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PubMed1981

Plasmid transformation of Streptococcus sanguis (Challis) occurs by circular and linear molecules.

Transformation of Streptococcus sanguis (Challis) by antibiotic resistance plasmids has shown that (a) competence developed with identical kinetics for chromosomal and plasmid DNA; (b) dependence of transformant yield on plasmid DNA concentration was second order; (c) open circular plasmid DNA transformed Challis, although at reduced frequency, (d) linearization of plasmid DNA by restriction enzymes cutting at unique sites inactivated the transforming capacity; (e) transforming activity was restored when linear plasmid molecules generated by different restriction enzymes were mixed; (f) restoration of transforming activity depended on the distance between the linearizing cuts, i.e. on the presence of sufficiently long overlapping homologous sequences; (g) when linear deletion mutants were mixed with linear parental plasmids the smaller plasmid was restored with significantly higher frequency. Based on these data, a model for plasmid transformation of Challis is proposed according to which circular plasmid is linearized during binding and uptake. One DNA strand enters the cell and restoration of circular plasmids inside the cell occurs by annealing of complementary single strands from two different donor molecules. Implications of this model for recombinant DNA experiments in streptococci are discussed.

Chromosomes, Bacterial↗
PubMed2005

Linear programming to optimize performance in a department of surgery.

BACKGROUND: Linear programming is an analytic method that can be used to develop models for health care that optimize distribution of resources through mathematical means. STUDY DESIGN: The linear programming model contained objective, decision, and constraint elements. The objective was to optimize financial outcomes for both the hospital and physicians in the Department of Surgery. The decision concerns procedure mix or the number of each type of surgical procedure. Constraints apply to resources that are consumed during the course of the patient's surgical encounter. RESULTS: The optimal solution produced an increase in professional payments of 3.6% and an increase in hospital total margin of 16.1%. This solution favored surgical procedures that require inpatient care; these patients had greater comorbidity, reflected in a higher case-mix index of 3.74 compared to 2.97. Substantial differences were noted in use of general care and ICU days, and in consumption of preoperative, intraoperative, and recovery room time. CONCLUSIONS: Aligning quality surgical care with optimal financial performance may be assisted by mathematical models such as linear programming.

Comorbidity↗
PubMed2005

Bayesian latent variable models for mixed discrete outcomes.

In studies of complex health conditions, mixtures of discrete outcomes (event time, count, binary, ordered categorical) are commonly collected. For example, studies of skin tumorigenesis record latency time prior to the first tumor, increases in the number of tumors at each week, and the occurrence of internal tumors at the time of death. Motivated by this application, we propose a general underlying Poisson variable framework for mixed discrete outcomes, accommodating dependency through an additive gamma frailty model for the Poisson means. The model has log-linear, complementary log-log, and proportional hazards forms for count, binary and discrete event time outcomes, respectively. Simple closed form expressions can be derived for the marginal expectations, variances, and correlations. Following a Bayesian approach to inference, conditionally-conjugate prior distributions are chosen that facilitate posterior computation via an MCMC algorithm. The methods are illustrated using data from a Tg.AC mouse bioassay study.

Acrylates↗
PubMed2000

Real-time renormalization group and charge fluctuations in quantum dots

We develop a perturbative renormalization-group method in real time to describe nonequilibrium properties of discrete quantum systems coupled linearly to an environment. We include energy broadening and dissipation and develop a cutoff-independent formalism. We present quantitatively reliable results for the linear and nonlinear conductance in the mixed-valence and empty-orbital regime of the nonequilibrium Anderson impurity model with finite on-site Coulomb repulsion.

Journal Article↗
PubMed2005

Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL.

