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PubMed2002

Modelling the epidemiology, transmission and control of lymphatic filariasis.

Wuchereria bancrofti transmitted by Culex quinquefasciatus accounts for >90% of the global burden of lymphatic filariasis (LF). Recent advances in diagnostic and control tools and a better epidemiological understanding of the disease have led to hope that LF is eradicable. The World Health Organization has helped a number of member countries to launch nation-wide programmes of mass treatment with antifilarial drugs such as diethylcarbamazine, albendazole and ivermectin, for the elimination of this disease. In order to make rational decisions about control strategies, reliable predictions of the long-term impact of such treatment, and of alternative interventions, need to be made, and these can only be based on a sound, quantitative understanding of the population biology of the parasites. Mathematical models have proven valuable in gaining quantitative insights into the population dynamics of the parasites, and may be used to make credible predictions of the likely outcomes of various control strategies. This article provides an overview of the development of the relevant mathematical/statistical models and of their application in studies of the epidemiology, transmission and control of lymphatic filariasis.

Animals↗

PubMed2006

A simple model-based control for Pichia pastoris allows a more efficient heterologous protein production bioprocess.

A predictive control algorithm coupled with a PI feedback controller has been satisfactorily implemented in the heterologous Rhizopus oryzae lipase production by Pichia pastoris methanol utilization slow (Mut(s)) phenotype. This control algorithm has allowed the study of the effect of methanol concentration, ranging from 0.5 to 1.75 g/L, on heterologous protein production. The maximal lipolytic activity (490 UA/mL), specific yield (11,236 UA/g(biomass)), productivity (4,901 UA/L . h), and specific productivity (112 UA/g(biomass)h were reached for a methanol concentration of 1 g/L. These parameters are almost double than those obtained with a manual control at a similar methanol set-point. The study of the specific growth, consumption, and production rates showed different patterns for these rates depending on the methanol concentration set-point. Results obtained have shown the need of implementing a robust control scheme when reproducible quality and productivity are sought. It has been demonstrated that the model-based control proposed here is a very efficient, robust, and easy-to-implement strategy from an industrial application point of view.

Bioreactors↗

PubMed2005

Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae.

Mathematical models have become a necessary tool for organizing the rapidly increasing amounts of large-scale data on biochemical pathways and for advanced evaluation of their structure and regulation. Most of these models have addressed specific pathways using either stoichiometric or flux-balance analysis, or fully kinetic Michaelis-Menten representations, metabolic control analysis, or biochemical systems theory. So far, the predictions of kinetic models have rarely been tested using direct experimentation. Here, we validate experimentally a biochemical systems theoretical model of sphingolipid metabolism in yeast. Simulations of metabolic fluxes, enzyme deletion and the effects of inositol (a key regulator of phospholipid metabolism) led to predictions that show significant concordance with experimental results generated post hoc. The model also allowed the simulation of the effects of acute perturbations in fatty-acid precursors of sphingolipids, a situation that is not amenable to direct experimentation. The results demonstrate that modelling now allows testable predictions as well as the design and evaluation of hypothetical 'thought experiments' that may generate new metabolomic approaches.

Computer Simulation↗

PubMed1998

Lead toxicokinetics. Development of a biokinetic model to understand and predict the outcome of treatment.

Quite often physicians contact the Dutch Poisons Control Centre for information on patients with increased lead exposure. The most important questions raised by physicians dealing with these patients are how to estimate the lead exposure and the total lead body burden, how to interpret blood lead concentrations and whether the patient needs treatment. In order to answer these questions we need knowledge of the toxicokinetics of lead in the human body. To achieve insight and to make this knowledge accessible to physicians a biokinetic model for lead metabolism in the human body was developed. A four-compartment model with first-order kinetics, based on the concept of Kneip, was used. A biokinetic model uses a mathematical approach to translate the complex biological and kinetic behaviour of lead. In order to develop this biokinetic model two computer programmes were used. At the moment the model is tested with clinical data from patient treated at the medical toxicology outpatient clinic of the Utrecht University Hospital (this department cooperates very closely with the National Poisons Control Centre). Especially with regard to chelation therapy for elevated blood lead levels due to chronic exposure, the model is very helpful in visualising the toxicokinetics of lead in the human body. Toxicokinetic model might help improve knowledge of lead toxicokinetics, leading to well-considered guidelines for treatment of lead intoxications.

