Single-compartment Model Research Articles

Inhibitory synaptic plasticity regulates pyramidal neuron spiking in the rodent hippocampus

Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E GABA). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E GABA by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12±0.07 Hz to 0.44±0.13 Hz ( n=11; P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E GABA, which effectively weakens inhibition. Depolarization of E GABA at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E GABA at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E GABA decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input–output transmission. Moreover, a depolarizing shift in E GABA at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up- and down-strokes of the first half of the theta rhythm ( P<0.05), without changing the preferred phase of firing ( P=0.783). This study provides the first explanation of how depolarizing E GABA affects pyramidal cell output within the hippocampus.

Ionic Mechanisms of Endogenous Bursting in CA3 Hippocampal Pyramidal Neurons: A Model Study

A critical property of some neurons is burst firing, which in the hippocampus plays a primary role in reliable transmission of electrical signals. However, bursting may also contribute to synchronization of electrical activity in networks of neurons, a hallmark of epilepsy. Understanding the ionic mechanisms of bursting in a single neuron, and how mutations associated with epilepsy modify these mechanisms, is an important building block for understanding the emergent network behaviors. We present a single-compartment model of a CA3 hippocampal pyramidal neuron based on recent experimental data. We then use the model to determine the roles of primary depolarizing currents in burst generation. The single compartment model incorporates accurate representations of sodium (Na+) channels (NaV1.1) and T-type calcium (Ca2+) channel subtypes (CaV3.1, CaV3.2, and CaV3.3). Our simulations predict the importance of Na+ and T-type Ca2+ channels in hippocampal pyramidal cell bursting and reveal the distinct contribution of each subtype to burst morphology. We also performed fast-slow analysis in a reduced comparable model, which shows that our model burst is generated as a result of the interaction of two slow variables, the T-type Ca2+ channel activation gate and the Ca2+-dependent potassium (K+) channel activation gate. The model reproduces a range of experimentally observed phenomena including afterdepolarizing potentials, spike widening at the end of the burst, and rebound. Finally, we use the model to simulate the effects of two epilepsy-linked mutations: R1648H in NaV1.1 and C456S in CaV3.2, both of which result in increased cellular excitability.

Quantification of liver perfusion with [15O]H2O-PET and its relationship with glucose metabolism and substrate levels

Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.

Kv4 (A‐type) potassium currents in the mouse medial nucleus of the trapezoid body

Principal neurones of the mouse medial nucleus of the trapezoid body (MNTB) possess multiple voltage-gated potassium currents, including a transient outward current (or A-current), which is characterized here. The A-current exhibited rapid voltage-dependent inactivation and was half inactivated at resting membrane potentials. Following a hyperpolarizing pre-pulse to remove inactivation, the peak transient current was 1.07 nA at -17 mV. The pharmacological characteristics of this A-current were consistent with Kv4 subunits in expression studies; the A-current was resistant to block by tetraethylammonium and dendrotoxin-I but sensitive to millimolar concentrations of 4-aminopyridine and 5 microM hanatoxin. Immunohistochemistry confirmed that Kv4.3 sub-units are present in the MNTB. In a single-compartment model of an MNTB neurone, the A-current served to accelerate the decay of the initial action potentials in a stimulus train and suggested that removal of A-current steady-state inactivation could raise firing threshold for non-calyceal synaptic inputs. This A-type current was not observed in the rat.

A-Type K+ Current Can Act as a Trigger for Bursting in the Absence of a Slow Variable

Models of bursting in single cells typically include two subsystems with different timescales. Variations in one or more slow variables switch the system between a silent and a spiking state. We have developed a model for bursting in the pituitary lactotroph that does not include any slow variable. The model incorporates fast, noninactivating calcium and potassium currents (the spike-generating mechanism), as well as the fast, inactivating A-type potassium current (I(A)). I(A) is active only briefly at the beginning of a burst, but this brief impulse of I(A) acts as a burst trigger, injecting the spike trajectory close to an unstable steady state. The spiraling of the trajectory away from the steady state produces a period of low-amplitude spiking typical of lactotrophs. Increasing the conductance of A-type potassium current brings the trajectory closer to the unstable steady state, increasing burst duration. However, this also increases interburst interval, and for larger conductance values, all activity stops. To our knowledge, this is the first example of a physiologically based, single-compartmental model of bursting with no slow subsystem.

