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PubMed2003

Optimal kinetics for quantification of antigen-induced cytokines in human peripheral blood mononuclear cells by real-time PCR and by ELISA.

Real-time polymerase chain reaction (PCR) has recently been described as a new tool to measure and accurately quantify mRNA levels. In this study, we have applied this technique to evaluate cytokine mRNA synthesis induced by antigenic stimulation with purified protein derivative (PPD) or heparin-binding haemagglutinin (HBHA) in human peripheral blood mononuclear cells (PBMC) from Mycobacterium tuberculosis-infected individuals. Whereas PPD and HBHA optimally induced IL-2 mRNA after respectively 8 and 16 to 24 h of in vitro stimulation, longer in vitro stimulation times were necessary for optimal induction of interferon-gamma (IFN-gamma) mRNA, respectively 16 to 24 h for PPD and 24 to 96 h for HBHA. IL-13 mRNA was optimally induced by in vitro stimulation after 16-48 h for PPD and after 48 to 96 h for HBHA. Comparison of antigen-induced Th1 and Th2 cytokines appears, therefore, valuable only if both cytokine types are analysed at their optimal time point of production, which, for a given cytokine, may differ for each antigen tested. Results obtained by real-time PCR for IFN-gamma and IL-13 mRNA correlated well with those obtained by measuring the cytokine concentrations in cell culture supernatants, provided they were high enough to be detected. We conclude that real-time PCR can be successfully applied to the quantification of antigen-induced cytokine mRNA and to the evaluation of the Th1/Th2 balance, only if the kinetics of cytokine mRNA appearance are taken into account and evaluated for each cytokine measured and each antigen analysed.

Antigens↗

PubMed1986

Relation of branching angles to optimality for four cost principles.

The literature has suggested that branching angles depend on some principle of optimality. Most often cited are the minimization of lumen surface, volume, power and drag. The predicted angles depend on the principle applied, chi and alpha. Assuming flow o r chi, chi can be determined from r chi 0 = r chi 1 + r chi 2 when the radii of the parent (r0) major (r1) and minor (r2) daughters are known. The term alpha = r2/r1. Using different values for chi and alpha, we present graphs for the major and minor branching angles theta 1 and theta 2 and psi = theta 1 + theta 2 for each of the four optimization principles. Because psi is almost independent of alpha for values of chi and alpha found in 198 junctions taken from a human pulmonary artery, we are able to produce a plot of psi versus chi for each of the four principles on one graph. A junction can be provisionally classified as optimizing for a given principle if, knowing chi, the psi obs - psi pred is least for that principle. We find that this nomographic classification agrees almost perfectly with a previous classification based on a more exacting measure, the percent cost index I, where I = observed cost/minimum cost. We explain why this is to be expected in most but not all cases. First we generate a contoured percent cost surface of c = I - 100 around the optimally located junction, J, and superimpose a surface of equal angular deviations a = psi pred-psi obs. We find that c increases and a usually increases with distance from J as the actual junction moves along a straight line away from J. We then produce a plot of c versus a for two competing principles. A comparison of the principles demonstrates that, for most cases, a is smaller for the principle which has the smaller c value.

Blood Flow Velocity↗

PubMed1989

The cost of departure from optimal radii in microvascular networks.

In the Murray optimality model of branching vasculatures, the radii of vessels are related to blood viscosity, vascular metabolic rate, and blood flow rate, in such a way as to minimize the total work (hydraulic and metabolic) of the system. The model predicts that flow is proportional to the cube of a vessel radius, and that at junctions the cube of the radius of the parent vessel equals the sum of the cubes of the daughter radii. In comparing real vasculatures to the Murray model, we have previously had no expressions for evaluating the apparent energy cost for departures from the optimal junction exponent of 3. Such expressions are derived here. They show that junction exponents, from about 1.5 to large positive values, are within 5% of the energy minimum. With the new equations, observed individual junctions or entire vascular trees can be compared, energy-wise, with the Murray optimum. Junctions in the transverse arteriolar trees of cat sartorius muscle were compared to the Murray optimality model, using these new expressions. The junction exponents for these small pre-capillary vessels had a broad range, with a median value greater than the Murray optimum of 3. The exponents were restricted, however, to values requiring, at individual junctions, little increase in energy. The majority of junctions had energy costs less than 1% above the Murray minimum. For entire trees involving many junctions the departures from optimality averaged less than 10%. Thus, while the branching geometry for these microvascular trees deviates significantly from the Murray optimum in the direction of larger daughter to parent ratios, the departures are small in energy terms.

Animals↗

PubMed2003

The effect of heterogeneity on optimal regimens in cancer chemotherapy.

Optimal drug regimens for cancer chemotherapy are determined when knowledge is only available on the behaviour of the tumour and the drugs used, over a population of patients. The case of two drugs is investigated where they are equivalent on average. Our calculations indicate that the optimal regimen has both drugs given initially but then sequences the two drugs. Our calculations also indicate that as tumour heterogeneity increases, the benefit to be gained from the optimal regimen can decrease in comparison to reasonable regimens. This has the effect of complicating the calculation of optimal regimens in a clinical setting, and may explain why results in experimental oncology fail to carry over to clinical oncology.

