have been transplanted with an autograft contaminated with a high number of potentially malignant B cells. Here we present a novel methodology for quantitation of blood circulating tumor cells by combining flow cytometry, cell sorting, limiting dilution and single cell RT-PCR. Such methodology has documented mobilization of clonal B cells following priming of the peripheral blood stem cell harvest and it can be used to identify minor populations and predict the efficacy of patient specific purging strategy. Consequently, quality assessment of autografts may include techniques which can predict fast three lineage engraftment as well as the risk for prolonged platelet recovery and can identify the group of patients/autografts with a strong contamination of potential tumor cells with a risk of early relapse. The future supportive cell therapy may depend upon improvements of such technologies and strategies including the selective administration of lineage specific growth factors e.g., trombopoietin as well as patient specific controlled purging strategies.
Antigens, CD19↗
Double pathology in Rasmussen's syndrome: a window on the etiology?
The syndrome of chronic encephalitis with epilepsy (Rasmussen's syndrome) typically occurs in children and is characterized by the development of intractable focal seizures, progressive hemiparesis and intellectual deterioration. The etiology is unknown, and the pathological abnormalities vary from those of active disease, with numerous microglial nodules, with or without neuronophagia, perivascular round cells and glial scarring, to those of remote disease, demonstrated by neuronal loss, gliosis and perivascular round cells but few microglial nodules. We describe five patients presenting with clinical features typical of Rasmussen's syndrome, in whom pathological examination showed a second, previously unsuspected pathology in addition to the changes of chronic encephalitis. Two of the patients had vascular abnormalities bearing some resemblance to cavernous angiomata, one had a tumor, one had tuberous sclerosis, and one the forme fruste of tuberous sclerosis. The coexistence of a second pathology in these patients may provide information about the underlying mechanism of this rare condition.
Adolescent↗
Surgical treatment of epilepsy in tuberous sclerosis: strategies and results in 18 patients.
BACKGROUND: Seizures in patients with tuberous sclerosis complex (TSC) are often intractable to antiepileptic medications and searching investigation may provide evidence that surgical treatment can be considered. OBJECTIVE: To review the results of investigation and surgical therapy, a treatment modality not generally considered in patients with medically refractory seizures and TSC. METHODS: We report 18 patients (9 male) with TSC who underwent surgical treatment of medically refractory epilepsy. Twelve patients had a well-localized epileptogenic lesion and were treated by lesionectomy or focal resection. Resections were: 7 frontal, 4 temporal, 1 frontotemporal, 1 occipital, and 1 frontoparietal. Four patients underwent more than one operation. Six patients had corpus callosotomy (CC). RESULTS: Follow-up ranged from 1 month to 47 years. Outcome of the patients treated by resection was excellent in 7 (5 were seizure-free and 2 had auras only), good in 1, fair in 3, and 1 was lost to follow-up. Best outcome was obtained in patients who had focal seizures and good imaging and EEG correlation, although they might have multiple seizure types, other imaging abnormalities, and multifocal or generalized EEG findings. When there was no such correlation, CC was found to be an option as five patients had at least some improvement and only one showed no change. CONCLUSION: Surgical treatment of patients with TSC and intractable epilepsy is most effective when a single tuber or epileptogenic area can be identified as the source of seizures and resected. This may be possible even when other tubers or diffuse EEG abnormalities are present. In patients with unlocalizable epileptic abnormalities, palliation may be obtained by CC.
Adolescent↗
Impaired learning correlates with size of excitotoxic hippocampal CA3 lesions in adult rats, but shows no amelioration by CA3 transplants.
Hippocampal CA3 pyramidal cells grafted as cell suspensions to excitotoxic hippocampal lesions in adult rats can exchange several types of short and long range nerve connections with the host brain. We now examined whether such grafts also had functional effects in terms of ameliorating lesion-induced learning and memory deficits. Adult, male rats with bilateral, one week old, ibotenic acid-lesions of the hippocampal CA3 region, were grafted with suspensions of fetal (E18-19) CA3 cells. Seven weeks later the animals were tested for spatial navigation in the Morris Watermaze, together with groups of lesion-only and sham-operated, control rats. The tests were performed over 5 days, with 4 trials per day. At the end of the trials, the size of the lesions and the size and structural incorporation of the transplants in the host brains were evaluated morphometrically for correlations with the behavioural data. We found significant differences in swim pathlength and latency to find the platform in the Morris Watermaze between the lesion-only group and the grafted group versus the sham operated group, but no significant difference between the lesion-only and the grafted group. There was a significant positive correlation between the size of the CA3 lesions and the paucity of performance of the rat in the Watermaze, just as spontaneous recovery accordingly had not occurred over the 8 weeks postlesion. We conclude that the behavioural improvement exerted by the CA3 cell suspension grafts, at a time point when graft-host connections have had time to establish, is at most incomplete by these transplants, pointing to the difficulties there may be in obtaining full functional integration.
