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Fulltext Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients

Kirubakaran R, Uster DW, Hennig S, Carland JE, Day RO, Wicha SG, et al.

Br J Clin Pharmacol, 2023 Mar;89(3):1162-1175.
PMID: 36239542 DOI: 10.1111/bcp.15566

AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction.
METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions.
RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P

Matched MeSH terms: Models, Biological
Fulltext A modeling study by response surface methodology and artificial neural network on culture parameters optimization for thermostable lipase production from a newly isolated thermophilic Geobacillus sp. strain ARM

Ebrahimpour A, Abd Rahman RN, Ean Ch'ng DH, Basri M, Salleh AB

BMC Biotechnol, 2008 Dec 23;8:96.
PMID: 19105837 DOI: 10.1186/1472-6750-8-96

BACKGROUND: Thermostable bacterial lipases occupy a place of prominence among biocatalysts owing to their novel, multifold applications and resistance to high temperature and other operational conditions. The capability of lipases to catalyze a variety of novel reactions in both aqueous and nonaqueous media presents a fascinating field for research, creating interest to isolate novel lipase producers and optimize lipase production. The most important stages in a biological process are modeling and optimization to improve a system and increase the efficiency of the process without increasing the cost.
RESULTS: Different production media were tested for lipase production by a newly isolated thermophilic Geobacillus sp. strain ARM (DSM 21496 = NCIMB 41583). The maximum production was obtained in the presence of peptone and yeast extract as organic nitrogen sources, olive oil as carbon source and lipase production inducer, sodium and calcium as metal ions, and gum arabic as emulsifier and lipase production inducer. The best models for optimization of culture parameters were achieved by multilayer full feedforward incremental back propagation network and modified response surface model using backward elimination, where the optimum condition was: growth temperature (52.3 degrees C), medium volume (50 ml), inoculum size (1%), agitation rate (static condition), incubation period (24 h) and initial pH (5.8). The experimental lipase activity was 0.47 Uml(-1) at optimum condition (4.7-fold increase), which compared well to the maximum predicted values by ANN (0.47 Uml(-1)) and RSM (0.476 Uml(-1)), whereas R2 and AAD were determined as 0.989 and 0.059% for ANN, and 0.95 and 0.078% for RSM respectively.
CONCLUSION: Lipase production is the result of a synergistic combination of effective parameters interactions. These parameters are in equilibrium and the change of one parameter can be compensated by changes of other parameters to give the same results. Though both RSM and ANN models provided good quality predictions in this study, yet the ANN showed a clear superiority over RSM for both data fitting and estimation capabilities. On the other hand, ANN has the disadvantage of requiring large amounts of training data in comparison with RSM. This problem was solved by using statistical experimental design, to reduce the number of experiments.

Matched MeSH terms: Models, Biological
Fulltext Thymic involution and rising disease incidence with age

Palmer S, Albergante L, Blackburn CC, Newman TJ

Proc Natl Acad Sci U S A, 2018 02 20;115(8):1883-1888.
PMID: 29432166 DOI: 10.1073/pnas.1714478115

For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

Matched MeSH terms: Models, Biological
Fulltext Soils on exposed Sunda shelf shaped biogeographic patterns in the equatorial forests of Southeast Asia

Slik JW, Aiba S, Bastian M, Brearley FQ, Cannon CH, Eichhorn KA, et al.

Proc Natl Acad Sci U S A, 2011 Jul 26;108(30):12343-7.
PMID: 21746913 DOI: 10.1073/pnas.1103353108

