938 resultados para Mathematical model
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Modern dietary habits are characterized by high-sodium and low-potassium intakes, each of which was correlated with a higher risk for hypertension. In this study, we examined whether long-term variations in the intake of sodium and potassium induce lasting changes in the plasma concentration of circulating steroids by developing a mathematical model of steroidogenesis in mice. One finding of this model was that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates renal potassium handling both in males and females under potassium restriction, independent of its role in reproduction. The increase in progesterone production by male mice was time dependent and correlated with decreased urinary potassium content. The progesterone-dependent ability to efficiently retain potassium was because of an RU486 (a progesterone receptor antagonist)-sensitive stimulation of the colonic hydrogen, potassium-ATPase (known as the non-gastric or hydrogen, potassium-ATPase type 2) in the kidney. Thus, in males, a specific progesterone concentration profile induced by chronic potassium restriction regulates potassium balance.
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Through significant developments and progresses in the last two decades, in vivo localized nuclear magnetic resonance spectroscopy (MRS) became a method of choice to probe brain metabolic pathways in a non-invasive way. Beside the measurement of the total concentration of more than 20 metabolites, (1)H MRS can be used to quantify the dynamics of substrate transport across the blood-brain barrier by varying the plasma substrate level. On the other hand, (13)C MRS with the infusion of (13)C-enriched substrates enables the characterization of brain oxidative metabolism and neurotransmission by incorporation of (13)C in the different carbon positions of amino acid neurotransmitters. The quantitative determination of the biochemical reactions involved in these processes requires the use of appropriate metabolic models, whose level of details is strongly related to the amount of data accessible with in vivo MRS. In the present work, we present the different steps involved in the elaboration of a mathematical model of a given brain metabolic process and its application to the experimental data in order to extract quantitative brain metabolic rates. We review the recent advances in the localized measurement of brain glucose transport and compartmentalized brain energy metabolism, and how these reveal mechanistic details on glial support to glutamatergic and GABAergic neurons.
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We report experimental and numerical results showing how certain N-dimensional dynamical systems are able to exhibit complex time evolutions based on the nonlinear combination of N-1 oscillation modes. The experiments have been done with a family of thermo-optical systems of effective dynamical dimension varying from 1 to 6. The corresponding mathematical model is an N-dimensional vector field based on a scalar-valued nonlinear function of a single variable that is a linear combination of all the dynamic variables. We show how the complex evolutions appear associated with the occurrence of successive Hopf bifurcations in a saddle-node pair of fixed points up to exhaust their instability capabilities in N dimensions. For this reason the observed phenomenon is denoted as the full instability behavior of the dynamical system. The process through which the attractor responsible for the observed time evolution is formed may be rather complex and difficult to characterize. Nevertheless, the well-organized structure of the time signals suggests some generic mechanism of nonlinear mode mixing that we associate with the cluster of invariant sets emerging from the pair of fixed points and with the influence of the neighboring saddle sets on the flow nearby the attractor. The generation of invariant tori is likely during the full instability development and the global process may be considered as a generalized Landau scenario for the emergence of irregular and complex behavior through the nonlinear superposition of oscillatory motions
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Introduction: According to guidelines, patients with coronary artery disease (CAD) should undergo revascularization if myocardial ischemia is present. While coronary angiography (CXA) allows the morphological assessment of CAD, the fractional flow reserve (FFR) has proved to be a complementary invasive test to assess the functional significance of CAD, i.e. to detect ischemia. Perfusion Cardiac Magnetic Resonance (CMR) has turned out to be a robust non-invasive technique to assess myocardial ischemia. The objective: is to compare the cost-effectiveness ratio - defined as the costs per patient correctly diagnosed - of two algorithms used to diagnose hemodynamically significant CAD in relation to the pretest likelihood of CAD: 1) aCMRto assess ischemia before referring positive patients to CXA (CMR + CXA), 2) a CXA in all patients combined with a FFR test in patients with angiographically positive stenoses (CXA + FFR). Methods: The costs, evaluated from the health care system perspective in the Swiss, German, the United Kingdom (UK) and the United States (US) contexts, included public prices of the different tests considered as outpatient procedures, complications' costs and costs induced by diagnosis errors (false negative). The effectiveness criterion wasthe ability to accurately identify apatient with significantCAD.Test performancesused in the model were based on the clinical literature. Using a mathematical model, we compared the cost-effectiveness ratio for both algorithms for hypothetical patient cohorts with different pretest likelihood of CAD. Results: The cost-effectiveness ratio decreased hyperbolically with increasing pretest likelihood of CAD for both strategies. CMR + CXA and CXA + FFR were equally costeffective at a pretest likelihood of CAD of 62% in Switzerland, 67% in Germany, 83% in the UK and 84% in the US with costs of CHF 5'794, Euros 1'472, £ 2'685 and $ 2'126 per patient correctly diagnosed. Below these thresholds, CMR + CXA showed lower costs per patient correctly diagnosed than CXA + FFR. Implications for the health care system/professionals/patients/society These results facilitate decision making for the clinical use of new generations of imaging procedures to detect ischemia. They show to what extent the cost-effectiveness to diagnose CAD depends on the prevalence of the disease.