Advanced Liver Fibrosis: Diagnosis with 3D Whole-Liver Perfusion MR Imaging—Initial Experience

Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. The purpose of this study was to prospectively evaluate sensitivity and specificity of various estimated perfusion parameters at three-dimensional (3D) perfusion magnetic resonance (MR) imaging of the liver in the diagnosis of advanced liver fibrosis (stage >or= 3), with histologic analysis, liver function tests, or MR imaging as the reference standard. Whole-liver 3D perfusion MR imaging was performed in 27 patients (17 men, 10 women; mean age, 55 years) after dynamic injection of 8-10 mL of gadopentetate dimeglumine. The following estimated perfusion parameters were measured with a dual-input single-compartment model: absolute arterial blood flow (F(a)), absolute portal venous blood flow (F(p)), absolute total liver blood flow (F(t)) (F(t) = F(a) + F(p)), arterial fraction (ART), portal venous fraction (PV), distribution volume (DV), and mean transit time (MTT) of gadopentetate dimeglumine. Patients were assigned to two groups (those with fibrosis stage <or= 2 and those with fibrosis stage >or= 3), and the nonparametric Mann-Whitney test was used to compare F(a), F(p), F(t), ART, PV, DV, and MTT between groups. Receiver operating characteristic curve analysis was used to assess the utility of perfusion estimates as predictors of advanced liver fibrosis. There were significant differences for all perfusion MR imaging-estimated parameters except F(p) and F(t). There was an increase in F(a), ART, DV, and MTT and a decrease in PV in patients with advanced fibrosis compared with those without advanced fibrosis. DV had the best performance, with an area under the receiver operating characteristic curve of 0.824, a sensitivity of 76.9% (95% confidence interval: 46.2%, 94.7%), and a specificity of 78.5% (95% confidence interval: 49.2%, 95.1%) in the prediction of advanced fibrosis.

Impact of respiratory mechanics model parameters on gas exchange efficiency

In this article, we are interested in the impact of the mechanical characteristics of the bronchial tree and lung parenchyma on the gas exchange capacity of the human lungs. Objectives. The precise role of the airway smooth muscle (ASM) remains a matter of debate. ASM could have a structural function, to confer transport optimized mechanical properties to the bronchial tree. To test this hypothesis, the present model analysis investigates how ASM-dependent changes in respiratory mechanics can influence the efficiency of the lungas gas exchangers. Method. To this aim, two models have been elaborated. The first one is a single compartment model of the respiratory system that is accurate enough to predict the behaviour of the system during a complex dynamical situation (the forced inspiratory-expiratory maneuver that is performed during spirometric evaluations). The second one is an oxygen absorption model. The two models are coupled in series. The effects of changes in the parameters of the mechanical model on the performance of the gas exchange model are described. Results. The model shows that the mechanical response of the bronchial tree to the dilating forces related to inspiration is among the determinants of this efficiency. At one extreme, a fully rigid bronchial tree would be counterproductive by preventing sufficient amounts of gas to flow through it and reach the alveoli. At the other extreme, a fully distensible bronchial tree would allow greater inspiratory volumes to enter the thorax, but would compromise gas exchange efficiency by decreasing the alveolar volume, hence the membrane surface available for oxygen transfer (deadspace effect). This supports the hypothesis that ASM has a transport optimizing structural function. Conclusions. This is supported by physiological observations compatible with deadspace increases following the administration of ASM-relaxing agents, i. e. bronchodilators.