The marked biogeographic difference between western (Malay Peninsula and Sumatra) and eastern (Borneo) Sundaland is surprising given the long time that these areas have formed a single landmass. A dispersal barrier in the form of a dry savanna corridor during glacial maxima has been proposed to explain this disparity. However, the short duration of these dry savanna conditions make it an unlikely sole cause for the biogeographic pattern. An additional explanation might be related to the coarse sandy soils of central Sundaland. To test these two nonexclusive hypotheses, we performed a floristic cluster analysis based on 111 tree inventories from Peninsular Malaysia, Sumatra, and Borneo. We then identified the indicator genera for clusters that crossed the central Sundaland biogeographic boundary and those that did not cross and tested whether drought and coarse-soil tolerance of the indicator genera differed between them. We found 11 terminal floristic clusters, 10 occurring in Borneo, 5 in Sumatra, and 3 in Peninsular Malaysia. Indicator taxa of clusters that occurred across Sundaland had significantly higher coarse-soil tolerance than did those from clusters that occurred east or west of central Sundaland. For drought tolerance, no such pattern was detected. These results strongly suggest that exposed sandy sea-bed soils acted as a dispersal barrier in central Sundaland. However, we could not confirm the presence of a savanna corridor. This finding makes it clear that proposed biogeographic explanations for plant and animal distributions within Sundaland, including possible migration routes for early humans, need to be reevaluated.

Matched MeSH terms: Models, Biological
Targeting oncogenes and tumor suppressors genes to mitigate chemoresistance

Fatemian T, Chowdhury EH

Curr Cancer Drug Targets, 2014;14(7):599-609.
PMID: 25308718

Malfunctions in membrane transporters or disruptions in signaling cascades induce resistance to chemotherapy in cancer cells resulting in treatment failure. To adjust the genetic alterations leading to these cellular protective measures, dissection and verification of the contributing routes would be required. In justification of knockdown of the key genes, RNA interference provides a reliable probing tool, enabling exploration of phenotypic manifestation of targeted genes. Investigation of the non-transporter targets, predominantly oncogenes and tumor suppressor genes, by means of small interfering RNA with the aim to re-sensitize cancer cells to therapeutics will be discussed in this review.

Matched MeSH terms: Models, Biological*
Internal radiation dosimetry of orally administered radiotracers for the assessment of gastrointestinal motility

Yeong CH, Ng KH, Abdullah BJJ, Chung LY, Goh KL, Perkins AC

Appl Radiat Isot, 2014 Dec;94:216-220.
PMID: 25222875 DOI: 10.1016/j.apradiso.2014.08.009

Radionuclide imaging using (111)In, (99m)Tc and (153)Sm is commonly undertaken for the clinical investigation of gastric emptying, intestinal motility and whole gut transit. However the documented evidence concerning internal radiation dosimetry for such studies is not readily available. This communication documents the internal radiation dosimetry for whole gastrointestinal transit studies using (111)In, (99m)Tc and (153)Sm labeled formulations. The findings were compared to the diagnostic reference levels recommended by the United Kingdom Administration of Radioactive Substances Advisory Committee, for gastrointestinal transit studies.

Matched MeSH terms: Models, Biological*
Automation of anaesthesia: a review on multivariable control

Chang JJ, Syafiie S, Kamil R, Lim TA

J Clin Monit Comput, 2015 Apr;29(2):231-9.
PMID: 24961365 DOI: 10.1007/s10877-014-9590-6

Anaesthesia is a multivariable problem where a combination of drugs are used to induce desired hypnotic, analgesia and immobility states. The automation of anaesthesia may improve the safety and cost-effectiveness of anaesthesia. However, the realization of a safe and reliable multivariable closed-loop control of anaesthesia is yet to be achieved due to a manifold of challenges. In this paper, several significant challenges in automation of anaesthesia are discussed, namely model uncertainty, controlled variables, closed-loop application and dependability. The increasingly reliable measurement device, robust and adaptive controller, and better fault tolerance strategy are paving the way for automation of anaesthesia.