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In the last decades; a growing stock of literature has been devoted to the criticism of GDP as an indicator of societal wealth. A relevant question is: what are the perspectives to build, on the existing knowledge and consensus, alternative measures of prosperity? A starting point may be to connect well-being research agenda with the sustainability one. However, there is no doubt that there is a lot of complexity and fuzziness inherent in multidimensional concepts such as sustainability and well-being. This article analyses the theoretical foundations and the empirical validity of some multidimensional technical tools that can be used for well-being evaluation and assessment. Of course one should not forget that policy conclusions derived through any mathematical model depend also on the conceptual framework used, i.e. which representation of reality (and thus which societal values and interests) has been considered.
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Background: We address the problem of studying recombinational variations in (human) populations. In this paper, our focus is on one computational aspect of the general task: Given two networks G1 and G2, with both mutation and recombination events, defined on overlapping sets of extant units the objective is to compute a consensus network G3 with minimum number of additional recombinations. We describe a polynomial time algorithm with a guarantee that the number of computed new recombination events is within ϵ = sz(G1, G2) (function sz is a well-behaved function of the sizes and topologies of G1 and G2) of the optimal number of recombinations. To date, this is the best known result for a network consensus problem.Results: Although the network consensus problem can be applied to a variety of domains, here we focus on structure of human populations. With our preliminary analysis on a segment of the human Chromosome X data we are able to infer ancient recombinations, population-specific recombinations and more, which also support the widely accepted 'Out of Africa' model. These results have been verified independently using traditional manual procedures. To the best of our knowledge, this is the first recombinations-based characterization of human populations. Conclusion: We show that our mathematical model identifies recombination spots in the individual haplotypes; the aggregate of these spots over a set of haplotypes defines a recombinational landscape that has enough signal to detect continental as well as population divide based on a short segment of Chromosome X. In particular, we are able to infer ancient recombinations, population-specific recombinations and more, which also support the widely accepted 'Out of Africa' model. The agreement with mutation-based analysis can be viewed as an indirect validation of our results and the model. Since the model in principle gives us more information embedded in the networks, in our future work, we plan to investigate more non-traditional questions via these structures computed by our methodology.
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MicroRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes. Cell-free miRNAs measured in blood plasma have emerged as specific and sensitive markers of physiological processes and disease. In this study, we investigated whether circulating miRNAs can serve as biomarkers for the detection of autologous blood transfusion, a major doping technique that is still undetectable. Plasma miRNA levels were analyzed using high-throughput quantitative real-time PCR. Plasma samples were obtained before and at several time points after autologous blood transfusion (blood bag storage time 42 days) in 10 healthy subjects and 10 controls without transfusion. Other serum markers of erythropoiesis were determined in the same samples. Our results revealed a distinct change in the pattern of circulating miRNAs. Ten miRNAs were upregulated in transfusion samples compared with control samples. Among these, miR-30b, miR-30c, and miR-26b increased significantly and showed a 3.9-, 4.0-, and 3.0-fold change, respectively. The origin of these miRNAs was related to pulmonary and liver tissues. Erythropoietin (EPO) concentration decreased after blood reinfusion. A combination of miRNAs and EPO measurement in a mathematical model enhanced the efficiency of autologous transfusion detection through miRNA analysis. Therefore, our results lay the foundation for the development of miRNAs as novel blood-based biomarkers to detect autologous transfusion.
