Saturable processes. Solving the FDG model. Leonard, AKH. Similar presentations. Upload Log in. My presentations Profile Feedback Log out. Log in. Auth with social network: Registration Forgot your password? Download presentation. Cancel Download. Presentation is loading. Please wait. Copy to clipboard.
Presentation on theme: "Fund BioImag 7: Two compartment modeling 1. How do 2-deoxyglucose. Download ppt "Fund BioImag 7: Two compartment modeling 1. About project SlidePlayer Terms of Service. Nevertheless, it should be noted that PET only measures the temporal distribution of radioactivity. Although imaging the distribution of a tracer at a certain time after intravenous injection may provide useful information, especially when uptake can be related to that in a reference region without specific signal i.
For true quantification of a molecular process a tracer kinetic model is essential. A tracer kinetic model is a mathematical description of the fate of a tracer in the body, with emphasis on the organ of interest. Using such a model, observed tissue uptake and clearance of the tracer can be related to various model parameters, provided the input function is also known. As most tracers are injected intravenously, they reach tissue through the bloodstream. Consequently, in most cases, measurement of the arterial concentration over time is also needed.
Although other types of models have also been proposed, in practice compartmental models are used. In these models, the distribution of activity is allocated to a number of not necessarily physical discrete compartments. The incorporation of dietary ALA into plasma phospholipids and the subsequent conversion to its n-3 fatty acid derivatives, expressed in percentages and absolute amounts of dietary ALA, are given in Table 4.
Incorporation of dietary ALA into plasma phospholipids and subsequent conversion to its n-3 fatty acid derivatives expressed in percentage and absolute amounts of dietary ALA. Values were first calculated using averaged data from the 29 subjects. Approximately Of this ALA pool, The remaining 0. As can be seen from Table 4 , the estimates based on the individual values were essentially similar. For example, U 2 corresponded to This EPA could have originated from seafood, which had to be consumed before the start of the study, as intake of these products was prohibited during the study.
It is also possible that this EPA was partly derived from ALA, which was consumed before or during the tracer study and stored in tissues other than plasma phospholipids. Similarly, the endogenous input [U 3 ] explained Except for the mean endogenous inflow into the DHA compartment, the estimates based on individual values were very comparable to the estimates based on the averaged data. This discrepancy In some individuals, this parameter was close to zero. When this happened, U 4 [and in some cases U 3 ] resulted in a small negative number to satisfy the mass balance requirement.
For these subjects, U 4 was set to zero. Furthermore, k 0,4 values close to zero could result from measurement variability or from individuals exhibiting slow clearance of tracer DHA, so that a loss from the DHA compartment [k 0,4 ] is difficult to estimate. Percentage fractional contribution of endogenous inputs and percentage fractional transfers.
However, our study suggests that this is not the limiting step, as nearly all EPA in the plasma phospholipid pool was derived from the ALA plasma phospholipid pool.
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Only a few studies have used stable isotopes to quantitatively study ALA metabolism in adults 12 — 16 , 32 , The higher n-3 conversion values observed by Emken, Adlof, and Gulley 15 may have been attributable to the use of AUCs. Indeed, Demmelmair et al. Compared with AUC values, compartmental modeling is considered to be more accurate, as it accounts for the appearance and disappearance rates of ALA and its various metabolites.
For our modeling framework, we chose plasma phospholipid fatty acid composition to reflect hepatic conversion. Plasma triacylglycerol TG , which contains even more ALA than phospholipids, could also have been an option. Data from the stable isotope studies of Burdge and colleagues 12 , 13 , however, showed that only trace amounts of the labeled elongation products of ALA are incorporated into plasma TG.
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In the present study, we also analyzed in 78 samples the 13 C-labeled n-3 fatty acid enrichments of plasma TG, which were isolated by thin-layer chromatography. Enrichments in the long-chain n-3 fatty acids were too low to be measured reliably. Except for phospholipids and TG, plasma total lipids also consist of free fatty acids, chylomicrons, and cholesteryl esters CEs.
We believe that neither of these lipid fractions reflects hepatic n-3 conversion reliably.
Development of compartmental models in stable-isotope experiments: application to lipid metabolism.
From the studies of Burdge and colleagues 12 , 13 , it can be estimated that in women only 2. For men, 4. Chylomicrons are also not representative for hepatic n-3 fatty acid conversion, as they contain a fraction of [ 13 C]ALA that has not yet been taken up and metabolized by the liver. Thus, if 13 C-labeled n-3 LCPUFAs are present in chylomicrons, these fatty acids may be derived from conversion within the enterocyte and not from conversion within the liver.