Matched MeSH terms: Models, Biological*
Optimising the production of succinate and lactate in Escherichia coli using a hybrid of artificial bee colony algorithm and minimisation of metabolic adjustment

Tang PW, Choon YW, Mohamad MS, Deris S, Napis S

J Biosci Bioeng, 2015 Mar;119(3):363-8.
PMID: 25216804 DOI: 10.1016/j.jbiosc.2014.08.004

Metabolic engineering is a research field that focuses on the design of models for metabolism, and uses computational procedures to suggest genetic manipulation. It aims to improve the yield of particular chemical or biochemical products. Several traditional metabolic engineering methods are commonly used to increase the production of a desired target, but the products are always far below their theoretical maximums. Using numeral optimisation algorithms to identify gene knockouts may stall at a local minimum in a multivariable function. This paper proposes a hybrid of the artificial bee colony (ABC) algorithm and the minimisation of metabolic adjustment (MOMA) to predict an optimal set of solutions in order to optimise the production rate of succinate and lactate. The dataset used in this work was from the iJO1366 Escherichia coli metabolic network. The experimental results include the production rate, growth rate and a list of knockout genes. From the comparative analysis, ABCMOMA produced better results compared to previous works, showing potential for solving genetic engineering problems.

Matched MeSH terms: Models, Biological*
Fulltext The theory and fundamentals of bioimpedance analysis in clinical status monitoring and diagnosis of diseases

Khalil SF, Mohktar MS, Ibrahim F

Sensors (Basel), 2014;14(6):10895-928.
PMID: 24949644 DOI: 10.3390/s140610895

Bioimpedance analysis is a noninvasive, low cost and a commonly used approach for body composition measurements and assessment of clinical condition. There are a variety of methods applied for interpretation of measured bioimpedance data and a wide range of utilizations of bioimpedance in body composition estimation and evaluation of clinical status. This paper reviews the main concepts of bioimpedance measurement techniques including the frequency based, the allocation based, bioimpedance vector analysis and the real time bioimpedance analysis systems. Commonly used prediction equations for body composition assessment and influence of anthropometric measurements, gender, ethnic groups, postures, measurements protocols and electrode artifacts in estimated values are also discussed. In addition, this paper also contributes to the deliberations of bioimpedance analysis assessment of abnormal loss in lean body mass and unbalanced shift in body fluids and to the summary of diagnostic usage in different kinds of conditions such as cardiac, pulmonary, renal, and neural and infection diseases.

Matched MeSH terms: Models, Biological*
Fulltext Non-density dependent pollen dispersal of Shorea maxwelliana (Dipterocarpaceae) revealed by a Bayesian mating model based on paternity analysis in two synchronized flowering seasons

Masuda S, Tani N, Ueno S, Lee SL, Muhammad N, Kondo T, et al.

PLoS One, 2013;8(12):e82039.
PMID: 24391712 DOI: 10.1371/journal.pone.0082039

Pollinator syndrome is one of the most important determinants regulating pollen dispersal in tropical tree species. It has been widely accepted that the reproduction of tropical forest species, especially dipterocarps that rely on insects with weak flight for their pollination, is positively density-dependent. However differences in pollinator syndrome should affect pollen dispersal patterns and, consequently, influence genetic diversity via the mating process. We examined the pollen dispersal pattern and mating system of Shorea maxwelliana, the flowers of which are larger than those of Shorea species belonging to section Mutica which are thought to be pollinated by thrips (weak flyers). A Bayesian mating model based on the paternity of seeds collected from mother trees during sporadic and mass flowering events revealed that the estimated pollen dispersal kernel and average pollen dispersal distance were similar for both flowering events. This evidence suggests that the putative pollinators - small beetles and weevils - effectively contribute to pollen dispersal and help to maintain a high outcrossing rate even during sporadic flowering events. However, the reduction in pollen donors during a sporadic event results in a reduction in effective pollen donors, which should lead to lower genetic diversity in the next generation derived from seeds produced during such an event. Although sporadic flowering has been considered less effective for outcrossing in Shorea species that depend on thrips for their pollination, effective pollen dispersal by the small beetles and weevils ensures outcrossing during periods of low flowering tree density, as occurs in a sporadic flowering event.