Absorption↗

PubMed2001

Foster care placement improves children's functioning.

OBJECTIVE: To examine changes in reported functioning over a 12-month follow-up period and predictors of those changes for a cohort of young children enrolled in foster care. DESIGN: Data came from a longitudinal follow-up of a cohort of young children entering foster care in one Connecticut region. These data were originally assembled to evaluate the effectiveness of a specialized set of services designed to provide a baseline multidisciplinary assessment and ongoing monitoring for young children entering foster care. SETTING AND PARTICIPANTS: From February 1, 1992, through July 31, 1993, all young children (N = 120) entering foster care in one Connecticut region were enrolled in this study. Children were assessed at entry into care and at 6 and 12 months after entry. Participation rates exceeded 90% at each follow-up period. MAIN OUTCOME MEASURES: The principal outcome of interest for these analyses is 12-month functioning as measured by the Vineland Adaptive Behavior Scale (VABS) scores completed by their foster mothers. RESULTS: At entry into foster care, children ranged in age from 11 to 76 months, were evenly divided by sex, and had a mean VABS score of 79.5 signifying functioning below the average range. At 6 months children gained an average of 7.87 points on their VABS score. By 12 months children showed an average change of 9.65 points, for a mean VABS score of 94.5, well within the nationally normed average range. The multivariate linear model predicting the 12-month VABS score showed that, controlling for the baseline VABS score, when children who were abused, older at placement, female, of African American ethnicity, spent more time in foster care, and had fewer recommended services while in care, they were more likely to show improvement on the foster mother-reported VABS evaluation. CONCLUSIONS: These results demonstrate that children's reported functioning improves over the course of placement in foster care and that sociodemographic characteristics, reason for placement, length of time in foster care, and fewer recommended services at entry into foster care identified children who were more likely to improve. These results argue for a careful examination of the foster care environment to better understand which aspects of the environment contribute to improved foster mother reported functioning. Such understanding will be critical for the care and development of maltreated children.

Child↗

PubMed2006

Association between the interleukin-1 family gene cluster and psoriatic arthritis.

OBJECTIVE: The interleukin-1 (IL-1) cytokine elicits a wide variety of biologic activities that initiate and promote an inflammatory response. The loci in the IL1 gene cluster have recently been associated with ankylosing spondylitis (AS). Since there is clinical and immunologic overlap between psoriatic arthritis (PsA) and AS, we wanted to examine the association between a panel of single-nucleotide polymorphisms (SNPs) in the IL1 gene family cluster and chromosome 2q12-13 in a PsA cohort. METHODS: Two hundred twelve PsA patients and 150 ethnically matched controls were genotyped with 11 SNPs in IL1A, 9 SNPs in IL1B, and 9 SNPs in IL1F5-10. Univariate analyses of the 29 single markers and short intragenic haplotypes identified several associated regions. Seventeen markers of interest were noted and further investigated to determine which markers or short haplotypes independently predict case-control status, using a stepwise logistic model. RESULTS; Two regions contributing independently to risk of disease in PsA were noted: a region spanned by markers rs3783547, rs3783543, and rs17561 in IL1A, and a region near the end of IL1B, through IL1F7, IL1F8, and into IL1F10. The best model contained markers rs3811047, rs1562304, and rs3811058, and 1 haplotype constructed from the 3 markers in region 1, with a likelihood ratio of 25.34 (4 degrees of freedom). CONCLUSION: The IL1 locus appears to be a high-priority susceptibility locus in PsA, with at least 2 independent regions that confer increased risk.