Plasma CEs are formed from cholesterol released from peripheral tissues through the action of LCAT, which transfers a fatty acid from a phospholipid to free cholesterol. CEs are also synthesized in the intestine and liver. If the CE-derived n-3 LCPUFAs originate from plasma phospholipids, the CE pool will not provide new information on hepatic ALA conversion, because these fatty acids are part of the loss parameters, leaving from the various plasma phospholipid compartments. Therefore, including masses of any other n-3 fatty acid lipid pool in the model would mainly increase the mass of the ALA compartment.
Masses of the other compartments would be minimally affected.
As a result, the increased mass of the ALA compartment would be reflected by an increased loss from the ALA compartment rather than by changed fluxes into the other compartments. Pawlosky et al. In contrast to our results, their findings suggested that only 0. As already discussed, plasma total lipids may not be the most appropriate lipid fraction for the quantification of hepatic n-3 fatty acid conversion. The discrepancies between our results and those of Pawlosky et al.
In contrast, Pawlosky et al. Because isotope intake clearly exceeded trace amounts, perturbation of the kinetic behavior of the 12 C-labeled n-3 fatty acids cannot be ruled out Another difference between our study and that of Pawlosky et al. As in most other studies, Pawlosky et al.
It has already been demonstrated by Vermunt et al. Burdge, Jones, and Wootton 12 also could not detect any significant DHA enrichment over a period of 21 days in plasma phosphatidylcholine, chylomicron TG, or nonesterified fatty acids after administration of a single bolus of [ 13 C]ALA. It is further known that, at least for LA, the mode of tracer administration influenced the modeling outcomes One possible limitation of our model is that it mirrored the hepatic conversion of dietary ALA.
Although it is generally accepted that in humans the liver is the most significant site for n-3 fatty acid conversion, studies with primates suggest that other tissues, such as nervous tissue, are also able to convert ALA Hence, the total n-3 fatty acid conversion might have been underestimated. However, from the present findings, we can conclude that the limited incorporation of dietary ALA into the phospholipid pool contributes to the low hepatic conversion of dietary ALA to EPA.
We further found that the conversion of EPA to DPA, which involves an elongation reaction, might be an additional bottleneck within the hepatic n-3 cascade. The authors gratefully acknowledge the expert contribution and assistance of Prof. David M. Gianna Toffolo and Prof. Claudio Cobelli University of Padua, Italy during the initial phase of model development. The authors thank V. Previous Section Next Section.
Subjects Thirty healthy volunteers 15 men and 15 women participated in the study. Diet This tracer study was part of a dietary intervention trial that studied the effects of polyunsaturated fatty acids on cardiovascular risk markers. View this table: In this window In a new window. TABLE 1. Fatty acid composition of the experimental fat.
General modeling strategy The main objective of a tracer study is to obtain information on tracer kinetics, which can be used to describe the kinetic behavior of the unlabeled or tracee substances Tracer model The final tracer model is shown in Fig. Tracer uptake The oral boluses of the tracer ex1 first enter the stomach, compartment q5. DHA compartment The amount of DHA in the plasma phospholipid compartment q4 was first described by a single inflow and a single outflow of tracer.
Compartmental Modeling and Tracer Kinetics : David H. Anderson :
Tracer results The rate constants describing the final model are presented in Table 2. TABLE 2. Results of the tracer model parameters and derived variables. Tracee model The rate constants obtained from the tracer model were used to calculate conversions and fluxes of the tracee data. The total dietary ALA input into the plasma ALA phospholipid compartment Q1 was given by As the fractional output d 1,6 from the delay compartment into compartment Q1 was defined as the ALA uptake could be rewritten as Furthermore, because at steady state the input into Q1 equaled the output from Q1, ALA UPTAKE could be presented as or alternatively The tracer and tracee models were then linked by the following constraint equation and both models were then solved simultaneously.
Calculations The steady-state masses in Qi were obtained by multiplying the 12 C-labeled fatty acid concentrations with 4. TABLE 3. Results of the tracee model parameters and derived variables. TABLE 4. TABLE 5. Previous Section. Voskuil, D. Feskens, M. Katan, and D. Intake and sources of alpha-linolenic acid in Dutch elderly men. Medline Google Scholar. Ollis, T. Meyer, and P. Australian food sources and intakes of omega-6 and omega-3 polyunsaturated fatty acids.
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Param. Imaging and Kinetic Modeling
Fishell, R. Hargrove, G. Zhao, and T. Polyunsaturated fatty acids in the food chain in the United States. Google Scholar. Innis, S. Essential fatty acid requirements in human nutrition. Bezard, J. Blond, A. Bernard, and P. The metabolism and availability of essential fatty acids in animal and human tissues. Connor, W. Alpha-linolenic acid in health and disease. Simopoulos, A. Human requirement for N-3 polyunsaturated fatty acids. Blank, C. Neumann, M. Makrides, and R. Optimizing DHA levels in piglets by lowering the linoleic acid to alpha-linolenic acid ratio.