Matched MeSH terms: Models, Biological*
Start-up, steady state performance and kinetic evaluation of a thermophilic integrated anaerobic-aerobic bioreactor (IAAB)

Chan YJ, Chong MF, Law CL

Bioresour Technol, 2012 Dec;125:145-57.
PMID: 23026327 DOI: 10.1016/j.biortech.2012.08.118

Thermophilic treatment of palm oil mill effluent (POME) was studied in a novel integrated anaerobic-aerobic bioreactor (IAAB). The IAAB was subjected to a program of steady-state operation over a range of organic loading rate (OLR)s, up to 30 g COD/L day in order to evaluate its treatment capacity. The thermophilic IAAB achieved high chemical oxygen demand (COD), biochemical oxygen demand (BOD) and total suspended solids (TSS) removal efficiencies of more than 99% for OLR up to 18.5 g COD/L day. High methane yield of 0.32 LCH(4) (STP)/g COD(removed) with compliance of the final treated effluent to the discharge limit were achieved. This is higher than that of the mesophilic system due to the higher maximum specific growth rate (μ(max)) of the thermophilic microorganisms. Besides, coupling the model of Grau second order model (anaerobic system) with the model of Monod (aerobic system) will completely define the IAAB system.

Matched MeSH terms: Models, Biological*
Relevance of diffusion through bacterial spore coats/membranes and the associated concentration boundary layers in the initial lag phase of inactivation: a case study for Bacillus subtilis with ozone and monochloramine

Fernando WJ, Othman R

Math Biosci, 2006 Feb;199(2):175-87.
PMID: 16387333

Disinfectants are generally used to inactivate microorganisms in solutions. The process of inactivation involves the disinfectant in the liquid diffusing towards the bacteria sites and thereafter reacting with bacteria at rates determined by the respective reaction rates. Such processes have demonstrated an initial lag phase followed by an active depletion phase of bacteria. This paper attempts to study the importance of the combined effects of diffusion of the disinfectant through the outer membrane of the bacteria and transport through the associated concentration boundary layers (CBLs) during the initial lag phase. Mathematical equations are developed correlating the initial concentration of the disinfectant with time required for reaching a critical concentration (C*) at the inner side of the membrane of the cell based on diffusion of disinfectant through the outer membranes of the bacteria and the formation of concentration boundary layers on both sides of the membranes. Experimental data of the lag phases of inactivation already available in the literature for inactivation of Bacillus subtilis spores with ozone and monochloramine are tested with the equations. The results seem to be in good agreement with the theoretical equations indicating the importance of diffusion process across the outer cell membranes and the resulting CBL's during the lag phase of disinfection.

Matched MeSH terms: Models, Biological*
Model-aided atpE gene knockout strategy in Escherichia coli for enhanced succinic acid production from glycerol

Mienda BS, Shamsir MS, Md Illias R

J Biomol Struct Dyn, 2016 Aug;34(8):1705-16.
PMID: 26513379 DOI: 10.1080/07391102.2015.1090341

Succinic acid is an important platform chemical with a variety of applications. Model-guided metabolic engineering strategies in Escherichia coli for strain improvement to increase succinic acid production using glucose and glycerol remain largely unexplored. Herein, we report what are, to our knowledge, the first metabolic knockout of the atpE gene to have increased succinic acid production using both glucose and alternative glycerol carbon sources in E. coli. Guided by a genome-scale metabolic model, we engineered the E. coli host to enhance anaerobic production of succinic acid by deleting the atpE gene, thereby generating additional reducing equivalents by blocking H(+) conduction across the mutant cell membrane. This strategy produced 1.58 and .49 g l(-1) of succinic acid from glycerol and glucose substrate, respectively. This work further elucidates a model-guided and/or system-based metabolic engineering, involving only a single-gene deletion strategy for enhanced succinic acid production in E. coli.

Matched MeSH terms: Models, Biological*
A fibril-based structural constitutive theory reveals the dominant role of network characteristics on the mechanical behavior of fibroblast-compacted collagen gels

Feng Z, Ishiguro Y, Fujita K, Kosawada T, Nakamura T, Sato D, et al.

