2-pool Model Research Articles

Demonstration of accurate multi-pool chemical exchange saturation transfer MRI quantification – Quasi-steady-state reconstruction empowered quantitative CEST analysis

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironment properties, yet CEST quantification has been challenging. This difficulty is because the CEST measurement depends not only on the underlying CEST system but also on the scan protocols, including RF saturation amplitude, duration, and repetition time. In addition, T1 normalization is not straightforward under non-equilibrium conditions. Recently, a quasi-steady-state (QUASS) algorithm was established to reconstruct the desired equilibrium state from experimental measurements. Our study aimed to determine the accuracy of spinlock-model-based multi-pool CEST quantification using numerical simulations and phantom experiments. In short, CEST Z-spectra were simulated for a representative 3-pool model, and CEST amplitudes were solved with spinlock model-based multi-pool fitting and assessed as a function of RF saturation time (Ts), repetition time (TR), and T1. Although the apparent CEST signals showed significant T1 dependence, such relationships were not observed following QUASS reconstruction. To test the accuracy of T1 correction, a multi-vial phantom of nicotinamide and creatine was doped with manganese chloride, resulting in T1 ranging from 1 s to beyond 2 s. The multi-labile signals determined from the routine measurements showed significant dependence on Ts, TR, and T1. In contrast, CEST signals from the QUASS reconstruction showed consistent quantification independent of such variables. To summarize, our study demonstrated that accurate CEST quantification is feasible in multi-pool CEST systems with the spinlock-model-based fitting of QUASS CEST MRI.

Comparison of modeled versus reported phosphate removal and modeled versus postdialysis serum phosphate levels in conventional hemodialysis.

We compared predictions of phosphate removal by a 2-pool kinetic model with measured phosphate removal in spent dialysate as reported by others. Twenty-six studies were identified that reported phosphate removal in 35 groups of patients. In almost all studies, patients were dialyzed for close to 4h (range 3 to 6h). For each study, group mean values of predialysis serum phosphate, body size, dialyzer K0 A urea, blood and dialysate flow rates, and session lengths were input into the kinetic model. Predictions of group mean phosphate removal and postdialysis serum phosphate were compared with reported measured values. Mean (by patient group) predicted phosphate removal was 931 ± 170 mg/treatment, somewhat higher (p < 0.001) than the reported measured value, 900 mg ± 287. The ratio of predicted/measured removal averaged 1.15 ± 0.427. In 5/35 patient groups (3/26 studies) the predicted/measured phosphate removal was greater than 1.50. If these groups were excluded, the mean measured phosphate removal was 990 mg versus 966 predicted, with a ratio of predicted/measured removal averaging 0.993. Measured group mean postdialysis serum phosphate values (reported in 25/35) were 2.64 ± 0.54, not significantly different from predicted (2.60 ± 0.24 mg/dl, p = NS). For conventional 4-h dialysis treatments, phosphate removal and postdialysis serum phosphate values predicted by a 2-pool kinetic model are similar to reported measured values.

Effect of amylases and storage length on losses, nutritional value, fermentation, and microbiology of silages of corn and sorghum kernels

