Increase in hippocampal water diffusion and volume during experimental pneumococcal meningitis is aggravated by bacteremia

BACKGROUND The hippocampus undergoes apoptosis in experimental pneumococcal meningitis leading to neurofunctional deficits in learning and memory function. The aim of the present study was 1) to investigate hippocampal apparent diffusion coefficient (ADC) and volume with MRI during the course of experimental pneumococcal meningitis, 2) to explore the influence of accompanying bacteremia on hippocampal water distribution and volume, 3) and to correlate these findings to the extent of apoptosis in the hippocampus. METHODS Experimental meningitis in rats was induced by intracisternal injection of live pneumococci. The study comprised of four experimental groups. I. Uninfected controls (n = 8); II. Meningitis (n = 11); III. Meningitis with early onset bacteremia by additional i.v. injection of live pneumococci (n = 10); IV. Meningitis with attenuated bacteremia by treatment with serotype-specific anti-pneumococcal antibodies (n = 14). T2 and diffusion weighted MR images were used to analyze changes in hippocampus volume and water diffusion (ADC). The results were correlated to ADC of the cortex, to ventricular volume, and to the extent of hippocampal apoptosis. RESULTS Both ADC and the volume of hippocampus were significantly increased in meningitis rats compared to uninfected controls (Kruskal-Wallis test, p = 0.0001, Dunns Post Test, p < 0.05), and were significantly increased in meningitis rats with an early onset bacteremia as compared to meningitis rats with attenuated bacteremia (p < 0.05). Hippocampal ADC and the volume and size of brain ventricles were positively correlated (Spearman Rank, p < 0.05), whereas no association was found between ADC or volume and the extent of apoptosis (p > 0.05). CONCLUSIONS In experimental meningitis increase in volume and water diffusion of the hippocampus are significantly associated with accompanying bacteremia.

Resolving diffusion in clay minerals at different time scales: Combination of experimental and modeling approaches

Since no single experimental or modeling technique provides data that allow a description of transport processes in clays and clay minerals at all relevant scales, several complementary approaches have to be combined to understand and explain the interplay between transport relevant phenomena. In this paper molecular dynamics simulations (MD) were used to investigate the mobility of water in the interlayer of montmorillonite (Mt), and to estimate the influence of mineral surfaces and interlayer ions on the water diffusion. Random Walk (RW) simulations based on a simplified representation of pore space in Mt were used to estimate and understand the effect of the arrangement of Mt particles on the meso- to macroscopic diffusivity of water. These theoretical calculations were complemented with quasielastic neutron scattering (QENS) measurements of aqueous diffusion in Mt with two pseudo-layers of water performed at four significantly different energy resolutions (i.e. observation times). The size of the interlayer and the size of Mt particles are two characteristic dimensions which determine the time dependent behavior of water diffusion in Mt. MD simulations show that at very short time scales water dynamics has the characteristic features of an oscillatory motion in the cage formed by neighbors in the first coordination shell. At longer time scales, the interaction of water with the surface determines the water dynamics, and the effect of confinement on the overall water mobility within the interlayer becomes evident. At time scales corresponding to an average water displacement equivalent to the average size of Mt particles, the effects of tortuosity are observed in the meso- to macroscopic pore scale simulations. Consistent with the picture obtained in the simulations, the QENS data can be described using a (local) 3D diffusion at short observation times, whereas at sufficiently long observation times a 2D diffusive motion is clearly observed. The effects of tortuosity measured in macroscopic tracer diffusion experiments are in qualitative agreement with RW simulations. By using experimental data to calibrate molecular and mesoscopic theoretical models, a consistent description of water mobility in clay minerals from the molecular to the macroscopic scale can be achieved. In turn, simulations help in choosing optimal conditions for the experimental measurements and the data interpretation. (C) 2014 Elsevier B.V. All rights reserved.