Biomaterials, 2015 Oct;67:365-81.
PMID: 26247391 DOI: 10.1016/j.biomaterials.2015.07.038

In this paper, we present a general, fibril-based structural constitutive theory which accounts for three material aspects of crosslinked filamentous materials: the single fibrillar force response, the fibrillar network model, and the effects of alterations to the fibrillar network. In the case of the single fibrillar response, we develop a formula that covers the entropic and enthalpic deformation regions, and introduce the relaxation phase to explain the observed force decay after crosslink breakage. For the filamentous network model, we characterize the constituent element of the fibrillar network in terms its end-to-end distance vector and its contour length, then decompose the vector orientation into an isotropic random term and a specific alignment, paving the way for an expanded formalism from principal deformation to general 3D deformation; and, more important, we define a critical core quantity over which macroscale mechanical characteristics can be integrated: the ratio of the initial end-to-end distance to the contour length (and its probability function). For network alterations, we quantitatively treat changes in constituent elements and relate these changes to the alteration of network characteristics. Singular in its physical rigor and clarity, this constitutive theory can reproduce and predict a wide range of nonlinear mechanical behavior in materials composed of a crosslinked filamentous network, including: stress relaxation (with dual relaxation coefficients as typically observed in soft tissues); hysteresis with decreasing maximum stress under serial cyclic loading; strain-stiffening under uniaxial tension; the rupture point of the structure as a whole; various effects of biaxial tensile loading; strain-stiffening under simple shearing; the so-called "negative normal stress" phenomenon; and enthalpic elastic behaviors of the constituent element. Applied to compacted collagen gels, the theory demonstrates that collagen fibrils behave as enthalpic elasticas with linear elasticity within the gels, and that the macroscale nonlinearity of the gels originates from the curved fibrillar network. Meanwhile, the underlying factors that determine the mechanical properties of the gels are clarified. Finally, the implications of this study on the enhancement of the mechanical properties of compacted collagen gels and on the cellular mechanics with this model tissue are discussed.

Matched MeSH terms: Models, Biological*
Validity of deuterium oxide dilution for the measurement of body fat among Singaporeans

Deurenberg-Yap M, Deurenberg P

Food Nutr Bull, 2002 Sep;23(3 Suppl):34-7.
PMID: 12362808

Body fat percent (BF%) was measured in 108 adult Chinese, 76 Malays, and 107 Indians in Singapore by densitometry, deuterium oxide dilution (hydrometry), dual energy x-ray absorptiometry (DXA) and a chemical four-compartment model (BF%4c). The hydration of the fat-free mass (FFM) was calculated. Subjects ranged in age from 18 to 69 years and their body mass index ranged from 16 to 40 kg/m2. BF%4c for the various subgroups were: Chinese females (33.5 +/- 7.5%), Chinese males (24.4 +/- 6.1%), Malay females (37.8 +/- 6.3%), Malay males (26.0 +/- 7.6%), Indian females (38.2 +/- 7.0%) and Indian males (28.1 +/- 5.5%). Biases were found between BF%4c and BF% measured by 2-compartment models (hydrometry, densitometry, DXA), with systematic underestimation by DXA and densitometry. On a group level hydrometry had the lowest bias while DXA gave the highest bias. When validated against BF%4c, 2-compartment models were found to be unsuitable for accurate measures of body fat due to high biases at the individual level and the violation of assumptions of constant hydration of FFM and density FFM among the ethnic groups. On a group level the best 2-compartment model for measuring body fat was found to be hydrometry.

