Polymorphic variants of the multidrug resistance gene Mdr1a and response to antiepileptic drug treatment in the kindling model of epilepsy

Allelic variants of the human P-glycoprotein encoding gene MDR1 (ABCB1) are discussed to be associated with different clinical conditions including pharmacoresistance of epilepsy. However, conflicting data have been reported with regard to the functional relevance of MDR1 allelic variants for the response to antiepileptic drugs. To our knowledge, it is not known whether functionally relevant genetic polymorphisms also occur in the two genes (Mdr1a/Abcb1a, Mdr1b/Abcb1b) coding for P-glycoprotein in the brain of rodents. Therefore, we have started to search for polymorphisms in the Mdr1a gene, which governs the expression of P-glycoprotein in brain capillary endothelial cells in rats. In the kindling model of temporal lobe epilepsy, subgroups of phenytoin-sensitive and phenytoin-resistant rats were selected in repeated drug trials. Sequencing of the Mdr1a gene coding sequence in the subgroups revealed no general differences between drug-resistant and drug-sensitive rats of the Wistar outbred strain. A comparison between different inbred and outbred rat strains also gave no evidence for polymorphisms in the Mdr1a coding sequence. However, in exon-flanking intron sequences, four genetic variants were identified by comparison between these rats strains. In conclusion, the finding that Wistar rats vary in their response to phenytoin, while having the same genetic background, argues against a major impact of Mdr1a genetics on pharmacosensitivity to antiepileptic drugs in the amygdala kindling model.

Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3-septum pathway

We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

The cranial bone window model: studying angiogenesis of primary and secondary bone tumors by intravital microscopy

The successful treatment of primary and secondary bone tumors in a huge number of cases remains one of the major unsolved challenges in modern medicine. Malignant primary bone tumor growth predominantly occurs in younger people, whereas older people predominantly suffer from secondary bone tumors since up to 85% of the most frequently occurring malignant solid tumors, such as lung, mammary, and prostate carcinomas, metastasize into the bone. It is well known that a tumor's course may be altered by its surrounding tissue. For this reason, reported here is the protocol for the surgical preparation of a cranial bone window in mice as well as the method to implant tumors in this bone window for further investigations of angiogenesis and other microcirculatory parameters in orthotopically growing primary or secondary bone tumors using intravital microscopy. Intravital microscopy represents an internationally accepted and sophisticated experimental method to study angiogenesis, microcirculation, and many other parameters in a wide variety of neoplastic and nonneoplastic tissues. Since most physiologic and pathophysiologic processes are active and dynamic events, one of the major strengths of chronic animal models using intravital microscopy is the possibility of monitoring the regions of interest in vivo continuously up to several weeks with high spatial and temporal resolution. In addition, after the termination of experiments, tissue samples can be excised easily and further examined by various in vitro methods such as histology, immunohistochemistry, and molecular biology.

The influence of a continuous rate infusion of dexmedetomidine on the nociceptive withdrawal reflex and temporal summation during isoflurane anaesthesia in dogs

Objective To examine the influence of a low dose dexmedetomidine infusion on the nociceptive withdrawal reflex and temporal summation in dogs during isoflurane anaesthesia. Study design Prospective experimental blinded cross-over study. Animals Eight healthy mixed breed dogs, body weight Mean +/- SD 26.5 +/- 8.4 kg and age 25 +/- 16 months. Methods Anaesthesia was induced with propofol and maintained with isoflurane (Fe'ISO 1.3%) delivered in oxygen and air. After stabilization, baseline recordings (time 0) were obtained, then a dexmedetomidine bolus (1 mug kg(-1) IV) followed by a continuous rate infusion (1 mug kg(-1) hour(-1) ) or saline placebo were administered. At times 10, 30 and 60 minutes after the initial bolus, electrical stimulations of increasing intensity were applied over the lateral plantar digital nerve, and administered both as single and as repeated stimuli. The resulting reflex responses were recorded using electromyography. Data were analysed using a multivariable linear regression model and a Kruskal Wallis test for single stimulation data, and repeated measures anova and paired t-test for repeated stimulation data. Results The AUC for the stimulus-response curves after single stimulation were similar for both treatments at time 0. At times 10, 30 and 60 the AUCs for the stimulus-response curves were significantly lower with dexmedetomidine treatment than with placebo. Temporal summation was evident in both treatments at times 0, 10, 30 and 60 starting from a stimulation intensity of 10 mA. The magnitude of temporal summation was smaller in dexmedetomidine than in placebo treated dogs at time 10, 30 and 60, but not at time 0. Conclusions During isoflurane anaesthesia, low dose dexmedetomidine suppresses the nociceptive reflex responses after single and repeated electrical stimulation. Clinical relevance This experimental study confirms previous reports on its peri-operative efficacy under clinical conditions, and further indicates that dexmedetomidine might reduce the risk of post-operative chronic pain development.