Effects of inertance on respiratory mechanics measurements in mechanically ventilated children

The use of the first-order linear single compartment model when studying respiratory mechanics classically neglects inertance (Irs). We hypothesized that Irs would affect compliance (Crs) and resistance (Rrs) estimates in mechanically ventilated young children. Prospective study; single-center evaluation. University-affiliated tertiary pediatric intensive care unit. Forty-four patients with and without respiratory disease. Patients were studied during volume-controlled constant inspiratory flow ventilation. Pressure (PaO) and flow (V') were analyzed according to two different models: a one-compartment first-order linear model according to PaO = (1/Crs) x V + Rrs x V' and a one-compartment second-order linear model according to PaO = (1/Crs) x V + Rrs x V' + Irs x V''. Irs was higher in children with vs. those without respiratory disease (median 0.00224 cm H2O/L/sec2, Q1-Q3 0.00180-0.00321 vs. median 0.00133 cm H2O/L/sec2, Q1-Q3 0.00072-0.00210; p < .001)). A positive correlation between Irs and the difference of Crs estimates between the first- and the second-order model was found in both groups (r = .84, p < .05 and r = .67, p < .05). Rrs estimates were similar in both groups. This study showed that the linear single-compartment model may not adequately estimate the respiratory mechanical properties in mechanically ventilated children, particularly in the presence of respiratory disease. Including an Irs term significantly diminished Crs estimates. A one-compartment second-order linear model might be a useful clinical tool in more adequately measuring respiratory mechanics and optimizing ventilatory settings in children with respiratory disease.

Evaluation of pharmacokinetic and bioequivalence of brands of sulphadoxine-pyrimethamine tablets used in intermittent preventive therapy for pregnant women in Nigeria

Objectives: The aim of this study is to investigate the pharmacokinetic and relative bioavailability of three tablet formulation containing sulphadoxine pyrimethamine (SP) used for intermittent preventive therapy in pregnant women in Nigeria to see whether there is need for dose adjustment. Methods: Twelve healthy volunteers(pregnant women at their fourth month of pregnancy) attending antenatal clinic (ANC)were randomised to receive a single oral dose of three SP tablets each containing 500mg sulphadoxine (XD)and 25mg pyrimethamine (PY) in form of A (innovator product) and B,C(locally manufactured SP tablet formulation),after an overnight fasting. Several blood samples (100μl) were collected from a finger prick in duplicates up to ten days and dried on a Whatman® filter paper. The samples were analysed for DX and PY using the High Performance Liquid Chromatography (HPLC) method. The pharmacokinetic parameters assessed were maximum plasma concentration (Cmax), area under curve (AUC), elimination half life (t1/2), time to attain maximum concentration (tmax) and relative bioavailability using the single compartment model. Results: Sample formulation B was significantly lower than samples A and C (p<0.1) in mean plasma concentration (Cmax), area under curve (AUC). Conclusion: The difference shows in vivo inequivalence between the products, and calls for caution in using these products, however the pharmacokinetic results shows that there is no need for dose adjustment of SP in pregnancy since they attain therapeutic concentration in vivo, indicating that their kinetics is not altered in pregnancy.

Influence of Long‐Term Sodic‐Water Irrigation, Gypsum, and Organic Amendments on Soil Properties and Nitrogen Mineralization Kinetics under Rice–Wheat System

Influence of long‐term sodic‐water (SW) irrigation with or without gypsum and organic amendments [green manure (GM), farmyard manure (FYM), and rice straw (RS)] on soil properties and nitrogen (N) mineralization kinetics was studied after 12 years of rice–wheat cropping in a sandy loam soil in northwest India. Long‐term SW irrigation increased soil pH, exchangeable sodium percentage (ESP), and sodium adsorption ratio (SAR) and decreased organic carbon (OC) and total N content. On the other hand, application of gypsum and organic amendments resulted in significant improvement in all these soil properties. Mineralization of soil N ranged from 54 to 111 mg N kg−1 soil in different treatments. Irrigation with SW depressed N mineralization. In SW‐irrigated plots, two flushes of N mineralization were observed; the first during 0 to 7 d and the second after 28 d. Amending SW irrigated plots with GM and FYM enhanced mineralization of soil N. Gypsum application along with SW irrigation reduced cumulative N mineralization at 56 days in RS‐amended plots but increased it under GM‐treated, FYM‐treated, or unamended plots. Nitrogen mineralization potential (No) ranged from 62 to 543 mg N kg−1 soil. In the first‐order zero‐order model (FOZO), the easily decomposable fraction ranged from 5.4 to 42 mg N kg−1 soil. Compared to the first‐order single compartment model, the FOZO model could better explain the variations in N mineralization in different treatments. Variations in No were influenced more by changes in pH, SAR, and ESP induced by long‐term SW irrigations and amendments rather than by soil OC.