Antineoplastic Agents↗

PubMed1998

Optimal harvesting with both population and price dynamics.

We consider the effects of large inflationary price fluctuations on the computed optimal harvest strategy for a randomized Schaefer model. Both prices and population sizes are assumed random with both background (Wiener) and jump (Poisson) components. Population fluctuations are assumed to be density independent, i.e., relative changes are independent of population size. Stochastic dynamic programming is employed to find the optimal harvesting effort and economic return for a realistic set of bioeconomic data for Pacific halibut. It is found that inflationary effects have a pronounced influence on the optimal return, even in a hazardous or disastrous environment. However, optimal harvesting effort levels are much less sensitive to inflationary effects.

Animals↗

PubMed1998

Optimal harvesting under stochastic fluctuations and critical depensation.

We consider the derivation of the optimal harvesting strategy maximizing the expected cumulative yield from present up to extinction, under the assumption that the harvested population fluctuates stochastically and is subjected to an Allee-effect. By relying on both stochastic calculus and the classical theory of linear diffusions, we derive both the optimal harvesting thresholds at which harvesting should be initiated at full capacity and the value of the optimal strategy. In contrast to ordinary models which are absent of critical depensation, we show that the presence of an Allee-effect leads to the introduction of a lower harvesting threshold at which the population should be immediately depleted under the optimal policy. Moreover, we demonstrate that discounting increases the incentives to harvest and, therefore, increases the probability of a soon extinction of the harvested population.

Animals↗

PubMed2003

Assessing predation risk: optimal behaviour and rules of thumb.

We look at a simple model in which an animal makes behavioural decisions over time in an environment in which all parameters are known to the animal except predation risk. In the model there is a trade-off between gaining information about predation risk and anti-predator behaviour. All predator attacks lead to death for the prey, so that the prey learns about predation risk by virtue of the fact that it is still alive. We show that it is not usually optimal to behave as if the current unbiased estimate of the predation risk is its true value. We consider two different ways to model reproduction; in the first scenario the animal reproduces throughout its life until it dies, and in the second scenario expected reproductive success depends on the level of energy reserves the animal has gained by some point in time. For both of these scenarios we find results on the form of the optimal strategy and give numerical examples which compare optimal behaviour with behaviour under simple rules of thumb. The numerical examples suggest that the value of the optimal strategy over the rules of thumb is greatest when there is little current information about predation risk, learning is not too costly in terms of predation, and it is energetically advantageous to learn about predation. We find that for the model and parameters investigated, a very simple rule of thumb such as 'use the best constant control' performs well.

Animals↗

PubMed2000

Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction. The Apomorphine Study Group.

OBJECTIVES: A sublingual (SL) formulation of apomorphine has been developed and found effective in penile erectile dysfunction (ED). This study assessed the efficacy and safety of several doses of apomorphine SL in a dose-optimization schedule compared with placebo. METHODS: In this 8-week, multicenter, double-blind clinical trial, 569 patients were randomized to four groups: a dose-optimization group in which patients began with 2 mg, increased or decreased the dosage as needed for 4 weeks, and thereafter maintained an optimal dose for 4 weeks; two fixed-dose groups of either 5 or 6 mg; and a placebo group. Efficacy was assessed by patient and partner responses to home-use questionnaires about sexual function and activity and by responses to the International Index of Erectile Function and the Brief Sexual Function Inventory. RESULTS: In all apomorphine SL groups, a significantly higher percentage of patients compared with the placebo group achieved and maintained an erection firm enough for intercourse (48% to 53% versus 35% for placebo, P < or =0.001) and a significantly higher percentage of attempts resulted in intercourse (45% to 51% versus 33%, P < or =0.001). The responses to the questionnaires completed by the patients and partners were similar. Apomorphine SL was well tolerated; nausea, the most common side effect, was dose related and diminished substantially during the second 4-week period at all doses. The dose-optimization schedule resulted in fewer adverse events without impacting efficacy. CONCLUSIONS: Apomorphine SL is an effective and safe treatment for ED, with 2 and 4 mg providing the most acceptable therapeutic index.

Administration, Sublingual↗

PubMed2003

Optimal scheduling of radiotherapy and angiogenic inhibitors.

We incorporate a previously validated mathematical model of a vascularized tumor into an optimal control problem to determine the temporal scheduling of radiotherapy and angiogenic inhibitors that maximizes the control of a primary tumor. Our results reveal that optimal antiangiogenic monotherapy gives a large initial injection to attain a 20:1 ratio of tumor cell volume to supporting vasculature volume. It thereafter maintains this 20:1 ratio via a continuous dose rate that is intensified over time. The optimal radiation monotherapy schedule is characterized by a modest dose intensification over time. The best performance is achieved by our optimal combination regimen, where the antiangiogenic treatment again maintains a constant tumor-to-vasculature ratio, but is administered in a dose-intensified manner only during the latter portion of the radiation fractionation schedule.

Angiogenesis Inhibitors↗

PubMed1996

Optimization of the Salmonella/mammalian microsome assay for urine mutagenesis by experimental designs.