Reanalysis-driven climate simulation over CORDEX North America domain using the Canadian Regional Climate Model, version 5: model performance evaluation

The performance of reanalysis-driven Canadian Regional Climate Model, version 5 (CRCM5) in reproducing the present climate over the North American COordinated Regional climate Downscaling EXperiment domain for the 1989–2008 period has been assessed in comparison with several observation-based datasets. The model reproduces satisfactorily the near-surface temperature and precipitation characteristics over most part of North America. Coastal and mountainous zones remain problematic: a cold bias (2–6 °C) prevails over Rocky Mountains in summertime and all year-round over Mexico; winter precipitation in mountainous coastal regions is overestimated. The precipitation patterns related to the North American Monsoon are well reproduced, except on its northern limit. The spatial and temporal structure of the Great Plains Low-Level Jet is well reproduced by the model; however, the night-time precipitation maximum in the jet area is underestimated. The performance of CRCM5 was assessed against earlier CRCM versions and other RCMs. CRCM5 is shown to have been substantially improved compared to CRCM3 and CRCM4 in terms of seasonal mean statistics, and to be comparable to other modern RCMs.

A Finite Model Property for Gödel Modal Logics

A new semantics with the finite model property is provided and used to establish decidability for Gödel modal logics based on (crisp or fuzzy) Kripke frames combined locally with Gödel logic. A similar methodology is also used to establish decidability, and indeed co-NP-completeness for a Gödel S5 logic that coincides with the one-variable fragment of first-order Gödel logic.

THE SOLAR WIND AS A POSSIBLE SOURCE OF FAST TEMPORAL VARIATIONS OF THE HELIOSPHERIC RIBBON

We present a possible source of pickup ions (PUIs) the ribbon observed by the Interstellar Boundary EXplorer (IBEX). We suggest that a gyrating solar wind and PUIs in the ramp and in the near downstream region of the termination shock (TS) could provide a significant source of energetic neutral atoms (ENAs) in the ribbon. A fraction of the solar wind and PUIs are reflected and energized during the first contact with the TS. Some of the solar wind may be reflected propagating toward the Sun but most of the solar wind ions form a gyrating beam-like distribution that persists until it is fully thermalized further downstream. Depending on the strength of the shock, these gyrating distributions can exist for many gyration periods until they are scattered/thermalized due to wave-particle interactions at the TS and downstream in the heliosheath. During this time, ENAs can be produced by charge exchange of interstellar neutral atoms with the gyrating ions. In order to determine the flux of energetic ions, we estimate the solar wind flux at the TS using pressure estimates inferred from in situ measurements. Assuming an average path length in the radial direction of the order of a few AU before the distribution of gyrating ions is thermalized, one can explain a significant fraction of the intensity of ENAs in the ribbon observed by IBEX. With a localized source and such a short integration path, this model would also allow fast time variations of the ENA flux.

Lateral sediment sources and knickzones as controls on spatio-temporal variations of sediment transport in an Alpine river

Modern mixed alluvial-bedrock channels in mountainous areas provide natural laboratories for understanding the time scales at which coarse-grained material has been entrained and transported from their sources to the adjacent sedimentary sink, where these deposits are preserved as conglomerates. This article assesses the shear stress conditions needed for the entrainment of the coarse-bed particles in the Glogn River that drains the 400 km2 Val Lumnezia basin, eastern Swiss Alps. In addition, quantitative data are presented on sediment transport patterns in this stream. The longitudinal stream profile of this river is characterized by three ca 500 m long knickzones where channel gradients range from 0·02 to 0·2 m m−1, and where the valley bottom confined into a <10 m wide gorge. Downstream of these knickzones, the stream is flat with gradients <0·01 m m−1 and widths ≥30 m. Measurements of the grain-size distribution along the trunk stream yield a mean D84 value of ca 270 mm, whereas the mean D50 is ca 100 mm. The consequences of the channel morphology and the grain-size distribution for the time scales of sediment transport were explored by using a one-dimensional step-backwater hydraulic model (Hydrologic Engineering Centre – River Analysis System). The results reveal that, along the entire trunk stream, a two to 10 year return period flood event is capable of mobilizing both the D50 and D84 fractions where the Shields stress exceeds the critical Shields stress for the initiation of particle motion. These return periods, however, varied substantially depending on the channel geometry and the pebble/boulder size distribution of the supplied material. Accordingly, the stream exhibits a highly dynamic boulder cover behaviour. It is likely that these time scales might also have been at work when coarse-grained conglomerates were constructed in the geological past.