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Introduction An impaired ability to oxidize fat may be a factor in the obesity's aetiology (3). Moreover, the exercise intensity (Fatmax) eliciting the maximal fat oxidation rate (MFO) was lower in obese (O) compared with lean (L) individuals (4). However, difference in fat oxidation rate (FOR) during exercise between O and L remains equivocal and little is known about FORs during high intensities (>60% ) in O compared with L. This study aimed to characterize fat oxidation kinetics over a large range of intensities in L and O. Methods 12 healthy L [body mass index (BMI): 22.8±0.4] and 16 healthy O men (BMI: 38.9±1.4) performed submaximal incremental test (Incr) to determine whole-body fat oxidation kinetics using indirect calorimetry. After a 15-min resting period (Rest) and 10-min warm-up at 20% of maximal power output (MPO, determined by a maximal incremental test), the power output was increased by 7.5% MPO every 6-min until respiratory exchange ratio reached 1.0. Venous lactate and glucose and plasma concentration of epinephrine (E), norepinephrine (NE), insulin and non-esterified fatty acid (NEFA) were assessed at each step. A mathematical model (SIN) (1), including three variables (dilatation, symmetry, translation), was used to characterize fat oxidation (normalized by fat-free mass) kinetics and to determine Fatmax and MFO. Results FOR at Rest and MFO were not significantly different between groups (p≥0.1). FORs were similar from 20-60% (p≥0.1) and significantly lower from 65-85% in O than in L (p≤0.04). Fatmax was significantly lower in O than in L (46.5±2.5 vs 56.7±1.9 % respectively; p=0.005). Fat oxidation kinetics was characterized by similar translation (p=0.2), significantly lower dilatation (p=0.001) and tended to a left-shift symmetry in O compared with L (p=0.09). Plasma E, insulin and NEFA were significantly higher in L compared to O (p≤0.04). There were no significant differences in glucose, lactate and plasma NE between groups (p≥0.2). Conclusion The study showed that O presented a lower Fatmax and a lower reliance on fat oxidation at high, but not at moderate, intensities. This may be linked to a: i) higher levels of insulin and lower E concentrations in O, which may induce blunted lipolysis; ii) higher percentage of type II and a lower percentage of type I fibres (5), and iii) decreased mitochondrial content (2), which may reduce FORs at high intensities and Fatmax. These findings may have implications for an appropriate exercise intensity prescription for optimize fat oxidation in O. References 1. Cheneviere et al. Med Sci Sports Exerc. 2009 2. Holloway et al. Am J Clin Nutr. 2009 3. Kelley et al. Am J Physiol. 1999 4. Perez-Martin et al. Diabetes Metab. 2001 5. Tanner et al. Am J Physiol Endocrinol Metab. 2002
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The dynamics of the control of Aedes (Stegomyia) aegypti Linnaeus, (Diptera, Culicidae) by Bacillus thuringiensis var israelensis has been related with the temperature, density and concentration of the insecticide. A mathematical model for biological control of Aedes aegypti with Bacillus thuringiensis var israelensis (Bti) was constructed by using data from the literature regarding the biology of the vector. The life cycle was described by differential equations. Lethal concentrations (LC50 and LC95) of Bti were determined in the laboratory under different experimental conditions. Temperature, colony, larvae density and bioinsecticide concentration presented marked differences in the analysis of the whole set of variables; although when analyzed individually, only the temperature and concentration showed changes. The simulations indicated an inverse relationship between temperature and mosquito population, nonetheless, faster growth of populations is reached at higher temperatures. As conclusion, the model suggests the use of integrated control strategies for immature and adult mosquitoes in order to achieve a reduction of Aedes aegypti.