This study evaluated the effect of two commercial amylases with known activity at low pH and storage length on fermentation profile, microbial diversity, and effective rumen degradation (ERD) of silages of rehydrated kernels of sorghum (RES) or flint corn (REC). Mature kernels were ground through a 1 mm diameter mesh screen with a stationary hammer mill and manually rehydrated to achieve a similar dry matter (DM) concentration (650 g/kg of fresh) for ensiling (4.74 ± 0.30 kg/silo). Treatments were formed using a 2 × 3 × 2 factorial combination of grain type (RES and REC), enzyme [control and amylases AMG (300 AGU/mL) and GAM (138 AGU/mL), both at 0.35 mL/kg of fresh kernels], and storage length (30 and 180 d), with six replicates. The ERD of DM was evaluated in situ with a 2-pool model (A and B fractions) and incubations for 0, 3, 6, 12, 18, and 48 h. The proportional change in ERD mass during silage storage (% of ensiled) was calculated. Lactic acid bacteria (LAB) and spore-forming aerobic bacteria (SAB) were quantified and identified. The loss of DM (6.8 vs. 5.3% of ensiled) and starch (23.9 vs. 13.6% of ensiled) were higher (P < 0.01) for REC than RES. The RES had higher (P < 0.01) DM fraction A (398 vs. 325 g/kg of DM) and ERD (593 vs. 554 g/kg of DM) and lower (P < 0.01) kd of DM fraction B (3.14 vs. 3.33%/h) than REC. Ensiling increased ERD mass of both kernels (+6.8% of ensiled). The RES showed a faster increase (P = 0.04) in ERD mass in response to ensiling than REC. Both amylases and a longer duration of storage reduced (P < 0.01) the starch content and increased (P < 0.01) DM loss. Enzymes induced a faster increase (P < 0.01) in ERD mass relative to control but reduced the gain in ERD mass in extended storage. Longer storage increased (P < 0.01) the ERD content and the pool size of fraction A of both RES and REC. Lactic acid was the primary organic acid in silage, followed by propionic acid. Long storage of sorghum increased (P < 0.01) butyrate and there was no effect of grain type and enzyme on butyrate at 30 days of storage. The RES ensiled for 180 days without enzyme had the highest (P < 0.01) butyrate. The species Levilactobacillus brevis, Lentilactobacillus buchneri, Lactiplantibacillus plantarum, and Pediococcus acidilactici were the most frequent, but in general, amylases reduced numerically their population. The SAB had a greater diversity and lower population than LAB. We concluded that RES was more degradable in the rumen and had a lower loss during storage than REC. The highest ERD mass recovery was observed for long storage without amylase. The amylases seem to be an option only when storage length is short. The LAB population dominated sorghum and corn kernels silage fermentation. Most microorganisms identified were involved in organic acids and alcohol metabolism.

Reliable Assessment of Swine Renal Fibrosis Using Quantitative Magnetization Transfer Imaging.

Quantitative magnetization transfer (qMT) is useful for measurement of murine renal fibrosis at high and ultrahigh field strengths. However, its utility at clinical field strengths and in human-like kidneys remains unknown. We tested the hypothesis that qMT would successfully detect fibrosis in swine kidneys with unilateral renal artery stenosis (RAS) at 3.0 T. The qMT protocol is composed of MT scans with variable flip angles and offset frequencies, and of B0, B1, and T1 mapping. Pigs were scanned 10 weeks after RAS or control. A 2-pool model was used to fit the bound pool fraction f of the renal cortex (CO) and outer medulla (OM). Then qMT-derived f in 5 normal and 10 RAS pigs was compared with histological fibrosis determined using Masson's trichrome staining and to renal perfusion assessed with computed tomography. The qMT 2-pool model provided accurate fittings of data collected on swine kidneys. Stenotic kidneys showed significantly elevated f in both the CO (9.8% ± 2.7% vs 6.4% ± 0.9%, P = 0.002) and OM (7.6% ± 2.2% vs 4.7% ± 1.1%, P = 0.002), as compared with normal kidneys. Histology-measured renal fibrosis and qMT-derived f correlated directly in both the cortex (Pearson correlation coefficient r = 0.93, P < 0.001) and OM (r = 0.84, P = 0.002), and inversely with stenotic kidney perfusion (r = 0.85, P = 0.002). This study demonstrates the feasibility of qMT for measuring fibrosis in human-like swine kidneys, and the association between tissue macromolecule content and renal perfusion. Therefore, qMT may be useful as a tool for noninvasive assessment of renal fibrosis in subjects with RAS at clinical field strengths.

Probing the myelin water compartment with a saturation-recovery, multi-echo gradient-recalled echo sequence.

To investigate the effect of varying levels of -weighting on the evolution of the complex signal from white matter in a multi-echo gradient-recalled echo (mGRE) saturation-recovery sequence. Analysis of the complex signal evolution in an mGRE sequence allows the contributions from short- and long- components to be separated, thus providing a measure of the relative strength of signals from the myelin water, and the external and intra-axonal compartments. Here we evaluated the effect of different levels of -weighting on these signals, expecting that the previously reported, short of the myelin water would lead to a relative enhancement of the myelin water signal in the presence of signal saturation. Complex, saturation-recovery mGRE data from the splenium of the corpus callosum from 5 healthy volunteers were preprocessed using a frequency difference mapping (FDM) approach and analyzed using the 3-pool model of complex signal evolution in white matter. An increase in the apparent as a function of echo time was demonstrated, but this increase was an order of magnitude smaller than that expected from previously reported myelin water -values. This suggests the presence of magnetization transfer and exchange effects which counteract the -weighting. Variation of the amplitude in a saturation-recovery mGRE sequence can be used to modulate the relative strength of signals from the different compartments in white matter, but the modulation is less than predicted from previously reported -values.