Present state of global wetland extent and wetland methane modelling: methodology of a model inter-comparison project (WETCHIMP)

The Wetland and Wetland CH4 Intercomparison of Models Project (WETCHIMP) was created to evaluate our present ability to simulate large-scale wetland characteristics and corresponding methane (CH4) emissions. A multi-model comparison is essential to evaluate the key uncertainties in the mechanisms and parameters leading to methane emissions. Ten modelling groups joined WETCHIMP to run eight global and two regional models with a common experimental protocol using the same climate and atmospheric carbon dioxide (CO2) forcing datasets. We reported the main conclusions from the intercomparison effort in a companion paper (Melton et al., 2013). Here we provide technical details for the six experiments, which included an equilibrium, a transient, and an optimized run plus three sensitivity experiments (temperature, precipitation, and atmospheric CO2 concentration). The diversity of approaches used by the models is summarized through a series of conceptual figures, and is used to evaluate the wide range of wetland extent and CH4 fluxes predicted by the models in the equilibrium run. We discuss relationships among the various approaches and patterns in consistencies of these model predictions. Within this group of models, there are three broad classes of methods used to estimate wetland extent: prescribed based on wetland distribution maps, prognostic relationships between hydrological states based on satellite observations, and explicit hydrological mass balances. A larger variety of approaches was used to estimate the net CH4 fluxes from wetland systems. Even though modelling of wetland extent and CH4 emissions has progressed significantly over recent decades, large uncertainties still exist when estimating CH4 emissions: there is little consensus on model structure or complexity due to knowledge gaps, different aims of the models, and the range of temporal and spatial resolutions of the models.

Methane emissions from floodplains in the Amazon Basin: challenges in developing a process-based model for global applications

Tropical wetlands are estimated to represent about 50% of the natural wetland methane (CH4) emissions and explain a large fraction of the observed CH4 variability on timescales ranging from glacial–interglacial cycles to the currently observed year-to-year variability. Despite their importance, however, tropical wetlands are poorly represented in global models aiming to predict global CH4 emissions. This publication documents a first step in the development of a process-based model of CH4 emissions from tropical floodplains for global applications. For this purpose, the LPX-Bern Dynamic Global Vegetation Model (LPX hereafter) was slightly modified to represent floodplain hydrology, vegetation and associated CH4 emissions. The extent of tropical floodplains was prescribed using output from the spatially explicit hydrology model PCR-GLOBWB. We introduced new plant functional types (PFTs) that explicitly represent floodplain vegetation. The PFT parameterizations were evaluated against available remote-sensing data sets (GLC2000 land cover and MODIS Net Primary Productivity). Simulated CH4 flux densities were evaluated against field observations and regional flux inventories. Simulated CH4 emissions at Amazon Basin scale were compared to model simulations performed in the WETCHIMP intercomparison project. We found that LPX reproduces the average magnitude of observed net CH4 flux densities for the Amazon Basin. However, the model does not reproduce the variability between sites or between years within a site. Unfortunately, site information is too limited to attest or disprove some model features. At the Amazon Basin scale, our results underline the large uncertainty in the magnitude of wetland CH4 emissions. Sensitivity analyses gave insights into the main drivers of floodplain CH4 emission and their associated uncertainties. In particular, uncertainties in floodplain extent (i.e., difference between GLC2000 and PCR-GLOBWB output) modulate the simulated emissions by a factor of about 2. Our best estimates, using PCR-GLOBWB in combination with GLC2000, lead to simulated Amazon-integrated emissions of 44.4 ± 4.8 Tg yr−1. Additionally, the LPX emissions are highly sensitive to vegetation distribution. Two simulations with the same mean PFT cover, but different spatial distributions of grasslands within the basin, modulated emissions by about 20%. Correcting the LPX-simulated NPP using MODIS reduces the Amazon emissions by 11.3%. Finally, due to an intrinsic limitation of LPX to account for seasonality in floodplain extent, the model failed to reproduce the full dynamics in CH4 emissions but we proposed solutions to this issue. The interannual variability (IAV) of the emissions increases by 90% if the IAV in floodplain extent is accounted for, but still remains lower than in most of the WETCHIMP models. While our model includes more mechanisms specific to tropical floodplains, we were unable to reduce the uncertainty in the magnitude of wetland CH4 emissions of the Amazon Basin. Our results helped identify and prioritize directions towards more accurate estimates of tropical CH4 emissions, and they stress the need for more research to constrain floodplain CH4 emissions and their temporal variability, even before including other fundamental mechanisms such as floating macrophytes or lateral water fluxes.

