The value of simplified models of radionuclide transport for the safety assessment of nuclear waste repositories: A benchmark study.

In order to assess sites for a deep geological repository for storing high-level nuclear waste safely in Germany, various numerical models and tools will be in use. For their interaction within one workflow, their reproducibility, and reliability version-controlled open-source solutions and careful documentation of model setups, results and verifications are of special value. However, spatially fully resolved models including all relevant physical and chemical processes are neither computationally feasible for large domains nor is the data typically available to parameterize such models. Thus, simplified models are crucial for the pre-assessment of possible sites to narrow down the list of suitable candidates for which detailed site investigations and fully resolved models will be done at a later stage. Still, the accuracy of these simplified models is of importance as the pre-assessment of suitable sites will be based on them. In this study, we compare the modelling capabilities of TransPyREnd, a one-dimensional transport code based on finite differences, specifically developed for the fast estimation of radionuclide transport by the German federal company for radioactive waste disposal (BGE), with OpenGeoSys, which is a modelling platform based on finite elements in up to three spatial dimensions. Both codes are used in the site selection procedure for the German nuclear waste repository. The comparison of the model results of TransPyREnd and OpenGeoSys is augmented by comparisons with an analytical solution for a homogeneous material. For the purpose of numerical benchmarking, we consider a geological profile located in southern Germany as an example where the hypothetical repository is located in a clay-stone formation. TransPyREnd and OpenGeoSys yield overall similar results. However, both codes use different discretizations which impact is the highest for strongly sorbing compounds, while the difference gets negligible for less sorbing and more diffusive compounds as higher diffusion tends to blur the initial conditions. Overall, the OpenGeoSys model is more exact whereas the TransPyREnd model has considerable faster run times. We found in our example, that significant substance amounts are only leaving the host rock formation, if apparent diffusion is high, for which case both codes give similar results, while relative differences are considerable for strongly sorbing compounds. However, in the latter case no significant substance amount of radionuclides leaves the host-rock formation, thus deeming the differences in the model results minor for the overall safety assessments of sites.

Detection of bornavirus-reactive antibodies and BoDV-1 RNA only in encephalitis patients from virus endemic areas: a comparative serological and molecular sensitivity, specificity, predictive value, and disease duration correlation study.

PURPOSE: Human Borna disease virus (BoDV-1) encephalitis is an emerging disease in Germany. This study investigates the spectrum of human BoDV-1 infection, characterizes anti-BoDV-1-antibodies and kinetics, and compares laboratory test performances. METHODS: Three hundred four encephalitis cases, 308 nation-wide neuropsychiatric conditions, 127 well-defined psychiatric cases from Borna disease-endemic areas, and 20 persons with contact to BoDV-1 encephalitis patients or animals were tested for BoDV-1 infections by serology and PCR. RESULTS: BoDV-1 infections were only found in encephalitis patients with residence in, or recent travel to, virus-endemic areas. Antibodies were detected as early as 12 days after symptom onset. Serum antibody levels correlated with disease duration. Serology was ordered after 50% of the disease duration had elapsed, reflecting low awareness. BoDV-1-antibodies were of IgG1 subclass, and the epitope on BoDV-1 antigens was determined. Specificity of the indirect immunofluorescence antibody test (IFAT) and lineblot (LB) from serum and cerebrospinal fluid (CSF), as well as PCR testing from CSF, was 100%. Sensitivity, depending on first or all samples, reached 75-86% in serum and 92-94% in CSF for the IFAT, and 33-57% in serum and 18-24% in CSF for the LB. Sensitivity for PCR in CSF was 25-67%. Positive predictive values were 100% each, while negative predictive values were 99% (IFAT), 91-97% (LB), and 90% (PCR). CONCLUSIONS: There is no hint that BoDV-1 causes other diseases than encephalitis in humans. Awareness has to be increased in virus-endemic areas. Tests are robust but lack sensitivity. Detection of IgG1 against specific peptides may facilitate diagnosis. Screening of healthy individuals is likely not beneficial.

Do German economic research institutes publish efficient growth and inflation forecasts? A Bayesian analysis.

We use Bayesian additive regression trees to reexamine the efficiency of growth and inflation forecasts for Germany. To this end, we use forecasts of four leading German economic research institutes for the sample period from 1970 to 2016. We reject the strong form of forecast efficiency and find evidence against the weak form of forecast efficiency for longer-term growth and longer-term inflation forecasts. We cannot reject weak efficiency of short-term growth and inflation forecasts and of forecasts disaggregated at the institute level. We find that Bayesian additive regression trees perform significantly better than a standard linear efficiency-regression model in terms of forecast accuracy.