P4477Editing of myosin phosphatase as a novel approach for sensitization of vascular smooth muscle to vasodilators (NO/cGMP/ROS) and lowering of blood pressure in hypertension

Abstract Background Despite the many drugs for treatment of hypertension, it remains inadequately treated in &gt;50% of patients and the number one contributor to cardiovascular mortality world-wide. Thus new targets and treatment strategies are badly needed. Myosin Phosphatase (MP) is a viable target: it is the primary effector of vascular smooth muscle relaxation and a critical mediator of signaling pathways regulating vessel tone. Purpose We are using complementary/ translatable approaches to test the hypothesis: editing of the Myosin Phosphatase Regulatory (Targeting) subunit (MYPT1), by shifting the expression of naturally occurring isoforms, will sensitize vascular smooth muscle to NO/cGMP/ROS mediated vasorelaxation and thereby lower BP in models of hypertension. A further goal is to determine mechanisms by which these signals activate MP thereby causing vasorelaxation. Methods LoxP sites were inserted in introns flanking alternative Exon24 (E24) of Mypt1. Mice were crossed with smMHCCreER mice and treated with Tamoxifen for smooth muscle specific deletion of E24 (SMcKO E24).Skipping E24 codes for a Mypt1 isoform that contains a C-terminal leucine zipper (LZ) motif required for cGMP-dependent protein kinase (cGK1) binding and NO/cGMP/ROS activation of MP. Second, we developed and tested guide RNAs for the purpose of AAV-CRISPR/CAS9 editing of Mypt1 E24 as a treatment for hypertension. Effect of editing is tested in otherwise normal mice and in the AngII sub-pressor model of hypertension. Results SMcKO E24 mice had mean BP that was 15+3 mmHg lower than control (n=5; p&lt;0.05). Mesenteric arteries from these mice were significantly more sensitive to DEA/NO mediated relaxation (EC50: 2.1+0.5 nM vs 18.2+5.6 mM; n=5–6, p&lt;0.05). Experiments testing response to AngII infusion are in progress and will be presented at the meeting. Preliminary biochemical assays support a 2-pool model, in which NO/cGMP/ROS activates the LZ+ pool, while contractile agonists inhibit the LZ- pool of MP, in the control of BP/ blood flow. We have generated a number of AAV Crispr/Cas9 gRNAs and validated their efficacy of editing of Mypt1 E24 in vitro. Experiments are in progress to test their efficacy and effect on BP in vivo. Conclusion These studies support that editing of Mypt1 E24 could be a novel strategy for vasodilator sensitization and effective lowering of blood pressure in humans with hypertension, thereby having a substantial impact on CV mortality world-wide. Acknowledgement/Funding NIH

Tundra microbial community taxa and traits predict decomposition parameters of stable, old soil organic carbon.

The susceptibility of soil organic carbon (SOC) in tundra to microbial decomposition under warmer climate scenarios potentially threatens a massive positive feedback to climate change, but the underlying mechanisms of stable SOC decomposition remain elusive. Herein, Alaskan tundra soils from three depths (a fibric O horizon with litter and course roots, an O horizon with decomposing litter and roots, and a mineral-organic mix, laying just above the permafrost) were incubated. Resulting respiration data were assimilated into a 3-pool model to derive decomposition kinetic parameters for fast, slow, and passive SOC pools. Bacterial, archaeal, and fungal taxa and microbial functional genes were profiled throughout the 3-year incubation. Correlation analyses and a Random Forest approach revealed associations between model parameters and microbial community profiles, taxa, and traits. There were more associations between the microbial community data and the SOC decomposition parameters of slow and passive SOC pools than those of the fast SOC pool. Also, microbial community profiles were better predictors of model parameters in deeper soils, which had higher mineral contents and relatively greater quantities of old SOC than in surface soils. Overall, our analyses revealed the functional potential of microbial communities to decompose tundra SOC through a suite of specialized genes and taxa. These results portray divergent strategies by which microbial communities access SOC pools across varying depths, lending mechanistic insights into the vulnerability of what is considered stable SOC in tundra regions.