Fine control of drug delivery for cochlear implant applications

Cochlear implants are neuroprostheses that are inserted into the inner ear to directly electrically stimulate the auditory nerve, thus replacing lost cochlear receptors, the hair cells. The reduction of the gap between electrodes and nerve cells will contribute to technological solutions simultaneously increasing the frequency resolution, the sound quality and the amplification of the signal. Recent findings indicate that neurotrophins (NTs) such as brain derived neurotrophic factor (BDNF) stimulate the neurite outgrowth of auditory nerve cells by activating Trk receptors on the cellular surface (1–3). Furthermore, small-size TrkB receptor agonists such as di-hydroxyflavone (DHF) are now available, which activate the TrkB receptor with similar efficiency as BDNF, but are much more stable (4). Experimentally, such molecules are currently used to attract nerve cells towards, for example, the electrodes of cochlear implants. This paper analyses the scenarios of low dose aspects of controlled release of small-size Trk receptor agonists from the coated CI electrode array into the inner ear. The control must first ensure a sufficient dose for the onset of neurite growth. Secondly, a gradient in concentration needs to be maintained to allow directive growth of neurites through the perilymph-filled gap towards the electrodes of the implant. We used fluorescein as a test molecule for its molecular size similarity to DHF and investigated two different transport mechanisms of drug dispensing, which both have the potential to fulfil controlled low-throughput drug-deliverable requirements. The first is based on the release of aqueous fluorescein into water through well-defined 60-μm size holes arrays in a membrane by pure osmosis. The release was both simulated using the software COMSOL and observed experimentally. In the second approach, solid fluorescein crystals were encapsulated in a thin layer of parylene (PPX), hence creating random nanometer-sized pinholes. In this approach, the release occurred due to subsequent water diffusion through the pinholes, dissolution of the fluorescein and then release by out-diffusion. Surprisingly, the release rate of solid fluorescein through the nanoscopic scale holes was found to be in the same order of magnitude as for liquid fluorescein release through microscopic holes.

Translational diffusion of water in compacted clay systems

The translational diffusion of water in compacted clays at a high hydration level has been investigated by quasielastic neutron scattering at a time-of-flight spectrometer FOCUS (SINQ). Four compacted clays with systematic structural differences have been studied: Na-montmorillonite, Na-illite, kaolinite and pyrophyllite. The QENS experiments were performed using two different incident wavelengths in order to access a larger Q range and verify the data analysis. The translational diffusion coefficient for water in Na-montmorillonite and Na-illite are lower than those for bulk water, whereas the preliminary results for kaolinite and pyrophyllite show larger diffusion coefficient.

Estimation and calibration of the water isotope differential diffusion length in ice core records

Palaeoclimatic information can be retrieved from the diffusion of the stable water isotope signal during firnification of snow. The diffusion length, a measure for the amount of diffusion a layer has experienced, depends on the firn temperature and the accumulation rate. We show that the estimation of the diffusion length using power spectral densities (PSDs) of the record of a single isotope species can be biased by uncertainties in spectral properties of the isotope signal prior to diffusion. By using a second water isotope and calculating the difference in diffusion lengths between the two isotopes, this problem is circumvented. We study the PSD method applied to two isotopes in detail and additionally present a new forward diffusion method for retrieving the differential diffusion length based on the Pearson correlation between the two isotope signals. The two methods are discussed and extensively tested on synthetic data which are generated in a Monte Carlo manner. We show that calibration of the PSD method with this synthetic data is necessary to be able to objectively determine the differential diffusion length. The correlation-based method proves to be a good alternative for the PSD method as it yields precision equal to or somewhat higher than the PSD method. The use of synthetic data also allows us to estimate the accuracy and precision of the two methods and to choose the best sampling strategy to obtain past temperatures with the required precision. In addition to application to synthetic data the two methods are tested on stable-isotope records from the EPICA (European Project for Ice Coring in Antarctica) ice core drilled in Dronning Maud Land, Antarctica, showing that reliable firn temperatures can be reconstructed with a typical uncertainty of 1.5 and 2 °C for the Holocene period and 2 and 2.5 °C for the last glacial period for the correlation and PSD method, respectively.