Adult↗

PubMed2005

Entropic interaction chromatography: separating proteins on the basis of size using end-grafted polymer brushes.

Partitioning of a macromolecule into the interfacial volume occupied by a grafted polymer brush decreases the configurational entropy (DeltaSbrush(c)) of the terminally attached linear polymer chains due to a loss of free volume. Self-consistent field theory (SCF) calculations are used to show that DeltaSbrush(c) is a strong function of both the size (MWp) of the partitioning macromolecule and the depth of penetration into the brush volume. We further demonstrate that the strong dependence of DeltaSbrush(c) on MWp provides a novel and powerful platform, which we call entropic interaction chromatography (EIC), for efficiently separating mixtures of proteins on the basis of size. Two EIC columns, differing primarily in polymer grafting density, were prepared by growing a brush of poly(methoxyethyl acrylamide) chains on the surface of a wide-pore (1,000-A pores, 64-microm diameter rigid beads) resin (Toyopearl AF-650M) bearing surface aldehyde groups. Semipreparative 0.1-L columns packed with either EIC resin provide reduced-plate heights of 2 or less for efficient separation of globular protein mixtures over at least three molecular-weight decades. Protein partitioning within these wide-pore EIC columns is shown to be effectively modeled as a thermodynamically controlled process, allowing partition coefficients (K(P)) and elution chromatograms to be accurately predicted using a column model that combines SCF calculation of K(P) values with an equilibrium-dispersion type model of solute transport through the column. This model is used to explore the dependence of column separation efficiency on brush properties, predicting that optimal separation of proteins over a broad MWp range is achieved at low to moderate grafting densities and intermediate chain lengths.

Acrylamides↗

PubMed1993

Model describing transdermal iontophoretic delivery of lidocaine incorporating consideration of cutaneous microvascular state.

A three-compartment pharmacokinetic model describing percutaneous absorption of iontophoretically driven topically applied lidocaine in the isolated perfused porcine skin flap is presented. Delivery from the active (drug-dosed) electrode to skin is estimated as a ramp input profile. Model parameters were estimated separately for dosing (4 h current-on) and washout (4 h current-off) periods in experiments with coadministered vasoactive drugs [tolazoline (vasodilator) and norepinephrine (vasoconstrictor)] and controls (lidocaine alone). The model presented was able to predict 8-h lidocaine absorptions and compartmental mass profiles for each of the three treatments, was able to document vascular effects of co-iontophoresed vasoactive compounds, and gives insight into the factors that modulate cutaneous disposition of iontophoretically delivered lidocaine in a biologically relevant model approximating in vivo delivery.

Administration, Cutaneous↗

PubMed2003

Cooling efficiency of cryogen spray during laser therapy of skin.

BACKGROUND AND OBJECTIVES: Cryogen spray cooling (CSC) is used extensively for epidermal protection during laser-induced photothermolysis of port wine stains and other vascular skin lesions. The efficacy of CSC depends critically on the heat transfer coefficient (H) at the skin surface for which, however, no reliable values exist. Reported values for H, based on tissue phantoms, vary from 1,600 to 60,000 W/m(2) K. STUDY DESIGN/MATERIALS AND METHODS: A simple experimental model was designed and constructed, consisting of a pure silver-measuring disk (diameter 10 mm, thickness approximately 1 mm), embedded in a thermal insulator. The disk was covered with a 10 microm thick stratum corneum layer, detached from in vivo human skin. The heat transfer coefficient of the stratum corneum/cryogen interface was measured during CSC with short spurts of atomized tetrafluoroethane. RESULTS: H was found to be dependent on the specific design of the cryogen valve and nozzle. With nozzles used in typical clinical settings, H was 11,500 W/m(2) K, when averaged over a 100 ms spurt, and 8,000 W/m(2) K when averaged over a 200 ms spurt. CONCLUSIONS: The presented model enables accurate prediction of H and thus improve control over temperature depth profile and cooling efficiency during laser therapy. Thereby, it may contribute to improvement of therapeutic outcome.