Biodiversity effects on nitrate concentrations in soil solution: a Bayesian model

Ecosystems are faced with high rates of species loss which has consequences for their functions and services. To assess the effects of plant species diversity on the nitrogen (N) cycle, we developed a model for monthly mean nitrate (NO3-N) concentrations in soil solution in 0-30 cm mineral soil depth using plant species and functional group richness and functional composition as drivers and assessing the effects of conversion of arable land to grassland, spatially heterogeneous soil properties, and climate. We used monthly mean NO3-N concentrations from 62 plots of a grassland plant diversity experiment from 2003 to 2006. Plant species richness (1-60) and functional group composition (1-4 functional groups: legumes, grasses, non-leguminous tall herbs, non-leguminous small herbs) were manipulated in a factorial design. Plant community composition, time since conversion from arable land to grassland, soil texture, and climate data (precipitation, soil moisture, air and soil temperature) were used to develop one general Bayesian multiple regression model for the 62 plots to allow an in-depth evaluation using the experimental design. The model simulated NO3-N concentrations with an overall Bayesian coefficient of determination of 0.48. The temporal course of NO3-N concentrations was simulated differently well for the individual plots with a maximum plot-specific Nash-Sutcliffe Efficiency of 0.57. The model shows that NO3-N concentrations decrease with species richness, but this relation reverses if more than approx. 25 % of legume species are included in the mixture. Presence of legumes increases and presence of grasses decreases NO3-N concentrations compared to mixtures containing only small and tall herbs. Altogether, our model shows that there is a strong influence of plant community composition on NO3-N concentrations.

Performance on auditory and visual temporal informationprocessing is related to psychometric intelligence

The present study investigated the relationship between psychometric intelligence and temporal resolution power (TRP) as simultaneously assessed by auditory and visual psychophysical timing tasks. In addition, three different theoretical models of the functional relationship between TRP and psychometric intelligence as assessed by means of the Adaptive Matrices Test (AMT) were developed. To test the validity of these models, structural equation modeling was applied. Empirical data supported a hierarchical model that assumed auditory and visual modality-specific temporal processing at a first level and amodal temporal processing at a second level. This second-order latent variable was substantially correlated with psychometric intelligence. Therefore, the relationship between psychometric intelligence and psychophysical timing performance can be explained best by a hierarchical model of temporal information processing.

Coherence and phase locking in the scalp EEG and between LORETA model sources, and microstates as putative mechanisms of brain temporo-spatial functional organization

Brain electric mechanisms of temporary, functional binding between brain regions are studied using computation of scalp EEG coherence and phase locking, sensitive to time differences of few milliseconds. However, such results if computed from scalp data are ambiguous since electric sources are spatially oriented. Non-ambiguous results can be obtained using calculated time series of strength of intracerebral model sources. This is illustrated applying LORETA modeling to EEG during resting and meditation. During meditation, time series of LORETA model sources revealed a tendency to decreased left-right intracerebral coherence in the delta band, and to increased anterior-posterior intracerebral coherence in the theta band. An alternate conceptualization of functional binding is based on the observation that brain electric activity is discontinuous, i.e., that it occurs in chunks of up to about 100 ms duration that are detectable as quasi-stable scalp field configurations of brain electric activity, called microstates. Their functional significance is illustrated in spontaneous and event-related paradigms, where microstates associated with imagery- versus abstract-type mentation, or while reading positive versus negative emotion words showed clearly different regions of cortical activation in LORETA tomography. These data support the concept that complete brain functions of higher order such as a momentary thought might be incorporated in temporal chunks of processing in the range of tens to about 100 ms as quasi-stable brain states; during these time windows, subprocesses would be accepted as members of the ongoing chunk of processing.

DYPTOP: a cost-efficient TOPMODEL implementation to simulate sub-grid spatio-temporal dynamics of global wetlands and peatlands

Simulating the spatio-temporal dynamics of inundation is key to understanding the role of wetlands under past and future climate change. Earlier modelling studies have mostly relied on fixed prescribed peatland maps and inundation time series of limited temporal coverage. Here, we describe and assess the the Dynamical Peatland Model Based on TOPMODEL (DYPTOP), which predicts the extent of inundation based on a computationally efficient TOPMODEL implementation. This approach rests on an empirical, grid-cell-specific relationship between the mean soil water balance and the flooded area. DYPTOP combines the simulated inundation extent and its temporal persistency with criteria for the ecosystem water balance and the modelled peatland-specific soil carbon balance to predict the global distribution of peatlands. We apply DYPTOP in combination with the LPX-Bern DGVM and benchmark the global-scale distribution, extent, and seasonality of inundation against satellite data. DYPTOP successfully predicts the spatial distribution and extent of wetlands and major boreal and tropical peatland complexes and reveals the governing limitations to peatland occurrence across the globe. Peatlands covering large boreal lowlands are reproduced only when accounting for a positive feedback induced by the enhanced mean soil water holding capacity in peatland-dominated regions. DYPTOP is designed to minimize input data requirements, optimizes computational efficiency and allows for a modular adoption in Earth system models.