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BACKGROUND & AIMS: In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015). METHODS: A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3-4/F0-2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0-0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1-10% with TVR/BOC-based triple therapy. Costs were euro60,000 for 12weeks of IFN-based new DAAs and two times higher for IFN-free regimens. RESULTS: Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (euro37,900/QALY gained), but not at F0-1 (euro103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective. CONCLUSIONS: Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.
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The Drivers Scheduling Problem (DSP) consists of selecting a set of duties for vehicle drivers, for example buses, trains, plane or boat drivers or pilots, for the transportation of passengers or goods. This is a complex problem because it involves several constraints related to labour and company rules and can also present different evaluation criteria and objectives. Being able to develop an adequate model for this problem that can represent the real problem as close as possible is an important research area.The main objective of this research work is to present new mathematical models to the DSP problem that represent all the complexity of the drivers scheduling problem, and also demonstrate that the solutions of these models can be easily implemented in real situations. This issue has been recognized by several authors and as important problem in Public Transportation. The most well-known and general formulation for the DSP is a Set Partition/Set Covering Model (SPP/SCP). However, to a large extend these models simplify some of the specific business aspects and issues of real problems. This makes it difficult to use these models as automatic planning systems because the schedules obtained must be modified manually to be implemented in real situations. Based on extensive passenger transportation experience in bus companies in Portugal, we propose new alternative models to formulate the DSP problem. These models are also based on Set Partitioning/Covering Models; however, they take into account the bus operator issues and the perspective opinions and environment of the user.We follow the steps of the Operations Research Methodology which consist of: Identify the Problem; Understand the System; Formulate a Mathematical Model; Verify the Model; Select the Best Alternative; Present the Results of theAnalysis and Implement and Evaluate. All the processes are done with close participation and involvement of the final users from different transportation companies. The planner s opinion and main criticisms are used to improve the proposed model in a continuous enrichment process. The final objective is to have a model that can be incorporated into an information system to be used as an automatic tool to produce driver schedules. Therefore, the criteria for evaluating the models is the capacity to generate real and useful schedules that can be implemented without many manual adjustments or modifications. We have considered the following as measures of the quality of the model: simplicity, solution quality and applicability. We tested the alternative models with a set of real data obtained from several different transportation companies and analyzed the optimal schedules obtained with respect to the applicability of the solution to the real situation. To do this, the schedules were analyzed by the planners to determine their quality and applicability. The main result of this work is the proposition of new mathematical models for the DSP that better represent the realities of the passenger transportation operators and lead to better schedules that can be implemented directly in real situations.
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Photosystem II (PSII) of oxygenic photosynthesis is susceptible to photoinhibition. Photoinhibition is defined as light induced damage resulting in turnover of the D1 protein subunit of the reaction center of PSII. Both visible and ultraviolet (UV) light cause photoinhibition. Photoinhibition induced by UV light damages the oxygen evolving complex (OEC) via absorption of UV photons by the Mn ion(s) of OEC. Under visible light, most of the earlier hypotheses assume that photoinhibition occurs when the rate of photon absorption by PSII antenna exceeds the use of the absorbed energy in photosynthesis. However, photoinhibition occurs at all light intensities with the same efficiency per photon. The aim of