Echo time-range effects on gradient-echo based myelin water fraction mapping at 3T.

To investigate the effect of the range of TE on multi-echo gradient echo-based myelin water fraction (MWF) mapping at 3 T. Myelin water fraction estimation was performed using 3 widely used models: magnitude multipool, magnitude 3-pool, and complex 3-pool model. Simulations were conducted using a hollow cylinder model with susceptibility anisotropy. The TE range was varied, and its effect on MWF estimation was observed. The same analysis was also performed with in vivo data from 4 healthy volunteers. Different MWFs were obtained depending on the range of TE data acquired. In the simulations, the results of both magnitude models had a bias with respect to the true values: a maximum bias of up to 20% for the multipool model, and a maximum bias of up to 8% for the 3-pool model. This bias was reduced using the complex 3-pool model (maximum bias was under 2%). These effects were also found in the in vivo data. The MWF values using the complex model was most stable with respect to the TE range. The results of the simulation and in vivo data suggest that MWF values fitted using magnitude models are more influenced by the TE range collected for fitting than using the complex model. The complex model is helpful in mitigating bias due to dependencies over the TE range selection.

Shutter-speed dynamic contrast-enhanced MRI: Is it fit for purpose?

To test the ability of shutter-speed dynamic contrast-enhanced (DCE) MRI to estimate water exchange (WX) using simulations and assess its performance in clinical case studies of malignant and benign breast tumors. Data were simulated using a 1-compartment tracer kinetic (TK) model combined with a 2-pool WX model (2PX) and with a 2-compartment TK model. Typical DCE-MRI acquisition parameters were used with both WX-sensitive (8°) and -insensitive (25°) flip angles. Clinical data were obtained from patients with malignant and benign breast tumors. Data were fitted using a 2-compartment TK model and a 1-compartment TK model combined with 4 WX models: fast exchange limit (FXL), no exchange, 2PX, and shutter-speed. Fits to the 1-compartment simulated data were excellent, but estimates of WX obtained using the 2PX and shutter-speed models were poor. One-compartment TK model fits to the clinical malignant tumor data were bad, except for the shutter-speed model. However, that overestimated TK parameters compared to the best-fit 2-compartment TK model, which predicted a significant blood volume and leaky capillaries (1 tracer compartment is insufficient, 2 are necessary). All models produced excellent fits to the clinical benign tumor data with little variation between parameter estimates (1 tracer compartment is sufficient). The 2PX and shutter-speed models were unable to estimate WX from the DCE-MRI data. A good fit to malignant tumor data using the shutter-speed model was not explained by WX, but the choice of an inappropriate TK model leading to distorted parameter estimates.

Short communication: Effect of washing method, grinding size, and the determination of an indigestible fraction on in situ degradation of starch in mature corn grain

The objectives of this study were to determine (1) the effect of grinding size (1, 2, 4, and 6 mm) to determine effective ruminal disappearance (ERD); (2) the most adequate method to estimate the rapidly degradable fraction (A); (3) a time point to measure the indigestible fraction (C); and (4) the viability of using fewer time points to estimate starch fractional disappearance rate (kd) of mature corn grain. Fraction A was determined by rinsing in a bucket or washing machine, rumen immersion followed by bucket or washing machine, and water immersion for 30 min followed by bucket or washing machine. Ruminal in situ incubations were performed at 48, 72, 96, and 120 h to determine fraction C, and at 0 (washing machine), 3, 6, 12, 18, 24, and 48 h to determine the kinetics of starch disappearance. Models were used with either 2 or 3 pools and kd was determined by the linear slope of the log-transformed bag residues as a proportion of incubated samples over time. The ERD was calculated as A + B [kd/(kd + kp)], where kp is the ruminal fractional passage rate = 16.0% h-1. Data were analyzed using PROC MIXED of SAS (SAS Institute Inc., Cary, NC) with the fixed effects of run (for fraction A analysis only) method (either washing or model), grinding size, and method by grinding size interaction, with cow as a random effect. Correlation between estimates calculated using all time points or combinations of 2 and 3 time points were determined using PROC CORR. Fraction A was reduced as grinding size increased, but was not altered by washing method. Samples ground at 6 mm had greater fraction C than other grinding sizes at 48, 72, or 96 h, but not at 120 h. Model affected the slowly degradable fraction (B) values solely, but the difference was minor (0.5 percentage units). Greater fractions B and C but reduced kd and ERD were observed as grinding size increased. Based on correlation analysis the 2-pool model, incubation times of 0, 3, and 48 h were suitable to evaluate ruminal starch degradation kinetics in mature corn. Ruminal in situ incubation at 120 h highlighted the lack of a fraction C of starch (0.13% of starch). Washing method did not affect determination of fraction A of starch. Ruminal in situ incubations of 0, 3, and 48 h for starch degradation kinetics using a 2-pool model were adequate for mature ground corn, but 120 h of incubation is suggested to confirm the existence or absence of a fraction C. Grinding size affected starch degradation kinetics and fraction A determination.