IQ-Motif Proteins Influence Intracellular Free Ca2+in Hippocampal Neurons Through Their Interactions With Calmodulin

Calmodulin (CaM) is most recognized for its role in activating Ca(2+)-CaM-dependent enzymes following increased intracellular Ca(2+). However, CaM's high intracellular concentration indicates CaM has the potential to play a significant role as a Ca(2+) buffer. Neurogranin (Ng) is a small neuronal IQ-motif-containing protein that accelerates Ca(2+) dissociation from CaM. In cells that contain high concentrations of both Ng and CaM, like CA1 pyramidal neurons, we hypothesize that the accelerated Ca(2+) dissociation from CaM by Ng decreases the buffering capacity of CaM and thereby shapes the transient dynamics of intracellular free Ca(2+). We examined this hypothesis using a mathematical model constructed on the known biochemistry of Ng and confirmed the simulation results with Ca(2+) imaging data in the literature. In a single-compartment model that contains no Ca(2+) extrusion mechanism, Ng increased the steady-state free Ca(2+). However, in the presence of a Ca(2+) extrusion mechanism, Ng accelerated the decay rate of free Ca(2+) through its ability to increase the Ca(2+) dissociation from CaM, which in turn becomes subject to Ca(2+) extrusion. Interestingly, PEP-19, another neuronal IQ-motif protein that accelerates both Ca(2+) association and dissociation from CaM, appears to have the opposite impact than that of Ng on free Ca(2+). As such, Ng may regulate, in addition to the Ca(2+)-CaM-dependent process, Ca(2+)-sensitive enzymes by influencing the buffering capacity of CaM and subsequently free Ca(2+) levels. We examined the relative impact of these Ng-induced effects in the induction of synaptic plasticity.

PET as a Diagnositic Tool in Unilateral Condylar Hyperactivity

PET as a Diagnositic Tool in Unilateral Condylar Hyperactivity

Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na+, delayed-rectifier K+, and slowly inactivating d-type K+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, g d, and it is delayed for larger g d. As g d further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their g d and in the strength of their Na+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction.

Comparison of Liver Perfusion Parameters Studied With Conventional Extravascular and Experimental Intravascular CT Contrast Agents

To compare liver perfusion parameters obtained by using an extravascular contrast agent and a blood-pool agent. Fifteen rabbits were imaged with a continuous 40-second single-slice computed tomography acquisition after a bolus injection of contrast agent (physiologic bolus duration 4-5 seconds, extravascular iohexol, n = 7; experimental nanoparticulated blood-pool agent WIN8883, n = 8). Time-density curves were generated for the aorta, portal vein, and liver. From the curves, arterial, portal, and total blood flows and hepatic perfusion index (HPI, arterial-to-total perfusion ratio) were determined by using two commonly applied fundamentally different analyzing methods: the single-compartment model and the peak gradient (PG) method. Also, the gamma variate fitting method was used. By using the single-compartment model, the obtained HPI and total blood flow were 0.14 +/- 0.04 and 2.29 +/- 0.40 (mL/min/mL(tissue)) for WIN8883, and 0.15 +/- 0.06 (P = .54) and 4.60 +/- 1.14 (mL/min/mL(tissue)) (P = .0002) for iohexol, respectively. With the PG, HPI and total blood flow were 0.15 +/- 0.08 and 1.27 +/- 0.24 (mL/min/mL(tissue)) for WIN8883, and 0.20 +/- 0.06 (P = .12) and 2.11 +/- 0.25 (mL/min/mL(tissue)) (P = .00002) for iohexol, respectively. With the blood pool agent, similar contrast enhancement to the conventional agent was achieved with about 36% reduced dosage of iodine per body weight (mg I/kg). HPI was found to be quite insensitive to different contrast agent types and analyzing methods. However, the arterial, portal and total liver blood flow values strongly depend on contrast agent type and modeling method.