Evaluation of the multiplex real-time PCR assays RealStar malaria S&T PCR kit 1.0 and FTD malaria differentiation for the differentiation of Plasmodium species in clinical samples.

BACKGROUND: Two commercial PCR assays were assessed in a retrospective study to determine their reliability as tools for the differentiation of Plasmodium species in human blood. METHODS: A total of 1022 blood samples from 817 patients with suspected or confirmed malaria submitted to the German National Reference Centre for Tropical Pathogens were subjected to malaria microscopy using thick and thin blood films as well as to a genus-specific malaria real-time PCR. Parasite-positive samples were analysed by RealStar Malaria S&T PCR Kit 1.0 (altona Diagnostics) and FTD Malaria Differentiation (Fast Track Diagnostics) multiplex real-time PCR assays targeting species-specific Plasmodium DNA. RESULTS: Out of the 1022 blood samples, 247 (24.2%) tested positive for Plasmodium spp. The two multiplex assays showed rather similar performance characteristics and provided concordant species information in 98.9% of samples positive by malaria microscopy and in 95.1% (RealStar) and 96.8% (FTD) of samples positive by genus-specific PCR. Compared to FTD, RealStar revealed slightly reduced sensitivity for submicroscopic, low-level P. falciparum infections, while FTD was unable to detect P. knowlesi. CONCLUSIONS: The two commercial malaria PCR assays assessed are suitable for discriminating Plasmodium species in clinical samples, and can provide additional information in cases of microscopically uncertain findings.

BadGluc, a ß-glucosidase from Bjerkandera adusta with anthocyanase properties.

A glycosidase of the basidiomycete Bjerkandera adusta (BadGluc) was found in screenings to possess a strong decolorizing ability towards malvidin-3-galactoside, an anthocyanin abundant in various berry fruits. The BadGluc was purified from the culture supernatant via FPLC, and the corresponding gene was identified which showed low similarity to other characterized glucosidases. Scanning the primary sequence with PROSITE no active site motif was detected. Eventually, a specific 18 aa consensus pattern was identified manually. The active site motif possessed an undescribed sequence which was only found in a few hypothetical proteins. The corresponding gene was cloned and expressed in Pichia pastoris GS115 yielding activities up to 100 U/L using 4-nitrophenyl-ß-d-glucopyranoside (pNPG) as substrate. The enzyme possessed a good temperature (70% after 1 h at 50°C) and pH stability (70% between pH 2 and 7.5), and preferably catalysed the hydrolysis of delphinidin-3-glucoside and cyanidin-3-glucoside, regardless of the position of the terminal Hexa-His tag. This novel glucosidase worked in aqueous solution as well as on pre-stained fabrics making it the first known candidate anthocyanase for applications in the detergent and food industries.

Cell-free one-pot conversion of (+)-valencene to (+)-nootkatone by a unique dye-decolorizing peroxidase combined with a laccase from Funalia trogii.

A combined system of a unique dye-decolorizing peroxidase (Ftr-DyP) and a laccase obtained from the basidiomycete Funalia trogii converted the precursor (+)-valencene completely to the high-value grapefruit flavour constituent (+)-nootkatone, reaching a concentration maximum of 1100 mg/L. In the presence of 1 mM Mn2+ and 2.5 mM p-coumaric acid, (+)-nootkatone was the predominating volatile product, and only traces of substrate and the nootkatols were detectable after 24 h. Hence, the two-enzyme-system reproduced the oxidizing activity observed before for the crude culture supernatant. The newly discovered Ftr-DyP was purified, sequenced and further characterized as a thermostable, non-glycosylated protein with a pH-optimum in the acidic range and a calculated mass of 52.3 kDa. Besides the typical activity of DyPs towards anthraquinone dyes, Ftr-DyP also oxidized Mn2+ and showed activity in the absence of hydrogen peroxide. Neither the DyP from Mycetinis scorodonius nor the manganese peroxidase from Nematoloma frowardii were able to replace Ftr-DyP in this reaction. A hypothetical reaction mechanism is presented.

Variants of PpuLcc, a multi-dye decolorizing laccase from Pleurotus pulmonarius expressed in Pichia pastoris.