AIM: The vehicle Cremophor EL (CrEL) has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal tract. The goal of this study was to develop a semimechanistic population pharmacokinetic model to study the influence of CrEL on the oral absorption of paclitaxel. METHOD: Paclitaxel plasma-concentration time profiles were available from 55 patients (M:F, 17 : 38; total 67 courses; 797 samples), receiving paclitaxel orally once or twice daily (dose range 60-360 mg m(-2)) together with 12-15 mg kg(-1) cyclosporin A. A population pharmacokinetic model was developed using the nonlinear mixed effect modelling program NONMEM. RESULTS: After absorption, paclitaxel pharmacokinetics were best described using a two-compartment model with linear distribution from the central compartment into a peripheral compartment and first-order elimination. Paclitaxel in the gastrointestinal tract was modelled as free fraction or bound to CrEL, with only the free fraction available for absorption into the central compartment. The equilibrium between free and bound paclitaxel was influenced by the concentration of CrEL present in the gastrointestinal tract. The concentration of CrEL in the gastrointestinal tract decreased with time with a first order rate constant of 1.73 h(-1). The bioavailability of paclitaxel was independent of the dose and of CrEL. Estimated apparent paclitaxel clearance and volume of distribution were 127 l h(-1) and 409 l, respectively. Large interpatient variability was observed. Covariate analysis did not reveal significant relationships with any of the pharmacokinetic parameters. CONCLUSION: A pharmacokinetic model was developed that described the pharmacokinetics of orally administered paclitaxel. CrEL strongly influenced paclitaxel absorption from the gastrointestinal tract resulting in time-dependent but no significant dose-dependent absorption over the examined dose range studied.

Absorption↗
PubMed1979

[Experimental studies of various model materials. 1. Comparative study on linear dimension behavior].

The linear dimensional behaviour of the model materials Begolith, Dentaloc, Tewestone, Impredur and Keramik-Cement was investigated at various mixing temperature, the thickness of layer ranging from 3 to 5 mm. It seems that the model materials Begolith, Dentaloc and Tewestone will yield good results in practice. Impredur may be recommended on certain conditions. On the contrary, Keramik-Cement is not suited as a model material.

Dental Materials↗
PubMed2006

An investigation into the usefulness of generalized regression neural network analysis in the development of level A in vitro-in vivo correlation.

Quantitative correlations between in vivo and in vitro data (IVIVC) reduce the number of human in vivo studies, thus decreasing the overall time and expenses necessary for the development of optimal drug product formulation. Although linear regression analysis represents the simplest relationship, it is recognized that IVIVC should not be limited to linear relationship. With regards to the implementation of non-linear IVIVC models and the ability of artificial neural network (ANN) computing to cope with non-linear relationships, the usefulness of ANN analysis in the development of IVIVC merits further evaluation. The present paper is an attempt to develop an IVIVC for model sustained release paracetamol matrix tablet formulations employing various correlation approaches based on linear and non-linear modeling of in vitro and in vivo data. Currently accepted compendial methodology was compared with the alternative approaches, involving general mixed effects model and generalized regression neural network (GRNN) analysis, in order to evaluate their usefulness for predicting the in vivo behavior of drug products. Although based on analogous approaches, data generated by GRNN were closer to those observed in vivo, leading to the higher level of IVIVC than obtained by convolution. It can be assumed that GRNN analysis was able to generalize complex relations between the output and input parameters and could account for the differences in drug release kinetics observed under various conditions in vitro, thus offering potential as a reliable and robust estimate of drug products in vivo behavior.

Acetaminophen↗
PubMed2004

Pharmacodynamics of controlled release verapamil in patients with hypertension: an analysis using spline functions.