Cryotherapy↗

PubMed1996

Self-Efficacy Beliefs and Mathematical Problem-Solving of Gifted Students

Path analysis was used to test the predictive and mediational role that self-efficacy beliefs play in the mathematical problem-solving of middle school gifted students (n = 66) mainstreamed with regular education students (n = 232) in algebra classes. Self-efficacy of gifted students made an independent contribution to the prediction of problem-solving in a model that controlled for the effects of math anxiety, cognitive ability, mathematics GPA, self-efficacy for self-regulated learning, and sex. Gifted girls surpassed gifted boys in performance but did not differ in self-efficacy. Gifted students reported higher math self-efficacy and self-efficacy for self-regulated learning as well as lower math anxiety than did regular education students. Although most students were overconfident about their capabilities, gifted students had more accurate self-perceptions and gifted girls were biased toward underconfidence. Results support the hypothesized role of self-efficacy in A. Bandura's (1986) social cognitive theory.

Journal Article↗

PubMed2002

The K-Cl cotransporter in the lobster stretch receptor neurone--a kinetic analysis.

Experiments were performed to define quantitatively the substrate (K(+) and Cl(-)) dependence of the transport function (production of equally large and oppositely directed K(+)and Cl(-) flows/currents) of an earlier (Theander et al., 1999) identified electroneutral K-Cl cotransporter in the slowly adapting stretch receptor neurone of the European lobster. The experiments were based on microelectrode techniques. This allowed us to perform steady-state measurements of the so-called "instantaneous" current-voltage relationships (around a holding voltage of -65 mV after a blockage of the cell's action potential and hyperpolarization-activated currents) and intracellular ion concentrations at various settings of the extracellular K(+) and Cl(-) concentrations. From the results, we could then define steady-state values of all of the cell's non-KCl cotransporter K(+) and Cl(-) currents. Finally, the negative sums of the inferred non-KCl cotransporter K(+) and Cl(-) currents could be taken as equivalents of the K-Cl cotransporter's K(+) and Cl(-) currents for the reason that, in steady state, all membrane currents add up to zero. For the cotransporter currents, thus inferred for a range from 2.5/410.5 to 40.0/448.0 mM external K(+)/Cl(-), we found that their absolute values increased in a nonlinear fashion from about 5 nA cell(-1) at the lowest, to about 20 nA cell(-1) at the highest external K(+)/Cl(-) concentrations. Formally, this relationship could be reproduced by a Hill function-based enzyme kinetic expression simulating inward and outward transmembrane electroneutral ion transports. Following insertion of this expression into a comprehensive model of electrical membrane functions and intracellular solute and solvent control in the lobster stretch receptor neurone, the model predictions suggested that the K-Cl cotransporter does play an important role in (a) keeping intracellular Cl(-) low for a proper function of the cell's inhibitory system, and (b) enabling rapid transmembrane K(+) shifts that provide for a stabilization of the cell's membrane voltage and membrane excitability in cases of varying extracellular K(+) concentrations. The model predictions gave, however, no clear evidence that the K-Cl cotransporter is critically involved in the cell's volume regulation in conditions of varying extracellular osmolalities.

Animals↗

PubMed1983

Human styrene exposure. V. Development of a model for biological monitoring.

The use of biological indicators to monitor workers' exposure to styrene requires a good understanding of the kinetics of the solvent in the organism. The absorption, distribution and elimination of styrene (STY), as well as the kinetics of formation and excretion of its metabolites (mandelic [MA] and phenylglyoxylic [PGA] acids) are simulated using a mathematical model. The results obtained compare well with experimental data for pulmonary (STY) and urinary (MA and PGA) excretion obtained during controlled human exposures. The model is then used to predict the behaviour of STY, MA and PGA during repeated occupational exposure. It is shown that the results are comparable to the data collected during field surveys in the polyester industry, if the level of physical activity of the workers is taken into account. This latter parameter appears to have a great influence on the urinary excretion of the metabolites. Based on the results obtained, biological limits of exposure are proposed (referenced to a TLV [threshold limit value] of 50 ppm) for MA and MA + PGA excretions in urine collected at the end of the shift (800 and 1000 mg/g creat.) and the next morning (150 and 300 mg/g creat.). Their validity is tested against experimental data obtained under field conditions.