Matched MeSH terms: Models, Biological*
Fulltext Modeling of hemoglobin in dengue fever and dengue hemorrhagic fever using bioelectrical impedance

Ibrahim F, Ismail NA, Taib MN, Wan Abas WA

Physiol Meas, 2004 Jun;25(3):607-15.
PMID: 15253113 DOI: 10.1088/0967-3334/25/3/002

This paper describes a model for predicting hemoglobin (Hb) by using bioelectrical impedance analysis (BIA) in dengue patients in the Hospital Universiti Kebangsaan Malaysia (HUKM). Bioelectrical impedance measurements were conducted on 83 (47 males and 36 females) serologically confirmed dengue fever (DF) and dengue hemorrhagic fever (DHF) patients during their hospitalization. The predictive equation for Hb was derived using multivariate analysis. We investigated all the parameters in BIA, patients' symptom and demographic data. In this developed model, four predictors (reactance (XC), sex, weight and vomiting) were found to be the best predictive factors for modeling Hb in dengue patients. However, the model can only explain approximately 42% of the variation in Hb status, thus single frequency bio-impedance stand-alone technique is insufficient to monitor Hb for the DF and DHF patients. Further investigation using multi-frequency BIA is recommended in modeling Hb to achieve the most parsimonious model.

Matched MeSH terms: Models, Biological*
Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug-Monitoring Data

Albitar O, Ballouze R, Harun SN, Mohamed Noor DA, Sheikh Ghadzi SM

J Clin Pharmacol, 2020 11;60(11):1474-1482.
PMID: 32557653 DOI: 10.1002/jcph.1670

Cyclosporine is a primary drug in transplant immunosuppression regimens. It has a narrow therapeutic index and variable pharmacokinetic behavior. This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P < .05) followed by backward elimination (P < .001). Prediction-corrected visual predictive check and sampling-importance resampling methods were used to validate the final model. A 1-compartment model with first-order absorption and elimination best fitted the data. All methods to handle missing doses performed well with the missing dose method being superior to other methods and thus was applied in the final model. Cyclosporine clearance (CL/F) was estimated as 15.1 L/h, and volume of distribution (V/F) was 108 L. Postoperative time, sex, and calcium channel blockers were identified as significant covariates on CL/F, whereas sex and cholesterol level were identified as significant covariates on V/F. This is the first population pharmacokinetic model developed in Malaysian renal transplant patients using a large sample with an evaluation of different methods to handle missing doses in less informative conventional therapeutic drug-monitoring data.

Matched MeSH terms: Models, Biological*
Fulltext Defining in vivo dose-response curves for kidney DNA adduct formation of aristolochic acid I in rat, mouse and human by an in vitro and physiologically based kinetic modeling approach

Abdullah R, Wesseling S, Spenkelink B, Louisse J, Punt A, Rietjens IMCM

J Appl Toxicol, 2020 12;40(12):1647-1660.
PMID: 33034907 DOI: 10.1002/jat.4024

Aristolochic acid I (AAI) is a well-known genotoxic kidney carcinogen. Metabolic conversion of AAI into the DNA-reactive aristolactam-nitrenium ion is involved in the mode of action of tumor formation. This study aims to predict in vivo AAI-DNA adduct formation in the kidney of rat, mouse and human by translating the in vitro concentration-response curves for AAI-DNA adduct formation to the in vivo situation using physiologically based kinetic (PBK) modeling-based reverse dosimetry. DNA adduct formation in kidney proximal tubular LLC-PK1 cells exposed to AAI was quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. Subsequently, the in vitro concentration-response curves were converted to predicted in vivo dose-response curves in rat, mouse and human kidney using PBK models. Results obtained revealed a dose-dependent increase in AAI-DNA adduct formation in the rat, mouse and human kidney and the predicted DNA adduct levels were generally within an order of magnitude compared with values reported in the literature. It is concluded that the combined in vitro PBK modeling approach provides a novel way to define in vivo dose-response curves for kidney DNA adduct formation in rat, mouse and human and contributes to the reduction, refinement and replacement of animal testing.