AIMS: To use a nonparametric approach involving longitudinal splines to model the baseline blood pressure profile and investigate the impact of this modelling on the pharmacodynamic analysis for verapamil in patients with angina or hypertension. METHODS: Dose ranging studies were conducted in patients with hypertension and with angina. Subjects received doses of 120, 180, 360 or 540 mg racemic verapamil. Pharmacodynamic data were created by subtracting the (systolic) blood pressure following active drug from the placebo response, either by direct subtraction or after modelling the baseline with a longitudinal spline model fitted to the placebo data by nonlinear mixed effects modelling. An Emax model was then used to describe the relationship between change in blood pressure and (R-)verapamil plasma concentration. RESULTS: The maximum decrease in systolic blood pressure was found to be 57.6 (+/- 26.1) mm and the C50 was 420 (+/- 349) microg/l for the data obtained by direct subtraction of the placebo data. Similar results were obtained when a cubic spline model was used to describe each individual's placebo response. However, the use of a population spline model only allowed a linear pharmacodynamic model to be fitted to the resulting data. Sparse data were created by randomly removing 66% of the data from the placebo and active phases. The population spline model gave very similar parameter estimates for the linear model applied to the sparse data to those obtained from the complete data set. CONCLUSIONS: The use of a longitudinal spline model together with nonlinear mixed effects modelling to account for baseline blood pressure response can be very powerful in a sparse data environment.

Adult↗
PubMed2003

Effects of elemental composition on the incorporation of dietary nitrogen and carbon isotopic signatures in an omnivorous songbird.

The use of stable isotopes to infer diet requires quantifying the relationship between diet and tissues and, in particular, knowing of how quickly isotopes turnover in different tissues and how isotopic concentrations of different food components change (discriminate) when incorporated into consumer tissues. We used feeding trials with wild-caught yellow-rumped warblers (Dendroica coronata) to determine delta15N and delta13C turnover rates for blood, delta15N and delta13C diet-tissue discrimination factors, and diet-tissue relationships for blood and feathers. After 3 weeks on a common diet, 36 warblers were assigned to one of four diets differing in the relative proportion of fruit and insects. Plasma half-life estimates ranged from 0.4 to 0.7 days for delta13C and from 0.5 to 1.7 days for delta15N . Half-life did not differ among diets. Whole blood half-life for delta13C ranged from 3.9 to 6.1 days. Yellow-rumped warbler tissues were enriched relative to diet by 1.7-3.6% for nitrogen isotopes and by -1.2 to 4.3% for carbon isotopes, depending on tissue and diet. Consistent with previous studies, feathers were the most enriched and whole blood and plasma were the least enriched or, in the case of carbon, slightly depleted relative to diet. In general, tissues were more enriched relative to diet for birds on diets with high percentages of insects. For all tissues, carbon and nitrogen isotope discrimination factors increased with carbon and nitrogen concentrations of diets. The isotopic signature of plasma increased linearly with the sum of the isotopic signature of the diet and the discrimination factor. Because the isotopic signature of tissues depends on both elemental concentration and isotopic signature of the diet, attempts to reconstruct diet from stable isotope signatures require use of mixing models that incorporate elemental concentration.

Animals↗
PubMed2000

Water uptake and relaxation processes in mixed unlimited swelling hydrogels.

The rheological oscillatory test parameters have been observed for highly concentrated hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose-sodium (NaCMC) and mixed HPMC/NaCMC hydrogels obtained by swelling of matrix tablets in 0.1 mol cm(-3) HCl and pH 6.8 phosphate buffer. The mechanical spectra of the gels have been analysed using theoretical models, i.e. a generalised Maxwell model and an adapted Maxwell model, both based on Ferry and Williams approximations. The relaxation time spectra as well as the parameters characteristic of linear viscoelastic behaviour have been calculated: zero shear viscosity (eta(0)), plateau moduli (G(N)(0), G(0)' and G(0)"), zero-relaxation time (tau(0)) and mean relaxation time (θ). The mechanical spectra of mixed HPMC/NaCMC hydrogels differ considerably from those of the pure ones, the type of the spectrum depending on the two polymers' ratios. In both media, the rheological models applied define the HPMC gels as homogeneous entangled networks, and those of NaCMC and mixed HPMC/NaCMC as heterogeneous physical gels. The relationship between the kinetic constants of water penetration and the mean relaxation times suggests that the molecular relaxation controls the water uptake velocity. With all the systems tested irrespective of pH of the aqueous phase, an inversely proportional dependence between the viscosity and the water penetration velocity has been noted. Since the degree of hydration is one of the factors determining the degree and velocity of drug release from the hydrogel matrices, the relation between the kinetic parameters of water penetration and the viscosity is a characteristic indicator for the gel structure, the degree of swelling and the drug release rate.