Separating fast and slow exchange transfer and magnetization transfer using off‐resonance variable‐delay multiple‐pulse (VDMP) MRI

To develop a method that can separate and quantify the fast (>1 kHz) and slow exchange transfer and magnetization transfer components in Z-spectra. Z-spectra were recorded as a function of mixing time using a train of selective pulses providing variable-delay multipulse build-up curves. Fast and slow transfer components in the Z-spectra were separated and quantified on a voxel-by-voxel basis by fitting the mixing time-dependent CEST signal using a 3-pool model. Phantom studies of glutamate solution, bovine serum albumin solution, and hair conditioner showed the capability of the proposed method to separate fast and slow transfer components. In vivo mouse brain studies showed a strong contrast between white matter and gray matter in the slow-transferring map, corresponding to an asymmetric component of the conventional semisolid magnetization transfer contrast. In addition, a fast-transferring proton map was found that was homogeneous across the brain and attributed to the total contributions of the fast-exchanging protons from proteins, metabolites, and a symmetric magnetization transfer contrast component. This new method provides a simple way to extract fast and slow transfer components from the Z-spectrum, leading to novel MRI contrasts, and providing insight into the different magnetization transfer contrast contributions.

Bi-exponential 3D-T1\u03c1 mapping of whole brain at 3\u2009T

Detection of multiple relaxation pools using MRI is useful in a number of neuro-pathologies including multiple sclerosis (MS), Alzheimer’s, and stroke. In this study we evaluate the feasibility of using T1ρ imaging for the detection of bi-exponential decays in the human brain. A prospective T1ρ imaging study was performed on model relaxation phantoms (eggs) and 7 healthy volunteers. The data was fitted using a single pool and a 2-pool model to estimate mono- and bi-exponential T1ρ maps, respectively. Bi-exponential decays were identified in the gray matter (GM) and white matter (WM) of the brain with 40.5% of GM, and 65.1% of WM pixels showing two T1ρ relaxation pools (significance level P < 0.05). Detection of T1ρ based bi-exponential decays in the brain provides complimentary information to T2 based contrast regarding the in vivo micro-environment in the brain.

DAG tales: the multiple faces of diacylglycerol—stereochemistry, metabolism, and signaling

The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a constant and controlled availability. Interestingly, DAG species are versatile in their chemical structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biological properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochemistry and their impact on cellular metabolism and signaling. Further, we describe intracellular DAG turnover and its stereochemistry in a 3-pool model to illustrate the spatial and stereochemical separation and hereby the diversity of cellular DAG metabolism.

Microbial models with data‐driven parameters predict stronger soil carbon responses to climate change

Long-term carbon (C) cycle feedbacks to climate depend on the future dynamics of soil organic carbon (SOC). Current models show low predictive accuracy at simulating contemporary SOC pools, which can be improved through parameter estimation. However, major uncertainty remains in global soil responses to climate change, particularly uncertainty in how the activity of soil microbial communities will respond. To date, the role of microbes in SOC dynamics has been implicitly described by decay rate constants in most conventional global carbon cycle models. Explicitly including microbial biomass dynamics into C cycle model formulations has shown potential to improve model predictive performance when assessed against global SOC databases. This study aimed to data-constrained parameters of two soil microbial models, evaluate the improvements in performance of those calibrated models in predicting contemporary carbon stocks, and compare the SOC responses to climate change and their uncertainties between microbial and conventional models. Microbial models with calibrated parameters explained 51% of variability in the observed total SOC, whereas a calibrated conventional model explained 41%. The microbial models, when forced with climate and soil carbon input predictions from the 5th Coupled Model Intercomparison Project (CMIP5), produced stronger soil C responses to 95 years of climate change than any of the 11 CMIP5 models. The calibrated microbial models predicted between 8% (2-pool model) and 11% (4-pool model) soil C losses compared with CMIP5 model projections which ranged from a 7% loss to a 22.6% gain. Lastly, we observed unrealistic oscillatory SOC dynamics in the 2-pool microbial model. The 4-pool model also produced oscillations, but they were less prominent and could be avoided, depending on the parameter values.