Au@Hg nanoalloy formation through direct amalgamation: Structural, spectroscopic, and computational evidence for slow nanoscale diffusion

Dynamic core-shell nanoparticles have received increasing attention in recent years. This paper presents a detailed study of Au-Hg nanoalloys, whose composing elements show a large difference in cohesive energy. A simple method to prepare Au@Hg particles with precise control over the composition up to 15 atom% mercury is introduced, based on reacting a citrate stabilized gold sol with elemental mercury. Transmission electron microscopy shows an increase of particle size with increasing mercury content and, together with X-ray powder diffraction, points towards the presence of a core-shell structure with a gold core surrounded by an Au-Hg solid solution layer. The amalgamation process is described by pseudo-zero-order reaction kinetics, which indicates slow dissolution of mercury in water as the rate determining step, followed by fast scavenging by nanoparticles in solution. Once adsorbed at the surface, slow diffusion of Hg into the particle lattice occurs, to a depth of ca. 3 nm, independent of Hg concentration. Discrete dipole approximation calculations relate the UV-vis spectra to the microscopic details of the nanoalloy structure. Segregation energies and metal distribution in the nanoalloys were modeled by density functional theory calculations. The results indicate slow metal interdiffusion at the nanoscale, which has important implications for synthetic methods aimed at core-shell particles.

Diffusion-driven transport in clayrock formations

Clay mineral-rich sedimentary formations are currently under investigation to evaluate their potential use as host formations for installation of deep underground disposal facilities for radioactive waste (e.g. Boom Clay (BE), Opalinus Clay (CH), Callovo-Oxfordian argillite (FR)). The ultimate safety of the corresponding repository concepts depends largely on the capacity of the host formation to limit the flux towards the biosphere of radionuclides (RN) contained in the waste to acceptably low levels. Data for diffusion-driven transfer in these formations shows extreme differences in the measured or modelled behaviour for various radionuclides, e. g. between halogen RN (Cl-36, I-129) and actinides (U-238,U-235, Np-237, Th-232, etc.), which result from major differences between RN of the effects on transport of two phenomena: diffusion and sorption. This paper describes recent research aimed at improving understanding of these two phenomena, focusing on the results of studies carried out during the EC Funmig IP on clayrocks from the above three formations and from the Boda formation (HU). Project results regarding phenomena governing water, cation and anion distribution and mobility in the pore volumes influenced by the negatively-charged surfaces of clay minerals show a convergence of the modelling results for behaviour at the molecular scale and descriptions based on electrical double layer models. Transport models exist which couple ion distribution relative to the clay-solution interface and differentiated diffusive characteristics. These codes are able to reproduce the main trends in behaviour observed experimentally, e.g. D-e(anion) < D-e(HTO) < D-e(cation) and D-e(anion) variations as a function of ionic strength and material density. These trends are also well-explained by models of transport through ideal porous matrices made up of a charged surface material. Experimental validation of these models is good as regards monovalent alkaline cations, in progress for divalent electrostatically-interacting cations (e.g. Sr2+) and still relatively poor for 'strongly sorbing', high K-d cations. Funmig results have clarified understanding of how clayrock mineral composition, and the corresponding organisation of mineral grain assemblages and their associated porosity, can affect mobile solute (anions, HTO) diffusion at different scales (mm to geological formation). In particular, advances made in the capacity to map clayrock mineral grain-porosity organisation at high resolution provide additional elements for understanding diffusion anisotropy and for relating diffusion characteristics measured at different scales. On the other hand, the results of studies focusing on evaluating the potential effects of heterogeneity on mobile species diffusion at the formation scale tend to show that there is a minimal effect when compared to a homogeneous property model. Finally, the results of a natural tracer-based study carried out on the Opalinus Clay formation increase confidence in the use of diffusion parameters measured on laboratory scale samples for predicting diffusion over geological time-space scales. Much effort was placed on improving understanding of coupled sorption-diffusion phenomena for sorbing cations in clayrocks. Results regarding sorption equilibrium in dispersed and compacted materials for weakly to moderately sorbing cations (Sr2+, Cs+, Co2+) tend to show that the same sorption model probably holds in both systems. It was not possible to demonstrate this for highly sorbing elements such as Eu(III) because of the extremely long times needed to reach equilibrium conditions, but there does not seem to be any clear reason why such elements should not have similar behaviour. Diffusion experiments carried out with Sr2+, Cs+ and Eu(III) on all of the clayrocks gave mixed results and tend to show that coupled diffusion-sorption migration is much more complex than expected, leading generally to greater mobility than that predicted by coupling a batch-determined K-d and Ficks law based on the diffusion behaviour of HTO. If the K-d measured on equivalent dispersed systems holds as was shown to be the case for Sr, Cs (and probably Co) for Opalinus Clay, these results indicate that these cations have a D-e value higher than HTO (up to a factor of 10 for Cs+). Results are as yet very limited for very moderate to strongly sorbing species (e.g. Co(II), Eu(III), Cu(II)) because of their very slow transfer characteristics. (C) 2011 Elsevier Ltd. All rights reserved.

Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging

A multimodal MR study including relaxometry, diffusion tensor imaging (DTI), and MR spectroscopy was performed on patients with classical phenylketonuria (PKU) and matched controls, to improve our understanding of white matter (WM) lesions. Relaxometry yields information on myelin loss or malformation and may substantiate results from DTI attributed to myelin changes. Relaxometry was used to determine four brain compartments in normal-appearing brain tissue (NABT) and in lesions: water in myelin bilayers (myelin water, MW), water in gray matter (GM), water in WM, and water with long relaxation times (cerebrospinal fluid [CSF]-like signals). DTI yielded apparent diffusion coefficients (ADCs) and fractional anisotropies. MW and WM content were reduced in NABT and in lesions of PKU patients, while CSF-like signals were significantly increased. ADC values were reduced in PKU lesions, but also in the corpus callosum. Diffusion anisotropy was reduced in lesions because of a stronger decrease in the longitudinal than in the transverse diffusion. WM content and CSF-like components in lesions correlated with anisotropy and ADC. ADC values in lesions and in the corpus callosum correlated negatively with blood and brain phenylalanine (Phe) concentrations. Intramyelinic edema combined with vacuolization is a likely cause of the WM alterations. Correlations between diffusivity and Phe concentrations confirm vulnerability of WM to high Phe concentrations.

Proton diffusion tensor spectroscopy of metabolites in human muscle in vivo

PURPOSE To study the apparent diffusivity and its directionality for metabolites of skeletal muscle in humans in vivo by (1) H magnetic resonance spectroscopy. METHODS The diffusion tensors were determined on a 3 Tesla MR system using optimized acquisition and processing methods including an adapted STEAM sequence with orientation-dependent diffusion weighting, pulse-triggering with individually adapted delays, eddy-current correction schemes, median filtering, and simultaneous prior-knowledge fitting of all related spectra. RESULTS The average apparent diffusivities, as well as the fractional anisotropies of taurine (ADCav  = 0.74 × 10(-3) s/mm(2) , FA = 0.46), creatine (ADCav  = 0.41 × 10(-3)  s/mm(2) , FA = 0.33), trimethylammonium compounds (ADCav  = 0.48 × 10(-3)  s/mm(2) , FA = 0.34), carnosine (ADCav  = 0.46 × 10(-3)  s/mm(2) , FA = 0.47), and water (ADCav  = 1.5 × 10(-3)  s/mm(2) , FA = 0.36) were estimated. The diffusivities of most metabolites and water were significantly different from each other. Diffusion was found to be anisotropic and the diffusion tensors showed tensor correlation coefficients close to 1 and were hence found to be essentially coaligned. The magnitudes of apparent metabolite diffusivities were largely ordered according to molecular weight, with taurine as the smallest molecule diffusing fastest, both along and across the fiber direction. CONCLUSION Diffusivities, directional dependence of diffusion and fractional anisotropies of (1) H MRS-visible muscle metabolites were presented. It was shown that metabolites share diffusion directionality with water and have similar fractional anisotropies, hinting at similar diffusion barriers. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Anisotropic diffusion at the field scale in a 4-year multi-tracer diffusion and retention experiment – I: Insights from the experimental data

