Input Compartment Research Articles

Identifiable Paths and Cycles in Linear Compartmental Models.

We introduce a class of linear compartmental models called identifiable path/cycle models which have the property that all of the monomial functions of parameters associated to the directed cycles and paths from input compartments to output compartments are identifiable and give sufficient conditions to obtain an identifiable path/cycle model. Removing leaks, we then show how one can obtain a locally identifiable model from an identifiable path/cycle model. These identifiable path/cycle models yield the only identifiable models with certain conditions on their graph structure and thus we provide necessary and sufficient conditions for identifiable models with certain graph properties. A sufficient condition based on the graph structure of the model is also provided so that one can test if a model is an identifiable path/cycle model by examining the graph itself. We also provide some necessary conditions for identifiability based on graph structure. Our proofs use algebraic and combinatorial techniques.

Multi-compartment kinetic–allometric (MCKA) model of radionuclide bioaccumulation in marine fish

Abstract. A model of the radionuclide accumulation in fish taking into account the contribution of different tissues and allometry is presented. The basic model assumptions are as follows. (i) A fish organism is represented by several compartments in which radionuclides are homogeneously distributed. (ii) The compartments correspond to three groups of organs or tissues: muscle, bones and organs (kidney, liver, gonads, etc.) differing in metabolic function. (iii) Two input compartments include gills absorbing contamination from water and digestive tract through which contaminated food is absorbed. (iv) The absorbed radionuclide is redistributed between organs or tissues according to their metabolic functions. (v) The elimination of assimilated elements from each group of organs or tissues differs, reflecting differences in specific tissues or organs in which elements were accumulated. (vi) The food and water uptake rates, elimination rate, and growth rate depend on the metabolic rate, which is scaled by fish mass to the 3/4 power. The analytical solutions of the system of model equations describing dynamics of the assimilation and elimination of 134Cs, 57Co, 60Co, 54Mn and 65Zn, which are preferably accumulated in different tissues, exhibited good agreement with the laboratory experiments. The developed multi-compartment kinetic–allometric model was embedded into the box model POSEIDON-R (Maderich et al., 2018b), which describes transport of radionuclides in water, accumulation in the sediment and transfer of radionuclides through the pelagic and benthic food webs. The POSEIDON-R model was applied for the simulation of the transport and fate of 60Co and 54Mn routinely released from Forsmark Nuclear Power Plant (NPP) located on the Baltic Sea coast of Sweden and for calculation of 90Sr concentration in fish after the accident at Fukushima Dai-ichi NPP. Computed concentrations of radionuclides in fish agree with the measurements much better than calculated using standard whole-body model and target tissue model. The model with the defined generic parameters could be used in different marine environments without calibration based on a posteriori information, which is important for emergency decision support systems.

Neuronal Constituents and Putative Interactions Within the Drosophila Ellipsoid Body Neuropil.

The central complex (CX) is a midline-situated collection of neuropil compartments in the arthropod central brain, implicated in higher-order processes such as goal-directed navigation. Here, we provide a systematic genetic-neuroanatomical analysis of the ellipsoid body (EB), a compartment which represents a major afferent portal of the Drosophila CX. The neuropil volume of the EB, along with its prominent input compartment, called the bulb, is subdivided into precisely tessellated domains, distinguishable based on intensity of the global marker DN-cadherin. EB tangential elements (so-called ring neurons), most of which are derived from the DALv2 neuroblast lineage, predominantly interconnect the bulb and EB domains in a topographically organized fashion. Using the DN-cadherin domains as a framework, we first characterized this connectivity by Gal4 driver lines expressed in different DALv2 ring neuron (R-neuron) subclasses. We identified 11 subclasses, 6 of which correspond to previously described projection patterns, and 5 novel patterns. These subclasses both spatially (based on EB innervation pattern) and numerically (cell counts) summate to the total EB volume and R-neuron cell number, suggesting that our compilation of R-neuron subclasses approaches completion. EB columnar elements, as well as non-DALv2 derived extrinsic ring neurons (ExR-neurons), were also incorporated into this anatomical framework. Finally, we addressed the connectivity between R-neurons and their targets, using the anterograde trans-synaptic labeling method, trans-Tango. This study demonstrates putative interactions of R-neuron subclasses and reveals general principles of information flow within the EB network. Our work will facilitate the generation and testing of hypotheses regarding circuit interactions within the EB and the rest of the CX.

Population pharmacokinetic model for tumescent lidocaine in women undergoing breast cancer surgery.