Absorption↗
PubMed1987

Estimation of hominoid phylogeny from a DNA hybridization data set.

Analysis of the expanded data set of Sibley and Ahlquist (1987) on primate phylogeny using a maximum likelihood mixed model analysis of variance method shows that there is significant evidence for resolving the Homo-Pan-Gorilla trifurcation in favor of a Homo-Pan clade. The resulting tree is close to that estimated by Sibley and Ahlquist (1984). The mixed model can be used to test a number of hypotheses about the existence of components of variance and the linearity of the relationship between branch length and expected distance. No evidence is found that there is a variance component for extract, or for the individual from which the extract was taken. A variance component for experiment does seem to exist, presumably arising as a result of error of measurement of the common standard from which all values in the same experiment were subtracted. There is significant evidence that the relationship between total branch length between species and their expected distances is nonlinear, or else that the measurement error on larger distances is greater than on smaller ones. Allowing for the nonlinearity might cause one to infer the time of distant common ancestors as less remote than the measured hybridization values would imply if used directly.

Analysis of Variance↗
PubMed2006

Quantile regression for longitudinal data using the asymmetric Laplace distribution.

In longitudinal studies, measurements of the same individuals are taken repeatedly through time. Often, the primary goal is to characterize the change in response over time and the factors that influence change. Factors can affect not only the location but also more generally the shape of the distribution of the response over time. To make inference about the shape of a population distribution, the widely popular mixed-effects regression, for example, would be inadequate, if the distribution is not approximately Gaussian. We propose a novel linear model for quantile regression (QR) that includes random effects in order to account for the dependence between serial observations on the same subject. The notion of QR is synonymous with robust analysis of the conditional distribution of the response variable. We present a likelihood-based approach to the estimation of the regression quantiles that uses the asymmetric Laplace density. In a simulation study, the proposed method had an advantage in terms of mean squared error of the QR estimator, when compared with the approach that considers penalized fixed effects. Following our strategy, a nearly optimal degree of shrinkage of the individual effects is automatically selected by the data and their likelihood. Also, our model appears to be a robust alternative to the mean regression with random effects when the location parameter of the conditional distribution of the response is of interest. We apply our model to a real data set which consists of self-reported amount of labor pain measurements taken on women repeatedly over time, whose distribution is characterized by skewness, and the significance of the parameters is evaluated by the likelihood ratio statistic.

Analgesics↗
PubMed2005

Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients.

AIM: To study the possible influence of patient characteristics on abacavir pharmacokinetics. METHODS: A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM. RESULTS: Abacavir pharmacokinetics was well described by a two-compartment open model with linear absorption and elimination. Typical population estimates for the absorption rate constant (Ka), the apparent central distribution volume (Vc/F), the apparent peripheral distribution volume (Vp/F), the apparent intercompartmental clearance (Q/F) and the apparent plasma clearance (CL/F) were 1.8 h(-1), 75 l, 23.6 l, 10 l h(-1) and 47.5 l h(-1), respectively. Apparent plasma clearance was positively related to bodyweight. Individual Bayesian estimates of CL/F were used to calculate abacavir AUC. The latter decreased from 10.7 +/- 5.0 to 5.7 +/- 1.6 mgh l(-1) when bodyweight increased from 36 to 102 kg. This drop in abacavir exposure could lead to suboptimal treatment for the heaviest patients, as antiviral efficacy of abacavir is known to be related to its AUC. A 400 mg abacavir dose would be necessary to achieve adequate exposure to abacavir in patients weighing more than 60 kg. CONCLUSIONS: The apparent plasma clearance of abacavir was positively related to bodyweight. The efficacy of the current recommended abacavir dosage for patients with high bodyweight should be evaluated in further studies.