Face identity aftereffects increase monotonically with adaptor extremity over, but not beyond, the range of natural faces

Face identity aftereffects have been used to test theories of the neural coding underlying expert face recognition. Previous studies reported larger aftereffects for adaptors that are morphed further from the average face than for adaptors closer to the average, which appeared to support opponent coding along face-identity dimensions. However, only two levels were tested and it is not clear where they were located relative to the range of naturally occurring faces. This range is of interest given the functional need of the visual system both to produce good discrimination of real everyday faces and to process novel kinds of faces that we may encounter. Here, Experiment 1 establishes the boundary of faces judged as being able to occur in everyday life. Experiment 2 then shows that aftereffects increase with adaptor extremity up to this natural-range boundary, drop significantly immediately outside the boundary, and then remain stable with no drop towards zero even for highly distorted adaptors far beyond the boundary. Computational modelling shows that this unexpected pattern cannot be explained either by a simple opponent or by a classic multichannel model. However, its qualitative features can be captured either by a combination of opponent and multichannel coding (raising the possibility that not all identity-related face dimensions are opponent coded), or by a 3-pool model containing two S-shaped-response channels and a central bell-shaped channel around the average face (raising the possibility of unexpected similarities with coding of eye and head direction).

Simplified and scalable numerical solution for describing multi-pool chemical exchange saturation transfer (CEST) MRI contrast

Chemical exchange saturation transfer (CEST) imaging is sensitive to dilute labile proton and microenvironment properties such as pH and temperature, and provides vital information complementary to the conventional MRI methods. Whereas the Bloch equations coupled by exchange terms (i.e., Bloch–McConnell equations) have been utilized to quantify 2-pool CEST contrast, it is tedious to extend the Bloch–McConnell equations to describe CEST contrast beyond four saturation transfer sites. Hence, it is necessary to develop a scalable yet reasonably accurate numerical solution to describe the complex multi-pool CEST contrast. It is postulated here that the multi-pool CEST contrast can be quantified by modifying the classic 2-pool model. Although the direct exchange among labile proton groups is often negligible, labile protons may be coupled indirectly through their interaction with bulk water protons, which has to be quantified. The coupling term was solved empirically, and the proposed simplified solution was shown in good agreement with the conventional simulation. Moreover, the proposed solution is scalable, and can be easily extended to describe multi-pool CEST contrast. In sum, our study established a simplified and scalable, yet reasonably accurate numerical solution, suitable for quantitatively describing multi-pool CEST contrast.

Solute-Solver: A Web-Based Tool for Modeling Urea Kinetics for a Broad Range of Hemodialysis Schedules in Multiple Patients

Practical application of urea kinetic modeling to measure the delivered dose of hemodialysis is hampered by lack of a reference or gold-standard program that would be widely available and freely distributed. We developed and here describe an open-source JavaScript tool, "Solute-Solver," capable of batch processing of urea kinetics calculations. The Solute-Solver online interface is available at (www.ureakinetics.org); in addition, the tool can be used as a standalone HTML file that is designed to be run using a web browser. Solute-Solver is written in uncompiled JavaScript for transparency and easy modification, and the source code is available for download and modification. The program uses fourth-order Runge-Kutta numerical integration applied to a variable-extracellular-volume 2-pool model to compute a variety of clearance measures, including 1-pool and 2-pool Kt/V, "standard" weekly Kt/V, and other equivalent clearance measures. The program accepts comma- or semicolon-delimited input (which can be produced from a spreadsheet) and generates a separator-delimited output file that can be imported back into a spreadsheet or other database. The program also produces individual patient-by-patient report pages. It typically provides kinetic output for 300 patient treatments in 30-60 seconds. Advantages of this program over previously available equations and algorithms include the capacity to properly model such newer dialysis schedules as 6-times-weekly short daily or nocturnal hemodialysis, as well as account for substantial variation in residual renal function. Ultimately, this effort may promote wider use of formal urea modeling and facilitate research that requires measurement of hemodialysis or hemodialysis adequacy, especially involving the newer expressions of continuous equivalent clearance, and expressions of clearance normalized to body surface area.