Tumescent lidocaine anesthesia (TLA) is an opportunity to perform mastectomy for breast cancer without general anesthesia in elderly women. Few reports are available on the pharmacokinetics of lidocaine in a context of TLA during a unilateral mastectomy. The aim of this study was to describe lidocaine pharmacokinetics in elderly women undergoing breast cancer surgery after TLA and to explore the risk of the toxicity of this technique. A prospective study was conducted to examine the pharmacokinetics of lidocaine in women undergoing TLA. TLA consists of an intradermal lidocaine instillation (20mL, 1% [200mg]) followed by a tumescent lidocaine infiltration (100mL of 1% lidocaine [1000mg] and 0.5mg epinephrine to 1L Ringer's lactate) via an infusion pump. A population pharmacokinetic (popPK) analysis was performed using the nonlinear mixed effects model (NONMEM). The analysis included 116 observations from 17 women with a median (range) age of 83.4 (60.5-90.0). The median tumescent lidocaine dose was 800mg (range 375-1000mg) infused over 48.0 ± 11.0min. A one-compartment disposition model with first order absorption, two input compartments, and a central elimination best described the pharmacokinetics of lidocaine. The estimates (between subject variability; relative standard error, %) of apparent volume, apparent clearance, tumescent absorption rate, and instillation absorption rate were 195.0 (46.3; 14.5%) L, 24.7 (48.9; 13.3%) Lh-1, 0.28 (39.6; 13.8%) h-1, and 2.56 (135.3; 44.9%) h-1, respectively. This is the first popPK model developed to describe kinetic profiles of TLA. These findings confirm the slow diffusion of lidocaine from the tumescent deposit.

Vastly accelerated linear least-squares fitting with numerical optimization for dual-input delay-compensated quantitative liver perfusion mapping.

To propose an efficient algorithm to perform dual input compartment modeling for generating perfusion maps in the liver. We implemented whole field-of-view linear least squares (LLS) to fit a delay-compensated dual-input single-compartment model to very high temporal resolution (four frames per second) contrast-enhanced 3D liver data, to calculate kinetic parameter maps. Using simulated data and experimental data in healthy subjects and patients, whole-field LLS was compared with the conventional voxel-wise nonlinear least-squares (NLLS) approach in terms of accuracy, performance, and computation time. Simulations showed good agreement between LLS and NLLS for a range of kinetic parameters. The whole-field LLS method allowed generating liver perfusion maps approximately 160-fold faster than voxel-wise NLLS, while obtaining similar perfusion parameters. Delay-compensated dual-input liver perfusion analysis using whole-field LLS allows generating perfusion maps with a considerable speedup compared with conventional voxel-wise NLLS fitting. Magn Reson Med 79:2415-2421, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Parametric imaging and quantitative analysis of the PET amyloid ligand [18F]flutemetamol

ObjectivesThe amyloid imaging PET tracer [18F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling. MethodsThe cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time–activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels. ResultsThe highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2′ (R2=0.98), or using a cohort mean k2′ (R2=0.97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70–90min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R2=0.97, RPM R2=0.96 and SUVR R2=0.95) Poorest agreement was seen with MRTM without pre-filtering (R2=0.68). ConclusionsParametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

Population pharmacokinetic analysis of bupivacaïne used in regional anaesthesia

Introduction The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight, sex and drugs co medication (Clonidine and Propofol) on pharmacokinetic parameters. Materials and method A total of 59 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. This pharmacokinetic model was validated using npde package for statistic software R. The simulations confirm that our final model was valid. Results and discussion Two compartment model with first order absorption, two input compartments, a central elimination and peripheral compartment was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model ( P = 0.837) showed this as a valid model. The description of the quality of the estimate by the graphic diagnostic suggests a good fitting of the final model. The selected model predicts a population clearance of 503 mL/min (residual standard error [RSE] = 16.5%, 95% CI = [534.9–866.9]) with between subject variability of 93.16%. The central and peripheral volumes of distribution were respectively 6850 L and 120 L. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00073/min for the lumbar site and 0.0037/min for the sciatic site. Within subject variability WSV% was 30, 3%. Drug Co medication, age, body weight and sex, have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.

Regulatory mechanisms underlying the differential growth of dendrites and axons.

A typical neuron is comprised of an information input compartment, or the dendrites, and an output compartment, known as the axon. These two compartments are the structural basis for functional neural circuits. However, little is known about how dendritic and axonal growth are differentially regulated. Recent studies have uncovered two distinct types of regulatory mechanisms that differentiate dendritic and axonal growth: dedicated mechanisms and bimodal mechanisms. Dedicated mechanisms regulate either dendritespecific or axon-specific growth; in contrast, bimodal mechanisms direct dendritic and axonal development in opposite manners. Here, we review the dedicated and bimodal regulators identified by recent Drosophila and mammalian studies. The knowledge of these underlying molecular mechanisms not only expands our understanding about how neural circuits are wired, but also provides insights that will aid in the rational design of therapies for neurological diseases.