Environmental Exposure↗

PubMed1984

Multimerization of high copy number plasmids causes instability: CoIE1 encodes a determinant essential for plasmid monomerization and stability.

Although the natural multicopy plasmid CoIE1 is maintained stably under most growth conditions, plasmid cloning vectors related to it are relatively unstable, being lost at frequencies of 10(-2)-10(-5) per cell per generation. Evidence suggests that CoIE1 and related plasmids are partitioned randomly at cell division and that plasmid stability is correlated inversely with plasmid multimerization; factors or conditions that reduce multimerization increase stability. Cells containing plasmid multimers segregate plasmid-free cells because the multimers are maintained at lower copy numbers than monomers, as predicted by origin-counting models for copy number control. CoIE1 is stable because it encodes a determinant, cer, that is necessary for recA-, recF-, and recE-independent recombination events that efficiently convert any multimers to monomers. We have localized monomerizing and stability determinants of CoIE1 to within a 0.38 kb region that, when cloned into plasmid vectors, greatly increases their stability.

Ampicillin↗

PubMed1990

Effect of 3,4-dichloroaniline and metavanadate on Daphnia populations.

Fourteen continuously fed populations of Daphnia magna were exposed to 3,4-dichloroaniline (3,4-DCA) or metavanadate and monitored for 20 (two controls), 14 (six with metavanadate), and 8 (six with 3,4-DCA) weeks. The controls showed a damped oscillation. Low concentrations of either 3,4-DCA or metavanadate stimulated the first population peak. High concentrations of metavanadate rendered population peaks less regular, and at the highest metavanadate concentration, one population perished. High concentrations of 3,4-DCA slightly reduced population size. Four periodically fed populations of D. magna were also monitored. The more they were fed, the larger they grew. In the continuously fed populations, ephippia were formed at and just after the population peaks. No ephippia were noted in the periodically fed populations. Metavanadate promoted the formation of ephippia (NOEC 0.56 mg/liter), and 3,4-DCA depressed sexual reproduction at all concentrations tested (6, 12, and 24 micrograms/liter). The population dynamics of the controls were compared with those predicted by Kooijman's model (1986a, in The Dynamics of Physiologically Structured Populations (J.A.J. Metz and O. Diekmann, Eds.), pp. 266-297, Springer Lecture Notes in Biomathematics; 1986b, J. Math. Biol. 23, 163-185) for growth and reproduction of individual daphnids. In general, there is reasonable agreement between model predictions and observations, but some adjustments to the model may be necessary.

Aniline Compounds↗

PubMed2001

Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics.