A laccase of the basidiomycete Pleurotus pulmonarius (PpuLcc) possessed strong decolorizing abilities towards artificial and natural dyes. The PpuLcc was purified from the culture supernatant via FPLC, and the corresponding gene cloned and expressed in Pichia pastoris GS115. To examine the impact of the C-terminal tail region and the signal peptide on the recombinant expression of PpuLcc, a non-modified version or different truncations (-2, -5, -13 AA) of the target protein were combined with different secretion signals. Heterologous expression of codon optimized constructs resulted in extracellular activities of the PpuLcc variants of up to 7000 U L-1 (substrate ABTS) which was six times higher than non-codon optimized constructs. In contrast to previous works, altering the C-terminal end of the protein did not influence kinetic parameters or the rate of expression. The His-Tag purified enzymes showed high temperature optima (50-70 °C) and thermo stability. All of the recombinant variants degraded triarylmethane and azo dyes. Rapid bleaching of ß-carotene (E 160a) and the polyene acid norbixin (E 160b) using a laccase was found for the first time. Thus, the enzyme may be useful in decolorizing unwanted polyene pigments, for example from the processing of cheese, bakery, desserts, ice cream or coloured casings.

Comparative Cold Shock Expression and Characterization of Fungal Dye-Decolorizing Peroxidases.

Dye-decolorizing peroxidases (DyPs) from Auricularia auricula-judae, Bjerkandera adusta, Pleurotus ostreatus and Marasmius scorodonius (Basidiomycota) were expressed in Escherichia coli using the cold shock-inducible expression system pCOLD I DNA. Functional expression was achieved without the addition of hemin or the co-expression of any chaperones. The presence or absence of the native signal sequence had a strong impact on the success of the expression, but the effect was not consistent for the different DyPs. While BaDyP and AajDyP were stable at 50 °C, the more thermolabile MsP2 and PoDyp, upon catalytic intervention, lend themselves to more rapid thermal inactivation. The bleaching of norbixin (E 160b) using MsP2 was most efficient at pH 4.0, while BaDyP and AajDypP worked best in the weakly acidic to neutral range, indicating a choice of DyPs for a broad field of applications in different food matrices.

Serotonin dependent masking of hippocampal sharp wave ripples.

Sharp wave ripples (SPW-Rs) are thought to play an important role in memory consolidation. By rapid replay of previously stored information during slow wave sleep and consummatory behavior, they result from the formation of neural ensembles during a learning period. Serotonin (5-HT), suggested to be able to modify SPW-Rs, can affect many neurons simultaneously by volume transmission and alter network functions in an orchestrated fashion. In acute slices from dorsal hippocampus, SPW-Rs can be induced by repeated high frequency stimulation that induces long-lasting LTP. We used this model to study SPW-R appearance and modulation by 5-HT. Although stimulation in presence of 5-HT permitted LTP induction, SPW-Rs were "masked"--but appeared after 5-HT wash-out. This SPW-R masking was dose dependent with 100 nM 5-HT being sufficient--if the 5-HT re-uptake inhibitor citalopram was present. Fenfluramine, a serotonin releaser, could also mask SPW-Rs. Masking was due to 5-HT1A and 5-HT2A/C receptor activation. Neither membrane potential nor membrane conductance changes in pyramidal cells caused SPW-R blockade since both remained unaffected by combining 5-HT and citalopram. Moreover, 10 and 30 µM 5-HT mediated SPW-R masking preceded neuronal hyperpolarization and involved reduced presynaptic transmitter release. 5-HT, as well as a 5-HT1A agonist, augmented paired pulse facilitation and affected the coefficient of variance. Spontaneous SPW-Rs in mice hippocampal slices were also masked by 5-HT and fenfluramine. While neuronal ensembles can acquire long lasting LTP during higher 5-HT levels, lower 5-HT levels enable neural ensembles to replay previously stored information and thereby permit memory consolidation memory.

Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3.

We investigated the effects of hypoxia on sharp wave-ripple complex (SPW-R) activity and recurrent epileptiform discharges in rat hippocampal slices, and the mechanisms underlying block of this activity. Oxygen levels were measured using Clark-style oxygen sensor microelectrodes. In contrast to recurrent epileptiform discharges, oxygen consumption was negligible during SPW-R activity. These network activities were reversibly blocked when oxygen levels were reduced to 20% or less for 3 min. The prolongation of hypoxic periods to 6 min caused reversible block of SPW-Rs during 20% oxygen and irreversible block when 0% oxygen (anoxia) was applied. In contrast, recurrent epileptiform discharges were more resistant to prolonged anoxia and almost fully recovered after 6 min of anoxia. SPW-Rs were unaffected by the application of 1-butyl-3-(4-methylphenylsulfonyl) urea, a blocker of KATP channels, but they were blocked by activation of adenosine A1 receptors. In support of a modulatory function of adenosine, the amplitude and incidence of SPW-Rs were increased during application of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Interestingly, hypoxia decreased the frequency of miniature excitatory post-synaptic currents in CA3 pyramidal cells, an effect that was converted into increased frequency by the adenosine A1 agonist DPCPX. In addition, DPCPX also delayed the onset of hypoxia-mediated block of SPW-Rs. Our data suggest that early adenosine release during hypoxia induces a decrease in pre-synaptic glutamate release and that both might contribute to transient block of SPW-Rs during hypoxia/anoxia in area CA3.