Population pharmacokinetics of bupivacaine in combined lumbar and sciatic nerve block

Objectives:The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight and sex on pharmacokinetic parameters.Materials and Methods:A total of 31 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine.Results:One compartment model with first order absorption, two input compartments and a central elimination was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model (P = 0.156) showed this as a valid model. The selected model predicts a population clearance of 930 ml/min (residual standard error [RSE] = 15.48%, IC 95% = 930 ± 282.24) with inter individual variability of 75.29%. The central volume of distribution was 134 l (RSE = 12.76%, IC = 134 ± 33.51 L) with inter individual variability of 63.40%. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00462/min for the lumbar site and 0.292/min for the sciatic site. Age, body weight and sex have no effect on the bupivacaine pharmacokinetics in this studied population.Conclusion:The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.

Blood–brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene

BackgroundP-glycoprotein is a blood–brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood–brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood–brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease.MethodsThirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction.ResultsIn healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T.ConclusionsIn Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood–brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain.

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.

Acute treatment with pentobarbital alters the kinetics of in vivo receptor binding in the mouse brain

The effect of pentobarbital, a sedative-hypnotic barbiturate, on the in vivo binding of benzodiazepine receptors in the mouse brain was investigated. Dose-related changes in the apparent binding of [3H]Ro15-1788 ([3H]flumazenil) in the cerebral cortex, cerebellum and pons-medulla were observed by pretreatment with pentobarbital. For quantification of the kinetic properties of the in vivo binding of [3H]Ro15-1788, time courses of radioactivity following its injection were examined, and kinetic analysis was performed using the compartment model. The time courses of radioactivity following injection of [3H]Ro15-1788 with 3 mg/kg Ro15-1788 were used as input function. In all regions studied, rate constants between input compartment and specific binding compartment were significantly decreased by pentobarbital. However, no significant alterations in the binding potential (BP=K3/K4) of benzodiazepine receptors by pentobarbital were observed in any of the regions. A saturation experiment indicated that the decrease in the input rate constant (K3), which includes both the association rate constant (k(on)) and the number of binding sites available (B(max)), was mainly due to decrease in k(on). These results suggest that apparent increases in binding at 20 min after tracer injection were due to the decrease in the association and dissociation rates of binding in vivo.

Audio system with partitioned input and output compartments

An audio system has a cabinet with several partitions. The partitions divide the interior of the cabinet into compartments. These include an input compartment, an output compartment above the input compartment, an outer compartment to one side of the input and output compartments, and an intermediate compartment between the outer compartment and the input and output compartments. Two tweeters are mounted one above the other in the outer compartment as are two midrange speakers. The outputs of the midrange speakers open into the intermediate compartment while the outputs of the tweeters open to the atmosphere. A woofer or subwoofer is mounted on a partition which borders the input compartment, and the output of the woofer or subwoofer opens into the input compartment. The output compartment is provided with a port, and a pair of pipes connects the input compartment with the output compartment. High-frequency components of the sound emitted by the woofer or subwoofer are largely eliminated by conducting the sound to the output compartment via the pipes.

A simple fish physiological model for radioecologists exemplified for [formula omitted] direct transfer and rainbow trout ( Oncorhynchus mykiss W.)

A simple kinetic model for the transfer of radionuclide to freshwater fish was formulated based on physiological (blood and flow rates), anatomical (volume of tissue compartments) and thermodynamic (tissue-to-blood partition coefficients) parameters. The present study describes 54 Mn direct transfer to young rainbow trout and exemplifies this new approach for radioecology. The model was calibrated on uptake and depuration kinetics datasets obtained for 14 organs/tissues during a 12-week experiment. Organs were classified into three compartments: an input compartment (gills), a distribution/reservoir compartment (muscles, skeleton and skin) and an excretional function compartment (digestive system and liver). For the three compartments, the partition coefficients and the residence time of the pollutant were, respectively: 161 and 4 h, 87 and 1.5 days, and 1465 and 14 days. As an indirect validation technique, a steady-state concentration factor was calculated for the whole organism from the partition coefficient values and fractional volumes of the compartment. The value of 8 l kg −1 w.w. is similar to those reported in the literature.

Development and experience lead to increased volume of subcompartments of the honeybee mushroom body

The mushroom bodies of insects are believed to be involved in higher order sensory integration and learning. In the honeybee, the mushroom body can be separated into three different, modality-specific input compartments and several morphologically inseparable output regions. By means of morphometric analysis we show that the volumes of these subcompartments depend on both the age of the adult bee and its experience. For the most part a significant, age-dependent increase in neuropile volume is observed. Additionally, the olfactory and visual input regions show experience-related differences. Unlike other subcompartments, the visual input region does not change in volume with age, but only with experience. We thus suggest that experience is an important factor in the structural development of higher order brain regions of an insect, the honeybee.