Previous clinical studies have demonstrated two distinctive pharmacokinetic behaviors of erythropoietin (EPO): changes in pharmacokinetics (PK) after a period of rhEPO treatment and nonlinear pharmacokinetics. The objective of this work was to study the temporal changes in EPO's PK following phlebotomy in order to propose possible mechanisms for this behavior. Five healthy adult sheep were phlebotomized on two separate occasions 4-6 weeks apart to hemoglobin levels of PK 3-4 g/dL. PK parameters were estimated from the concentration-time profiles obtained following repeated intravenous bolus PK studies using tracer doses of biologically active 125I-rhEPO. Based on the changes in clearances, a PK model was derived to provide a mechanistic receptor-based description of the observed phenomena. Phlebotomy resulted in a rapid increase in the EPO plasma concentration, which peaked at 760 +/- 430 mU/mL (mean +/- SD) at 1.8 +/- 0.65 days, and which coincided with a transient reduction in EPO clearance from prephlebotomy values, i.e., from 45.6 +/- 11.2 mL/hr/kg to 24.3 +/- 9.7 mL/hr/kg. As plasma EPO levels returned toward baseline levels in the next few days, a subsequent increase in EPO clearance was noted. EPO clearance peaked at 90.2 +/- 26.2 mL/hr/kg at 8.5 +/- 3.3 days and returned to baseline by 4-5 weeks postphlebotomy. The proposed model derived from these data includes positive feedback control of the EPO receptor (EPOR) pool. The model predicts that: 1) the initial reduction in EPO plasma clearance is due to a transient saturation of EPORs resulting from the phlebotomy-induced high EPO concentration; and 2) the EPOR pool is expandable not only to compensate for EPOR loss but also to adjust to a greater need for EPORs/progenitor cells to restore hemoglobin (Hb) concentration to normal levels.

Animals↗

PubMed1997

A thermal beam-shape phantom for ultrasound physiotherapy transducers.

Acoustic beam nonuniformities are not uncommon in physiotherapy ultrasound equipment and can lead to errors in delivered dose. A relatively simple thermal technique is described for mapping the intensity distribution in physiotherapy ultrasound beams that could be used for routine QA checks. The technique uses a thermochromic material sandwiched between layers that absorb ultrasound. The structure is used in a water bath to intersect the ultrasound beam. Thermal models predict that, with suitable absorbing materials and careful control of the surface temperature of the layers, sufficient spatial resolution and sensitivity can be achieved to show the intensity distribution in physiotherapy ultrasound beams. Thermal images of sections through physiotherapy ultrasound beams using this method correlate well with corresponding intensity maps generated by planar scanning with a hydrophone.

Hot Temperature↗

PubMed2002

The role of calcium-activated potassium channels in respiratory control.

The introduction of pharmacological and genetic tools has helped to understand the functional role of specific ion channel subtypes in the neural control of breathing. This review outlines the role one family of potassium channels, those, which are regulated by intracellular calcium. Calcium-activated potassium channels (K(+)ca) play important roles in determining the duration of single action potentials and in the frequency of action potentials in excitable cells. They have been classified based on their unitary conductances combined with their inhibition by a variety of pharmacologic substances. In this review the role of K(+)ca channels in respiratory control is outlined. The predictions of their contributions from modeling the respiratory system and the results of experiments in which they are individually blocked are discussed. Recently mice have been generated in which the expression of a single member of the K(+)ca channel family can be conditionally regulated. The repression of this small-conductance K(+)ca channel (SK3) as well as its overexpression affect baseline respiratory rhythm and the ventilatory response to hypoxia.

Animals↗

PubMed2004

Physical activity as a predictor of body composition in American Indian children.

OBJECTIVE: To examine physical activity in second grade American Indian children as a predictor of percentage body fat 3 years later. RESEARCH METHODS AND PROCEDURES: Physical activity was assessed as average vector magnitude (AVM) counts from an accelerometer in 454 second grade children as part of the Pathways study. BMI was assessed, and skinfolds and bioelectrical impedance were used to estimate fat mass, fat-free body mass, and percentage body fat in validated prediction equations. Associations were examined using mixed models regression controlling for baseline body composition. RESULTS: In normal-weight children, higher AVM counts were significantly associated with decreases in percentage body fat. Among overweight children, higher AVM counts were significantly associated with increases in BMI, fat mass, and fat-free mass but not percentage body fat. DISCUSSION: Higher physical activity levels in second grade were associated with lower levels of percentage body fat in fifth grade in normal-weight but not in overweight children. BMI showed no association with physical activity among normal-weight children, and increases in BMI were associated with increasing amounts of physical activity among overweight children. These findings emphasize the importance of valid body composition measures and may indicate important differences in associations between physical activity and adiposity in normal-weight as compared with overweight children.

Body Composition↗