Histaminergic modulation of acetylcholine-induced γ oscillations in rat hippocampus.

We investigated the interaction between ambient histamine and acetylcholine by studying γ oscillations in rat hippocampus, induced by bath application of acetylcholine (10 µM combined with 2 µM physostigmine). The power of γ was significantly increased by the H1 antagonist, fexofenadine, and H2 receptor agonist, dimaprit, and reduced by the H2 receptor antagonist, cimetidine. These effects suggest an interference with ambient histamine. Depletion of histamine from their fibers by hypoxia and blockade of histamine uptake resulted in loss of the fexofenadine-mediated and cimetidine-mediated effects on acetylcholine-induced γ. We conclude that acetylcholine can cause histamine release from histaminergic fibers and thereby can influence attentional states by augmenting γ. This effect is likely due to activation of H2 receptors by histamine and thereby might contribute to the previously described enhancement of working memory.

Partial disinhibition is required for transition of stimulus-induced sharp wave-ripple complexes into recurrent epileptiform discharges in rat hippocampal slices.

Sharp wave-ripple complexes (SPW-Rs) in the intact rodent hippocampus are characterized by slow field potential transients superimposed by close to 200-Hz ripple oscillations. Similar events have been recorded in hippocampal slices where SPW-Rs occur spontaneously or can be induced by repeated application of high-frequency stimulation, a standard protocol for induction of long-lasting long-term potentiation. Such stimulation is reminiscent of protocols used to induce kindling epilepsy and ripple oscillations may be predictive of the epileptogenic zone in temporal lobe epilepsy. In the present study, we investigated the relation between recurrent epileptiform discharges (REDs) and SPW-Rs by studying effects of partial removal of inhibition. In particular, we compared the effects of nicotine, low-dose bicuculline methiodide (BMI), and elevated extracellular potassium concentration ([K(+)](o)) on induced SPW-Rs. We show that nicotine dose-dependently transformed SPW-Rs into REDs. This transition was associated with reduced inhibitory conductance in CA3 pyramidal cells. Similar results were obtained from slices where the GABAergic conductance was reduced by application of low concentrations of BMI (1-2 µM). In contrast, sharp waves were diminished by phenobarbital. Elevating [K(+)](o) from 3 to 8.5 mM did not transform SPW-Rs into REDs but significantly increased their incidence and amplitude. Under these conditions, the equilibrium potential for inhibition was shifted in depolarizing direction, whereas inhibitory conductance was significantly increased. Interestingly, the propensity of elevated [K(+)](o) to induce seizure-like events was reduced in slices where SPW-Rs had been induced. In conclusion, recruitment of inhibitory cells during SPW-Rs may serve as a mechanism by which hyperexcitation and eventually seizure generation might be prevented.

Monoamines block kainate- and carbachol-induced gamma-oscillations but augment stimulus-induced gamma-oscillations in rat hippocampus in vitro.

Monoamines are implicated in a cognitive processes in a variety of brain regions, including the hippocampal formation, where storage and retrieval of information are facilitated by synchronous network activities. We have investigated the effects of norepinephrine, serotonin, and dopamine on carbachol-, kainate-, and stimulus-induced hippocampal gamma-oscillations employing combined extra- and intracellular recordings. Monoamines dose-dependently and reversibly suppressed kainate- and carbachol-induced gamma-oscillations while increasing the frequency. The effect of serotonin was mimicked by fenfluramine, which releases serotonin from presynaptic terminals. Forskolin also suppressed kainate- and carbachol-induced gamma-oscillations. This effect was mimicked by 8-Br-cAMP and isoproterenol, an agonist of noradrenergic beta-receptor suggesting that the monoamines-mediated suppression of these oscillations could involve intracellular cyclic adenosine 3',5'-cyclic monophosphate (AMP). By contrast, stimulus-induced gamma-oscillations were dose-dependently augmented in power and duration after monoamines application. Intracellular recordings from pyramidal cells revealed that monoamines prolonged the stimulus-induced depolarization and membrane potential oscillations. Stimulus-induced gamma-oscillations were also suppressed by isoproterenol, the D1 agonist SKF-38393 forskolin, and 8-Br-cAMP. This suggests that the augmentation of stimulus-induced gamma-oscillations by monoamines involves--at least in part-different classes of cells than in case of carbachol- and kainate-induced gamma-oscillations.