my thesis work was to build a model of photoinhibition that fits the experimental features of photoinhibition. I studied the role of electron transfer reactions of PSII in photoinhibition and found that changing the electron transfer rate had only minor influence on photoinhibition if light intensity was kept constant. Furthermore, quenching of antenna excitations protected less efficiently than it would protect if antenna chlorophylls were the only photoreceptors of photoinhibition. To identify photoreceptors of photoinhibition, I measured the action spectrum of photoinhibition. The action spectrum showed resemblance to the absorption spectra of Mn model compounds suggesting that the Mn cluster of OEC acts as a photoreceptor of photoinhibition under visible light, too. The role of Mn in photoinhibition was further supported by experiments showing that during photoinhibition OEC is damaged before electron transfer activity at the acceptor side of PSII is lost. Mn enzymes were found to be photosensitive under visible and UV light indicating that Mn-containing compounds, including OEC, are capable of functioning as photosensitizers both in visible and UV light. The experimental results above led to the Mn hypothesis of the mechanism of continuous-light-induced photoinhibition. According to the Mn hypothesis, excitation of Mn of OEC results in inhibition of electron donation from OEC to the oxidized primary donor P680+ both under UV and visible light. P680 is oxidized by photons absorbed by chlorophyll, and if not reduced by OEC, P680+ may cause harmful oxidation of other PSII components. Photoinhibition was also induced with intense laser pulses and it was found that the photoinhibitory efficiency increased in proportion to the square of pulse intensity suggesting that laser-pulse-induced photoinhibition is a two-photon reaction. I further developed the Mn hypothesis suggesting that the initial event in photoinhibition under both continuous and pulsed light is the same: Mn excitation that leads to the inhibition of electron donation from OEC to P680+. Under laser-pulse-illumination, another Mn-mediated inhibitory photoreaction occurs within the duration of the same pulse, whereas under continuous light, secondary damage is chlorophyll mediated. A mathematical model based on the Mn hypothesis was found to explain photoinhibition under continuous light, under flash illumination and under the combination of these two.
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L'étude du mouvement des organismes est essentiel pour la compréhension du fonctionnement des écosystèmes. Dans le cas des écosystèmes marins exploités, cela amène à s'intéresser aux stratégies spatiales des pêcheurs. L'une des approches les plus utilisées pour la modélisation du mouvement des prédateurs supé- rieurs est la marche aléatoire de Lévy. Une marche aléatoire est un modèle mathématique composé par des déplacements aléatoires. Dans le cas de Lévy, les longueurs des déplacements suivent une loi stable de Lévy. Dans ce cas également, les longueurs, lorsqu'elles tendent vers l'in ni (in praxy lorsqu'elles sont grandes, grandes par rapport à la médiane ou au troisième quartile par exemple), suivent une loi puissance caractéristique du type de marche aléatoire de Lévy (Cauchy, Brownien ou strictement Lévy). Dans la pratique, outre que cette propriété est utilisée de façon réciproque sans fondement théorique, les queues de distribution, notion par ailleurs imprécise, sont modélisée par des lois puissances sans que soient discutées la sensibilité des résultats à la dé nition de la queue de distribution, et la pertinence des tests d'ajustement et des critères de choix de modèle. Dans ce travail portant sur les déplacements observés de trois bateaux de pêche à l'anchois du Pérou, plusieurs modèles de queues de distribution (log-normal, exponentiel, exponentiel tronqué, puissance et puissance tronqué) ont été comparés ainsi que deux dé nitions possible de queues de distribution (de la médiane à l'in ni ou du troisième quartile à l'in ni). Au plan des critères et tests statistiques utilisés, les lois tronquées (exponentielle et puissance) sont apparues les meilleures. Elles intègrent en outre le fait que, dans la pratique, les bateaux ne dépassent pas une certaine limite de longueur de déplacement. Le choix de modèle est apparu sensible au choix du début de la queue de distribution : pour un même bateau, le choix d'un modèle tronqué ou l'autre dépend de l'intervalle des valeurs de la variable sur lequel le modèle est ajusté. Pour nir, nous discutons les implications en écologie des résultats de ce travail.