Administration, Oral↗
PubMed2000

A mixed-penalty biphasic finite element formulation incorporating viscous fluids and material interfaces.

The fluid viscosity term of the fluid phase constitutive equation and the interface boundary conditions between biphasic, solid and fluid domains have been incorporated into a mixed-penalty finite element formulation of the linear biphasic theory for hydrated soft tissue. The finite element code can now model a single-phase viscous incompressible fluid, or a single-phase elastic solid, as limiting cases of a biphasic material. Interface boundary conditions allow the solution of problems involving combinations of biphasic, fluid and solid regions. To incorporate these conditions, the volume-weighted mixture velocity is introduced as a degree of freedom at interface nodes so that the kinematic continuity conditions are satisfied by conventional finite element assembly techniques. Results comparing our numerical method with an independent, analytic solution for the problem of Couette flow over rigid and deformable porous biphasic layers show that the finite element code accurately predicts the viscous fluid flows and deformation in the porous biphasic region. Thus, the analysis can be used to model the interface between synovial fluid and articular cartilage in diarthrodial joints. This is an important step toward modeling and understanding the mechanisms of joint lubrication and another step toward fully modeling the in vivo behavior of a diarthrodial joint.

Biomechanical Phenomena↗
PubMed1998

The effects of inbreeding on the lifetime performance of dairy cattle.

The effects of inbreeding on the lifetime performance of dairy cattle were examined using data for production, somatic cell score, and linear type for all Holstein cows that were scored between 1983 and 1993. The results of fixed and mixed animal models differed. Relative net income adjusted for opportunity cost for the 2,610,123 cows with an 84-mo opportunity for herdlife was depressed by $14.79 for fluid market pricing and by $12.40 for manufacturing pricing per 1% increase in inbreeding. Mixed model estimates of depression per 1% of increase in inbreeding were +0.55 d for age at first calving, -6 d for days of productive life, and -4.8 for days in milk. Inbreeding decreased the mature equivalent production of milk, fat, and protein during first lactation by 27, 0.9, and 0.8 kg and the lifetime production of milk, fat, and protein by 177, 6.0, and 5.5 kg, respectively, per 1% increase in inbreeding. Inbreeding had little effect on conformation traits. The effects of inbreeding were cumulative, and effects on lifetime profit functions were relatively larger than the effects on lactation traits. Registered cows had higher levels of inbreeding and larger standard deviations than did grade cows. Inbreeding in registered cows depressed relative net income adjusted for opportunity cost for fluid and manufacturing prices by $24.43 and $21.78, respectively; income was depressed $9.43 and $9.02, respectively, for grade cows. The difference between registered and grade cattle is likely due to the incomplete pedigree information in grade animals. Inbreeding among cows in this study was not high on average, but economic losses represented a significant cost to the producer.

Animals↗
PubMed2003

Closing service system gaps for homeless clients with a dual diagnosis: integrated teams and interagency cooperation.