Neurofitter: a parameter tuning package for a wide range of electrophysiological neuron models

One of the major tasks of a neuroscientist who is developing a neuron model is to find suitable values for all the parameters of the model. This is, in general, a very complex job that can take a lot of time and that requires a lot of know-how when the parameter tuning is done by hand. We have developed a software tool called Neurofitter that can be used to automate the process of parameter searching for neuron models. The user has to provide time series data recorded during an experiment in the form of traces. Neurofitter will then run the computer model several times with different sets of values for the model parameters and will compare model output traces with the experimental data traces using the phase-plane trajectory method [1]. This way Neurofitter maps every set of parameters values onto a fitness value that shows how well a model is able to reproduce the experimental data. This transforms the search for optimal parameters into a problem that can be solved with general optimization algorithms. The algorithms used by Neurofitter include Evolutionary Strategies, Particle Swarm Optimization and Mesh Adaptive Search. We will show some results obtained using the method to fit a single compartmental model, a simple network model and a complicated model of a Purkinje cell [2]. The source code can be freely downloaded from Sourceforge http://neurofitter.sourceforge.net Figure 1 Voltage traces showing output of a simple single-compartmental model of a rhythm generating neuron in the pre-Botzinger complex [3]. A. Reference traces used to fit the model to. B. A trace showing the output generated by increasing the persistent ...

PHARMACOKINETICS OF ORALLY ADMINISTERED IBUPROFEN IN AFRICAN AND ASIAN ELEPHANTS (LOXODONTA AFRICANA AND ELEPHAS MAXIMUS)

The pharmacokinetic parameters of S(+) and R(-) ibuprofen were determined in 20 elephants after oral administration of preliminary 4-, 5-, and 6-mg/kg doses of racemic ibuprofen. Following administration of 4 mg/kg ibuprofen, serum concentrations of ibuprofen peaked at 5 hr at 3.9 +/- 2.07 microg/ml R(-) and 10.65 +/- 5.64 microg/ml S(+) (mean +/- SD) in African elephants (Loxodonta africana) and at 3 hr at 5.14 +/- 1.39 microg/ml R(-) and 13.77 +/- 3.75 microg/ml S(+) in Asian elephants (Elephas maximus), respectively. Six-milligram/kilogram dosages resulted in peak serum concentrations of 5.91 +/- 2.17 microg/ml R(-) and 14.82 +/- 9.71 microg/ml S(+) in African elephants, and 5.72 +/- 1.60 microg/ml R(-) and 18.32 +/- 10.35 microg/ml S(+) in Asian elephants. Ibuprofen was eliminated with first-order kinetics characteristic of a single-compartment model with a half-life of 2.2-2.4 hr R(-) and 4.5-5.1 hr S(+) in African elephants and 2.4-2.9 hr R(-) and 5.9-7.7 hr S(+) in Asian elephants. Serum concentrations of R(-) ibuprofen were undetectable at 24 hr, whereas S(+) ibuprofen decreased to below 5 microg/ml 24 hr postadministration in all elephants. The volume of distribution was estimated to be between 322 and 356 ml/kg R(-) and 133 and 173 ml/kg S(+) in Asian elephants and 360-431 ml/kg R(-) and 179-207 ml/kg S(+) in African elephants. Steady-state serum concentrations of ibuprofen ranged from 2.2 to 10.5 microg/ml R(-) and 5.5 to 32.0 microg/ml S(+) (mean: 5.17 +/- 0.7 R(-) and 13.95 +/- 0.9 S(+) microg/ml in African elephants and 5.0 +/- 1.09 microg/ml R(-) and 14.1 +/- 2.8 microg/ml S(+) in Asian elephants). Racemic ibuprofen administered at 6 mg/kg/12 hr for Asian elephants and at 7 mg/kg/12 hr for African elephants results in therapeutic serum concentrations of this antiinflammatory agent.