Abstract Claystones are considered worldwide as barrier materials for nuclear waste repositories. In the Mont Terri underground research laboratory (URL), a nearly 4-year diffusion and retention (DR) experiment has been performed in Opalinus Clay. It aimed at (1) obtaining data at larger space and time scales than in laboratory experiments and (2) under relevant in situ conditions with respect to pore water chemistry and mechanical stress, (3) quantifying the anisotropy of in situ diffusion, and (4) exploring possible effects of a borehole-disturbed zone. The experiment included two tracer injection intervals in a borehole perpendicular to bedding, through which traced artificial pore water (APW) was circulated, and a pressure monitoring interval. The APW was spiked with neutral tracers (HTO, HDO, H2O-18), anions (Br, I, SeO4), and cations (Na-22, Ba-133, Sr-85, Cs-137, Co-60, Eu-152, stable Cs, and stable Eu). Most tracers were added at the beginning, some were added at a later stage. The hydraulic pressure in the injection intervals was adjusted according to the measured value in the pressure monitoring interval to ensure transport by diffusion only. Concentration time-series in the APW within the borehole intervals were obtained, as well as 2D concentration distributions in the rock at the end of the experiment after overcoring and subsampling which resulted in �250 samples and �1300 analyses. As expected, HTO diffused the furthest into the rock, followed by the anions (Br, I, SeO4) and by the cationic sorbing tracers (Na-22, Ba-133, Cs, Cs-137, Co-60, Eu-152). The diffusion of SeO4 was slower than that of Br or I, approximately proportional to the ratio of their diffusion coefficients in water. Ba-133 diffused only into �0.1 m during the �4 a. Stable Cs, added at a higher concentration than Cs-137, diffused further into the rock than Cs-137, consistent with a non-linear sorption behavior. The rock properties (e.g., water contents) were rather homogeneous at the centimeter scale, with no evidence of a borehole-disturbed zone. In situ anisotropy ratios for diffusion, derived for the first time directly from field data, are larger for HTO and Na-22 (�5) than for anions (�3�4 for Br and I). The lower ionic strength of the pore water at this location (�0.22 M) as compared to locations of earlier experiments in the Mont Terri URL (�0.39 M) had no notable effect on the anion accessible pore fraction for Cl, Br, and I: the value of 0.55 is within the range of earlier data. Detailed transport simulations involving different codes will be presented in a companion paper.

Dynamics of supercooled water in highly compacted clays studied by neutron scattering

The freezing behavior of water confined in compacted charged and uncharged clays (montmorillonite in Na-and Ca-forms, illite in Na-and Ca-forms, kaolinite and pyrophyllite) was investigated by neutron scattering. Firstly, the amount of frozen (immobile) water was measured as a function of temperature at the IN16 backscattering spectrometer, Institute Laue-Langevin (ILL). Water in uncharged, partly hydrophobic (kaolinite) and fully hydrophobic (pyrophyllite) clays exhibited a similar freezing and melting behavior to that of bulk water. In contrast, water in charged clays which are hydrophilic could be significantly supercooled. To observe the water dynamics in these clays, further experiments were performed using quasielastic neutron scattering. At temperatures of 250, 260 and 270 K the diffusive motion of water could still be observed, but with a strong reduction in the water mobility as compared with the values obtained above 273 K. The diffusion coefficients followed a non-Arrhenius temperature dependence well described by the Vogel-Fulcher-Tammann and the fractional power relations. The fits revealed that Na-and Ca-montmorillonite and Ca-illite have similar Vogel-Fulcher-Tammann temperatures (T-VFT, often referred to as the glass transition temperature) of similar to 120 K and similar temperatures at which the water undergoes the 'strong-fragile' transition, T-s similar to 210 K. On the other hand, Na-illite had significantly larger values of T-VFT similar to 180 K and T-s similar to 240 K. Surprisingly, Ca-illite has a similar freezing behavior of water to that of montmorillonites, even though it has a rather different structure. We attribute this to the stronger hydration of Ca ions as compared with the Na ions occurring in the illite clays.