BACKGROUND: There is great concern about fragmentation of mental health service delivery, especially for dually diagnosed homeless people, and apprehension that such fragmentation adversely affects service access and outcomes. AIMS OF THE STUDY: This study first seeks to articulate two alternative approaches to the integration of psychiatric and substance abuse services, one involving an integrated team model and the other a collaborative relationship between agencies. It then applies this conceptualization to a sample of dually diagnosed homeless people who participated in the ACCESS demonstration. METHODS: Longitudinal outcome data were obtained through interviews at baseline, 3 months, and 12 months with homeless clients with a dual diagnosis (N = 1074) who received ACT-like case management services through the ACCESS demonstration. A survey of ACCESS case managers was conducted to obtain information on: (i) the proportion of clients who received substance abuse services directly from ACCESS case management teams, and the proportion who received services from other agencies; and (ii) the perceived quality of the relationship (i.e. communication, cooperation and trust) between providers--both within the same teams and between agencies. Hierarchical linear modeling was then used to examine the relationship of these two factors to service use and outcome with mixed-model regression analysis. RESULTS: Significant (p<.05) and positive relationships were observed in 4 of the 20 analyses of the association of service use and measures of communication, cooperation, and trust (either intrateam or inter-agency) while none were significant and negative. At 12 months, receipt of a higher proportion of services from agencies other than the ACCESS team was associated with fewer days homeless, and greater reduction of psychiatric symptoms, contradicting the hypothesis that integrated team care is more effective than interagency collaborations. DISCUSSION AND LIMITATIONS: This study broadens the conceptual framework for addressing service system fragmentation by considering both single team integration and interagency coordination, and by considering both program structure and the quality of relationships between providers. Data from a multi-site outcome study demonstrated suggestive associations between perceptions of communication, cooperation and measures of clinical service use. However, the proportion of clients treated entirely within a single team was associated with poorer housing and psychiatric outcomes. These empirical results must be regarded as illustrative rather than conclusive because of the use of a non-experimental study design, imperfections in the available measures, and the incomplete sampling of case managers. IMPLICATIONS FOR HEALTH POLICY: This study suggests that fragmentation of services for dually diagnosed clients may be reduced by improving the interactions within and between agencies providing these services. While primary emphasis has been placed on developing integrated teams, interagency approaches should not be prematurely excluded. IMPLICATIONS FOR FUTURE RESEARCH: Research on approaches to reducing system fragmentation have focused on either global efforts to integrate numerous agencies in a community or highly focused efforts to develop specialized teams. Future research should also focus on the possibility of fostering constructive relationships between selected pairs or subsets of agencies. Research in this area will also benefit from the further development measures of team integration and of both intra-team and inter-agency communication, collaboration, and trust.

Case Management↗
PubMed1970

Comparison of physical models used to explain condensation effects in lecithin-cholesterol mixed films.

The apparent condensation effect observed with mixed monolayers of lecithin and cholesterol has been examined with respect to both molecular interaction and molecular cavity models. For each, model equations are presented which predict the surface areas of the film components as a function of the mole fraction of each component. For mixed monolayers where linearity does not exist in plots of mean surface area vs. mole fraction, and where there are breaks in the curve at mole fraction values other than 0.5, the size of the cavities are not invariant with respect to mole fraction.

Chemical Phenomena↗
PubMed1989

The use of a non-linear regression approach for the analysis of the ouabain-K+ interaction with (Na+ + K+)-ATPase from guinea pig and rat hearts.

1. The interaction between ouabain and K+ and their effects on (Na+ + K+)-ATPase activity were studied using microsomes from guinea pig and rat heart. 2. Microsomes were incubated in the presence of various concentrations of K+ and ouabain and ATPase activity was estimated by measuring the inorganic phosphate liberated. The experimental data were analyzed statistically by micro-computer, using a non-linear regression program based on the steepest descent technique. 3. The experimental data were best fitted by a model which assumes that ouabain acts like a mixed inhibitor with respect to the apparently cooperative K+ activation of (Na+ + K+)-ATPase. This quantitative approach provided estimates (with approximate standard deviations) of all the parameters involved in the model. 4. The inhibition constant for the uncompetitive term of the effect was 7- to 9-fold higher than the inhibition constant for the competitive term for both the guinea pig and rat heart preparations. 5. The present results indicate that graphical analyses are helpful for illustrative purposes but suggest that a computerized, non-linear regression program simultaneously analyzing all the non-linearized data should be used to quantify the complex kinetic parameters and to discriminate objectively among possible models.

Animals↗