Using the single-compartment ratio model to calculate half-life, NT-proBNP as an example

Background The single-compartment model offers a simple way to calculate the half-life of a compound if it is secreted or injected at the known rate compared with another compound whose half-life is known. This model may be easier to use than the exponential decay model. Investigators disagree on the value of the half-life of NT-proBNP, with published values ranging from 70 to 120 min. Prior studies used values from sheep, which may not be appropriate in humans. Therefore, we have re-evaluated the half-life of NT-proBNP using a single-compartment model. Methods The single-compartment model allows one to evaluate the half-life of NT-proBNP using the NT-proBNP:BNP ratio and the BNP half-life. We calculated the NT-proBNP:BNP ratio from 26 subjects without cardiac abnormalities. Results The mean ratio of the NT-proBNP to BNP was 1.24 with an SEM of 0.1. Using a half-life of 20 min for BNP, the calculated half-life for NT-proBNP would be 24.8 min. Conclusions The single-compartment ratio model requires neither strictly first-order decay after stimulation, nor the collection of times samples. The re-calculated half-life for NT-proBNP is 25 min for humans, which differs greatly from the current literature value of 90 min and thus its half-life is closer to that of BNP in normal subjects. Accordingly its estimated time to return to a steady-state after a disturbance is 100 min, and therefore it could be useful in the monitoring of patients over short time periods. The single-compartment ratio model is fairly robust in the presence of cross-reactivity.

The prediction of radiation‐induced liver dysfunction using a local dose and regional venous perfusion model

We have shown that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. The ability to safely deliver higher doses is primarily limited by the development of radiation-induced liver disease, characterized by venous occlusion. In this study, we investigated whether portal venous perfusion measured prior to the end of radiation therapy (RT) together with dose could predict liver venous perfusion dysfunction after treatment. Ten patients with unresectable intrahepatic cancer participated in an IRB-approved computer tomography (CT) perfusion study. Hepatic arterial and portal vein perfusion distributions were estimated by using dynamic contrast enhanced CT and the single compartmental model. Scans were obtained at four time points: prior to treatment, after 15 and 30 fractions of 1.5 Gy treatments, and one month following the completion of RT. Multivariant linear regression was used to determine covariances among the first three time point measurements plus dose for prediction of the post RT measurement. The reduction in the regional venous perfusion one month following RT was predicted by the local accumulated dose and the change in the regional venous perfusion after -30 fractions (F=90.6,p <0.000 01). Each Gy produced an approximately 1.2% of reduction in the venous perfusion. This local dose and venous perfusion model has the potential to predict individual sensitivity to radiation. This is the first step toward developing a method to deliver higher and potentially more curative radiation doses to the patients who can safely receive these higher doses.

Neurofitter: a parameter tuning package for a wide range of electrophysiological neuron models.

The increase in available computational power and the higher quality of experimental recordings have turned the tuning of neuron model parameters into a problem that can be solved by automatic global optimization algorithms. Neurofitter is a software tool that interfaces existing neural simulation software and sophisticated optimization algorithms with a new way to compute the error measure. This error measure represents how well a given parameter set is able to reproduce the experimental data. It is based on the phase-plane trajectory density method, which is insensitive to small phase differences between model and data. Neurofitter enables the effortless combination of many different time-dependent data traces into the error measure, allowing the neuroscientist to focus on what are the seminal properties of the model.We show results obtained by applying Neurofitter to a simple single compartmental model and a complex multi-compartmental Purkinje cell (PC) model. These examples show that the method is able to solve a variety of tuning problems and demonstrate details of its practical application.

An efficient method for calculating kinetic parameters in a dual-input single-compartment model

Quantitative measurement of hepatic perfusion has the potential to provide important information in the assessment and management of various liver diseases. The utility of hepatic perfusion characterization relies on the resolution of each component of its dual blood supply, i.e. the hepatic artery and portal vein. In this study, a linear equation was derived by integrating the differential equation describing the kinetic behaviour of contrast agent (CA) in a dual-input single-compartment model, from which the kinetic parameters can be easily obtained using the linear least-squares method. The usefulness of this method was investigated using computer simulations, in comparison with the non-linear least-squares (NLSQ) method. This method calculated the kinetic parameters faster than the NLSQ method by a factor of approximately 10, with almost the same accuracy as the NLSQ method. This method will be useful for analysing the kinetic behaviour of CA in the unique liver environment, especially by generating the functional images of kinetic parameters.