Acetylcholine-induced seizure-like activity and modified cholinergic gene expression in chronically epileptic rats.

The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10-100 microm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.

Effects of 4-aminopyridine on sharp wave-ripples in rat hippocampal slices.

Sharp wave-ripple complexes (SPW-Rs) are characterized by approximately 60 ms field potential transients superimposed by ripple oscillations of approximately 200 Hz. In chronic epileptic rodents and humans, faster ripples have been recorded showing frequencies of up to 500 Hz. In this study, we tested whether the blockade of K currents by 4-aminopyridine (4-AP) contribute to the generation of high-frequency ripples, as changes in K channel expression have been observed in chronic epileptic tissue. We showed that 4-AP significantly increased the amplitudes and incidence of induced SPW-Rs without significantly changing their ripple frequency. alpha-Dendrotoxin or BDS-I did not mimick these changes suggesting that 4-AP acts via Kv1.4 channels. Thus, the incidence of SPW-Rs, but not the ripple frequency is regulated by 4-AP-sensitive potassium currents.

Hypoxia suppresses kainate-induced gamma-oscillations in rat hippocampal slices.

Hypoxia or global ischemia causes rapid loss of consciousness and a sudden increase in spontaneous transmitter release suggesting that coordinated synaptic activity is impaired. Gamma oscillations (30-100 Hz) are thought to provide for binding of parallel processed information in the brain, contributing to cognition and formation of short-term memory. We hypothesized that gamma-oscillations are rapidly blocked by hypoxia and that prolonged hypoxia reduces the capability to generate such activity. In ventral hippocampal slices, kainate-induced gamma-oscillations reversibly declined 40 s after onset of 3 min hypoxia. Repetition of such hypoxic periods led to accumulative impairment of gamma-activities. By contrast, 6 min of hypoxia led to a transient anoxic depolarization after which gamma-oscillations remained almost completely blocked.

Cholinergic dysfunction in temporal lobe epilepsy.

The entorhinal cortex-hippocampus complex is believed to be the site of origin of seizure activity in the majority of patients with temporal lobe epilepsy (TLE). Both these regions are enriched with cholinergic innervation, which plays a key role in the normal control of neuronal excitability and in higher cognitive processes. In TLE, anatomical and functional changes occur in all cellular components of the local neural circuit. Thus, while it is not surprising that cholinergic functions are altered in the epileptic temporal lobe, the exact nature and role of these changes in the pathogenesis of the disease are not known. In this report, we summarize the scientific background and experimental data supporting a "cholinergic hypothesis of TLE." We conclude that while the exact role of cholinergic dysfunction in TLE is not known, there is a firm basis for suggesting that changes in the expression of key cholinergic proteins-and the associated cholinergic dysfunction-are key factors in the basic mechanisms underlying TLE.

6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active crohn disease: results from a randomized, controlled, open trial.

BACKGROUND: A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA. METHODS: After 2 weeks of standard therapy, patients (n = 71) were randomized into standard (n = 32) or adapted-dose (n = 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 x 10(8) erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary). RESULTS: After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery x h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery x h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 x 10(8) Ery were not associated with hepatotoxicity. CONCLUSION: Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery x h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks.

Hippocampal sharp wave-ripple complexes (SPW-Rs) occur during slow-wave sleep and behavioral immobility and are thought to represent stored information that is transferred to the neocortex during memory consolidation. Here we show that stimuli that induce long-term potentiation (LTP), a neurophysiological correlate of learning and memory, can lead to the generation of SPW-Rs in rat hippocampal slices. The induced SPW-Rs have properties that are identical to spontaneously generated SPW-Rs: they originate in CA3, propagate to CA1 and subiculum and require AMPA/kainate receptors. Their induction is dependent on NMDA receptors and involves changes in interactions between clusters of neurons in the CA3 network. Their expression is blocked by low-frequency stimulation but not by NMDA receptor antagonists. These data indicate that induction of LTP in the recurrent CA3 network may facilitate the generation of SPW-Rs.

Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study.

BACKGROUND: Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance. METHODS: We analyzed data from a 6-month prospective study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured. RESULTS: Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C > A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes . h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C > A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C > A mutant allele carrier status. CONCLUSIONS: Patients with ITPA 94C > A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.