Journal Article↗
ECoG findings in extratemporal epilepsy: the MNI experience.
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Academies and Institutes↗
Post-excision residual spiking after frontal lobe removal: outcome.
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Electroencephalography↗
[The human hematopoietic stem cell biology and clinical use].
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Hematopoietic Stem Cell Transplantation↗
Parameters influencing potency of Bacillus thuringiensis var. israelensis products.
Bioassays of products based on Bacillus thuringiensis var. israelensis have been carried out according to standard protocols. These analyses revealed that the slopes of the log-probit transformed concentration mortality curves of various products were different from that of the international standards (IPS82 for B. thuringiensis israelensis). For statistical reasons, this invalidates the tests. Products giving various slopes of the concentration mortality curves will obtain different potencies when estimated at a LC90 level than when estimated at LC50 level, as normally done. The LC90 level is probably more relevant for the field effect. Changing the median particle size of a product in a non destructive way results in change of slope and LC50 and thereby potency. Therefore, potency of a product as measured in these bioassays is not just a measure of the quantity of B. thuringiensis israelensis crystal protein present, but a function of product parameters like median particle size. Biochemical methods for quantification of toxin can therefore not relate simply to potency of the products obtained with this method. It is suggested that standard protocols for bioassay may be changed to assure equal particle size of products and samples to obtain parallel dose response.
Aedes↗
Chronic encephalitis and epilepsy in adults and adolescents: a variant of Rasmussen's syndrome?
Chronic encephalitis and epilepsy (Rasmussen's encephalitis) is a rare progressive disorder of uncertain etiology that usually occurs in children, producing focal epilepsy, hemiparesis, and intellectual deterioration. We identified 13 patients in whom seizures developed in adolescence or adulthood with a pathologic picture of chronic encephalitis. The clinical characteristics were more variable than those occurring in children, with the patients falling into three groups: five patients developed seizures in adulthood, but otherwise showed many resemblances to the childhood form; five developed seizures in adolescence, with similar presentation but rather more benign course than in the younger patients; and three presented with clinical features initially suggestive of a tumor. Occipital onset to the seizures appeared to be more common than in the childhood form, and bilateral disease also occurred.
Adolescent↗
Ascaris suum: a revision of its early migratory path and implications for human ascariasis.
During the course of carrying out studies on the role of intestinal immunity in blocking the migration of larval Ascaris suum in the pig, it was discovered that the prevailing understanding of larval penetration sites was at variance with our observations. Therefore, a detailed investigation of the migration of A. suum 1.2 larvae through the intestine was initiated. The results demonstrate that the 1.2 larvae invade almost exclusively the wall of the pig cecum and colon and not the small intestine as is generally believed. The larvae were recovered from the mucosa of the cecum and colon as early as 3 hr postinoculation (PI) with infective eggs and were recovered from the liver by 6 hr PI. The maximal recovery of larvae (total larvae and larval/g of mucosa) from the intestinal mucosa occurred between 6 and 12 hr PI; by 24 hr PI, virtually all of the larvae had disappeared from the mucosa. These observations correct a common misunderstanding of this aspect of the life cycle of A. suum in the pig, and they raise 2 issues related to the biology and pathogenesis of Ascaris in humans. What is the actual migratory and development behavior of Ascaris lumbricoides and A. suum in humans and the potential risk for liver lesions? Most authors, in describing the life cycle of A. lumbricoides, either ignore or discount a possible obligatory liver stage of development, and, consequently, the potential for lesion formation similar to that which occurs in pigs infected with A. suum. This issue takes on added importance with the growing evidence that A. suum is an important zoonoses.
Animals↗