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OBJECTIVE: To evaluate the power of various parameters of the vestibulo-ocular reflex (VOR) in detecting unilateral peripheral vestibular dysfunction and in characterizing certain inner ear pathologies. STUDY DESIGN: Prospective study of consecutive ambulatory patients presenting with acute onset of peripheral vertigo and spontaneous nystagmus. SETTING: Tertiary referral center. PATIENTS: Seventy-four patients (40 females, 34 males) and 22 normal subjects (11 females, 11 males) were included in the study. Patients were classified in three main diagnoses: vestibular neuritis: 40; viral labyrinthitis: 22; Meniere's disease: 12. METHODS: The VOR function was evaluated by standard caloric and impulse rotary tests (velocity step). A mathematical model of vestibular function was used to characterize the VOR response to rotational stimulation. The diagnostic value of the different VOR parameters was assessed by uni- and multivariable logistic regression. RESULTS: In univariable analysis, caloric asymmetry emerged as the most powerful VOR parameter in identifying unilateral vestibular deficit, with a boundary limit set at 20%. In multivariable analysis, the combination of caloric asymmetry and rotational time constant asymmetry significantly improved the discriminatory power over caloric alone (p<0.0001) and produced a detection score with a correct classification of 92.4%. In discriminating labyrinthine diseases, different combinations of the VOR parameters were obtained for each diagnosis (p<0.003) supporting that the VOR characteristics differ between the three inner ear disorders. However, the clinical usefulness of these characteristics in separating the pathologies was limited. CONCLUSION: We propose a powerful logistic model combining the indices of caloric and time constant asymmetries to detect a peripheral vestibular loss, with an accuracy of 92.4%. Based on vestibular data only, the discrimination between the different inner ear diseases is statistically possible, which supports different pathophysiologic changes in labyrinthine pathologies.
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Introduction An impaired ability to oxidize fat may be a factor in the obesity's aetiology (3). Moreover, the exercise intensity (Fatmax) eliciting the maximal fat oxidation rate (MFO) was lower in obese (O) compared with lean (L) individuals (4). However, difference in fat oxidation rate (FOR) during exercise between O and L remains equivocal and little is known about FORs during high intensities (>60% ) in O compared with L. This study aimed to characterize fat oxidation kinetics over a large range of intensities in L and O. Methods 12 healthy L [body mass index (BMI): 22.8±0.4] and 16 healthy O men (BMI: 38.9±1.4) performed submaximal incremental test (Incr) to determine whole-body fat oxidation kinetics using indirect calorimetry. After a 15-min resting period (Rest) and 10-min warm-up at 20% of maximal power output (MPO, determined by a maximal incremental test), the power output was increased by 7.5% MPO every 6-min until respiratory exchange ratio reached 1.0. Venous lactate and glucose and plasma concentration of epinephrine (E), norepinephrine (NE), insulin and non-esterified fatty acid (NEFA) were assessed at each step. A mathematical model (SIN) (1), including three variables (dilatation, symmetry, translation), was used to characterize fat oxidation (normalized by fat-free mass) kinetics and to determine Fatmax and MFO. Results FOR at Rest and MFO were not significantly different between groups (p≥0.1). FORs were similar from 20-60% (p≥0.1) and significantly lower from 65-85% in O than in L (p≤0.04). Fatmax was significantly lower in O than in L (46.5±2.5 vs 56.7±1.9 % respectively; p=0.005). Fat oxidation kinetics was characterized by similar translation (p=0.2), significantly lower dilatation (p=0.001) and tended to a left-shift symmetry in O compared with L (p=0.09). Plasma E, insulin and NEFA were significantly higher in L compared to O (p≤0.04). There were no significant differences in glucose, lactate and plasma NE between groups (p≥0.2). Conclusion The study showed that O presented a lower Fatmax and a lower reliance on fat oxidation at high, but not at moderate, intensities. This may be linked to a: i) higher levels of insulin and lower E concentrations in O, which may induce blunted lipolysis; ii) higher percentage of type II and a lower percentage of type I fibres (5), and iii) decreased mitochondrial content (2), which may reduce FORs at high intensities and Fatmax. These findings may have implications for an appropriate exercise intensity prescription for optimize fat oxidation in O. References 1. Cheneviere et al. Med Sci Sports Exerc. 2009 2. Holloway et al. Am J Clin Nutr. 2009 3. Kelley et al. Am J Physiol. 1999 4. Perez-Martin et al. Diabetes Metab. 2001 5. Tanner et al. Am J Physiol Endocrinol Metab. 2002