Numerical Simulation Model of Hyperacute/Acute Stage White Matter Infarction

Although previous studies have revealed the mechanisms of changes in diffusivity (apparent diffusion coefficient [ADC]) in acute brain infarction, changes in diffusion anisotropy (fractional anisotropy [FA]) in white matter have not been examined. We hypothesized that membrane permeability as well as axonal swelling play important roles, and we therefore constructed a simulation model using random walk simulation to replicate the diffusion of water molecules. We implemented a numerical diffusion simulation model of normal and infarcted human brains using C++ language. We constructed this 2-pool model using simple tubes aligned in a single direction. Random walk simulation diffused water. Axon diameters and membrane permeability were then altered in step-wise fashion. To estimate the effects of axonal swelling, axon diameters were changed from 6 to 10 microm. Membrane permeability was altered from 0% to 40%. Finally, both elements were combined to explain increasing FA in the hyperacute stage of white matter infarction. The simulation demonstrated that simple water shift into the intracellular space reduces ADC and increases FA, but not to the extent expected from actual human cases (ADC approximately 50%; FA approximately +20%). Similarly, membrane permeability alone was insufficient to explain this phenomenon. However, a combination of both factors successfully replicated changes in diffusivity indices. Both axonal swelling and reduced membrane permeability appear important in explaining changes in ADC and FA based on eigenvalues in hyperacute-stage white matter infarction.

A comparison between equations describing in vivo MT: The effects of noise and sequence parameters

Quantitative models of magnetization transfer (MT) allow the estimation of physical properties of tissue which are thought to reflect myelination, and are therefore likely to be useful for clinical application. Although a model describing a two-pool system under continuous wave-saturation has been available for two decades, generalizing such a model to pulsed MT, and therefore to in vivo applications, is not straightforward, and only recently have a range of equations predicting the outcome of pulsed MT experiments been proposed. These solutions of the 2-pool model are based on differing assumptions and involve differing degrees of complexity, so their individual advantages and limitations are not always obvious. This paper is concerned with the comparison of three differing signal equations. After reviewing the theory behind each of them, their accuracy and precision is investigated using numerical simulations under variable experimental conditions such as degree of T1-weighting of the acquisition sequence and SNR, and the consistency of numerical results is tested using in vivo data. We show that while in conditions of minimal T1-weighting, high SNR, and large duty cycle the solutions of the three equations are consistent, they have a different tolerance to deviations from the basic assumptions behind their development, which should be taken into account when designing a quantitative MT protocol.

Fast multislice mapping of the myelin water fraction using multicompartment analysis of T decay at 3T: A preliminary postmortem study

Quantitative mapping of the myelin water content can provide significant insight into the pathophysiology of several white matter diseases, such as multiple sclerosis and leukoencephalopathies, and can potentially become a useful clinical tool for early diagnosis of these diseases. In this study, multicompartment analysis of T(2)(*) decay (MCAT(2)(*)) was used for the quantitative mapping of myelin water fraction (MWF). T(2)(*) decay of each voxel at multiple slice locations was acquired in fixed human brains using a multigradient-echo (MGRE) pulse sequence with alternating readout gradient polarities. Compared to prior techniques using Carr-Purcell-Meiboom-Gill (CPMG) acquisition, the MGRE acquisition approach has: 1) a very short first echo time ( approximately 2 ms) and echo-spacing ( approximately 1 ms), which allows for the acquisition of multiple sampling points during the fast decay of the myelin water signal; 2) a low RF duty cycle, which is especially important for achieving acceptable specific absorption rate (SAR) levels at high field strengths. Multicompartment analysis was then applied to the T(2)(*) decay in each pixel using a 3-pool model of white matter to detect the signal arising from the myelin water, myelinated axonal water, and mixed water compartments.