On the transformation of compartmental systems and the indeterminacy of the volume of distribution.

A general compartmental system with multiple-point elimination is transformable to a single-point elimination system. Transformation is achieved by a similarity transformation of the rate constant matrix, A, with a diagonal matrix, D. The elements of D (1, d1, d2,...) are equivalent to the "first-pass" effect between compartments and compartment 1. Application of the derived transformation demonstrates that the volume of distribution as defined by the normalized first-moment function is a minimal volume of distribution when there is no "first-pass" effect between the drug input compartment and the observation compartment. In all other cases, the volume of distribution is a meaningless metric since it may be a minimal or maximal metric and the exact status is indeterminate. Theorems on the non-negativity of the elements of (-A)-1 are derived.

The nitrogen cycle in the broadbalk wheat experiment: A model for the turnover of nitrogen through the soil microbial biomass

A simple four-compartment model is presented for the turnover of N through the soil microbial biomass, based on measurements made in the Broadbalk Continuous Wheat Experiment at Rothamsted. The model comprises an input compartment (containing the N in roots and other plant debris entering the soil plus the inorganic N immobilized during the decomposition of this debris), feeding two organic compartments, the microbial biomass compartment and the humus compartment, which in turn feed the soil inorganic N compartment. The model was fitted to data from the plot receiving 192 kg N ha −1 yr −1 by iterative adjustment of the five independent parameters it contains. The value thus modelled for the turnover time of N in the soil microbial biomass is 1.52yr, the corresponding annual flux through the biomass being 125 kg N ha −1 yr −1. Of this flux, 59 kg comes from the input compartment and 66 kg from the humus compartment.

Computer model for simulation of first transit cardiac radionuclide curves--I.

A discrete-time, lumped-parameter mathematical model of the human cardiopulmonary circulation as it appears during a first-transit radionuclide study is developed. Eleven compartments, four delays, and 26 transfer paths are modeled, including the entire circulation from an input compartment before the vena cava to an output compartment after the aorta. The 26 transfer paths include forward and reverse flow through the heart valves, backflow from the atria into the veins, and five types of shunts. A method of modeling continuously-variable delay segments with only discrete-time sample points is devised to allow more versatility in specifying delays. The model simulates discrete time-activity curves for the various compartments of the cardiopulmonary system. The curves are obtained for end-systole and end-diastole. Simulation of curves indicative of a normal heart and several heart defects is presented. The use of this model for computer analysis of first-transit cardio-radionuclide curves is discussed.

A hybrid compartmental model for the alligator Purkinje cell. I: Preferred somatopetal conduction of dendritic spikes and soma-axon interaction.

A compartmental hardware model of an alligator Purkinje cell is described, consisting of a branched dendritic tree with four zones of spike generation and electrically excitable soma and initial-segment regions. Passive properties of the model compartments are represented by a cable analog circuit. Simulated action potentials, generated by a combination of depolarizing and hyperpolarizing conductance changes, are triggered in active compartments when the simulated membrane potential passes through preset thresholds. These were set at values corresponding to 28mV depolarization in the dendrites, 22 mV in the soma, and 7 mV in the initial-segment compartment. Synaptic inputs consisting of brief (0.35 msec) rectangular conductance changes give rise to exponentially decaying postsynaptic potentials in the input compartment which are electrotonically spread to other compartments. Orthodromic activation of the model neuron by computer-generated random pulse trains generates a simple spike discharge in the initial-segment compartment without evoking complex spikes. Synchronized excitatory input to the same compartments, however, does evoke a complex spike response in the soma and initial segment, coupled with dendritic spikes. Following antidromic activation of the model neuron, dendritic spikes are not generated, demonstrating a tendency in the dendritic tree for preferential conduction of spikes toward the soma. Investigation of some of the factors underlying this tendency suggests that variations in voltage attenuation due to dendritic geometry, convergence of electrotonically spread dendritic spikes, and the relative durations of dendritic and somatic action potentials may contribute to it. The presence of a threshold gradient in the dendritic tree, proposed by Llinás and his coworkers, was not found to be necessary to explain this tendency toward somatopetal conduction, although it cannot be excluded by the model. Examination of the role of the conically shaped initial-segment region suggests that this zone may provide a low-pass filter for signals conducted electrotonically from the axon to the soma, blocking repolarization of the soma during the complex spike burst generated in the axon.