Matched MeSH terms: Models, Biological*
Fulltext Body fat measurement among Singaporean Chinese, Malays and Indians: a comparative study using a four-compartment model and different two-compartment models

Deurenberg-Yap M, Schmidt G, van Staveren WA, Hautvast JG, Deurenberg P

Br J Nutr, 2001 Apr;85(4):491-8.
PMID: 11348564 DOI: 10.1079/bjn2000276

This cross-sectional study compared body fat percentage (BF%) obtained from a four-compartment (4C) model with BF% from hydrometry (using 2H2O), dual-energy X-ray absorptiometry (DXA) and densitometry among the three main ethnic groups (Chinese, Malays and Indians) in Singapore, and determined the suitability of two-compartment (2C) models as surrogate methods for assessing BF% among different ethnic groups. A total of 291 subjects (108 Chinese, seventy-six Malays, 107 Indians) were selected to ensure an adequate representation of age range (18-75 years) and BMI range (16-40 kg/m2) of the general adult population, with almost equal numbers from each gender group. Body weight was measured, together with body height, total body water by 2H2O dilution, densitometry with Bodpod and bone mineral content with Hologic QDR-4500. BF% measurements with a 4C model for the subgroups were: Chinese females 33.5 (sd 7.5), Chinese males 24.4 (sd 6.1), Malay females 37.8 (sd 6.3), Malay males 26.0 (sd 7.6), Indian females 38.2 (sd 7.0), Indian males 28.1 (sd 5.5). Differences between BF% measured by the 4C and 2C models (hydrometry, DXA and densitometry) were found, with underestimation of BF% in all the ethnic-gender groups by DXA of 2.1-4.2 BF% and by densitometry of 0.5-3.2 BF%). On a group level, the differences in BF% between the 4C model and 2H2O were the lowest (0.0-1.4 BF% in the different groups), while differences between the 4C model and DXA were the highest. Differences between the 4C model and 2H2O and between the 4C model and DXA were positively correlated with the 4C model, water fraction (f(water)) of fat-free mass (FFM) and the mineral fraction (f(mineral)) of FFM, and negatively correlated with density of the FFM (D(FFM)), while the difference between 4C model and densitometry correlated with these variables negatively and positively respectively (i.e. the correlations were opposite). The largest contributors to the observed differences were f(water) and D(FFM). When validated against the reference 4C model, 2C models were found to be unsuitable for accurate measurements of BF% at the individual level, owing to the high errors and violation of assumptions of constant hydration of FFM and D(FFM) among the ethnic groups. On a group level, the best 2C model for measuring BF% among Singaporeans was found to be 2H2O.

Matched MeSH terms: Models, Biological*
Stress distributions in maxillary central incisors restored with various types of post materials and designs

Madfa AA, Kadir MR, Kashani J, Saidin S, Sulaiman E, Marhazlinda J, et al.

Med Eng Phys, 2014 Jul;36(7):962-7.
PMID: 24834856 DOI: 10.1016/j.medengphy.2014.03.018

Different dental post designs and materials affect the stability of restoration of a tooth. This study aimed to analyse and compare the stability of two shapes of dental posts (parallel-sided and tapered) made of five different materials (titanium, zirconia, carbon fibre and glass fibre) by investigating their stress transfer through the finite element (FE) method. Ten three-dimensional (3D) FE models of a maxillary central incisor restored with two different designs and five different materials were constructed. An oblique loading of 100 N was applied to each 3D model. Analyses along the centre of the post, the crown-cement/core and the post-cement/dentine interfaces were computed, and the means were calculated. One-way ANOVAs followed by post hoc tests were used to evaluate the effectiveness of the post materials and designs (p=0.05). For post designs, the tapered posts introduced significantly higher stress compared with the parallel-sided post (p<0.05), especially along the centre of the post. Of the materials, the highest level of stress was found for stainless steel, followed by zirconia, titanium, glass fibre and carbon fibre posts (p<0.05). The carbon and glass fibre posts reduced the stress distribution at the middle and apical part of the posts compared with the stainless steel, zirconia and titanium posts. The opposite results were observed at the crown-cement/core interface.

Matched MeSH terms: Models, Biological*

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