Assessing urine mutagenicity with the Salmonella mutagenicity test is often limited by the volumes of the samples. Optimization of the assay was performed with factorial and Doehlert designs. Two fractional factorial designs 2(3-1) (3 factors, 4 experiments) were used to estimate the main effects of the percent S9 in the mix, the time of liquid incubation, the inoculum size and the growth conditions. A Doehlert design (3 factors, 13 experiments) was used to study the main effects and the interactions of the NADP, G6P and S9 in the mix. The positive markers were benzo[a]pyrene (BaP, 0.3 microgram/plate) and a pool of smokers' urine (SU, 1.25 ml equivalent/plate). The response was limited to the induction factor (IF, number of induced revertants/number of spontaneous revertants) with Salmonella typhimurium TA98. The optimal conditions for BaP were: a 60 min period of liquid incubation and a volume of 0.1 ml (approx. 10(8) cells/plate) of an overnight culture grown in 50 ml of Nutrient Broth No. 2 from a 250 ml flask. The S9 mix (0.1 ml, final volume) included 1.5% of S9, 1.0 mM NADP and 4.4 mM G6P. The maximal IF was 15.79. The optimal conditions for SU were: a 60 min period of liquid incubation and a volume of 0.1 ml (approx. 10(8) cells/plate) of an overnight culture grown in 7 ml of Nutrient Broth No. 2 from a 20 x 180 mm tube. The S9 mix (0.1 ml, final volume) included: 4% S9, 4.2 mM NADP and 5.2 mM G6P. The maximal IF was 10.95. These optimal conditions did not modify the spontaneous frequencies of the tester strains: TA97a, TA98, TA100 and TA102. The dose-response curves of mutagenic urine samples were found to be non-linear. This micromethod required 8-fold less urine sample and 12.5-fold less liver homogenate as compared to the standard plate incorporation assay and was from 6.2- to 11.8-fold more sensitive to evaluate urine mutagenicity. The sensitivity of this technique was found to be limited to individuals smoking more than approx. 5 cigarettes/day by the standard extraction-concentration procedure.

Dose-Response Relationship, Drug↗

PubMed2001

Optimization in high dose rate brachytherapy for utero-vaginal applications.

BACKGROUND AND PURPOSE: High dose rate (HDR) remote afterloading intracavitary brachytherapy is an effective treatment modality which has some advantages over low dose rate (LDR) techniques for gynaecological cancer. Optimization is one of the possibilities of modern brachytherapy techniques, especially the stepping source technology. The use of the term 'optimization' implies achieving the desired optimum dose distribution by changing some parameters of the treatment. The aim of this study was to theoretically evaluate the optimization possibilities by modifying dwell times and dwell positions of the uterine and vaginal sources. MATERIALS AND METHODS: Working on a virtual utero-vaginal model, the dose distribution variations in the rectum, bladder, mean point B reference points and volume parameters were investigated whilst giving a standard dose to point A in the Manchester system. In this model, the intrauterine tandem consisted of 27 dwell positions for 2.5 mm steps and 14 dwell positions for 5 mm steps. Vaginal colpostats consisted of five dwell positions each for 2.5 mm steps. Using a Nucletron Plato treatment planning system and a Microselectron Ir-192 HDR stepping source unit, the dwell times of the intrauterine (T(u)) and vaginal sources (T(v)) were modified at the ratios of (T(u)/T(v)) 1:1; 1:2; 1:3; 1:4; 1:0.50; 1:0.33; and 1:0.25 for the two different dwell positions, 2.5 and 5 mm steps, of the intrauterine tandem. RESULTS: All evaluated parameters decreased with increasing dwell time ratios of uterine tandem to vaginal colpostats, with the greatest fall in the percentage of rectum reference dose (D(R) %), 23 and 28% for 2.5 and 5 mm dwell positions respectively; in addition, the reference isodose volume decreased by 14 and 17% for 2.5 and 5 mm dwell positions, respectively. All evaluated parameters increased with decreasing dwell time ratios of uterine tandem to vaginal colpostats for both dwell positions. The DR% of 1:1-1:4 (T(u)/T(v)) weightings showed an increase from 40.6 to 58.3 (44%) for 2.5 mm and from 49.2 to 67.5 (37%) for 5 mm dwell positions. The volume was increased by 27 and 37% for 2.5 and 5 mm dwell positions respectively. CONCLUSION: Modern brachytherapy techniques enable the individualization of treatments by optimization procedures in gynaecological brachytherapy applications. By altering the dwell time and position, some important changes in reference points, volume and treatment time can be achieved, whilst maintaining a standard dose to point A.

Brachytherapy↗

PubMed2001

Evaluation of a leaf position optimization tool for intensity modulated radiation therapy of head and neck cancer.

BACKGROUND AND PURPOSE: Since 1996, patients are treated at Ghent University Hospital with a multi-segment technique using MultiLeaf Collimators. The segments were obtained by using the Beam's eye view projections of the planning target volume (PTV) and the organs at risk (OARs), after which the segments weights were optimized. To investigate if optimization of the leaf positions would further improve the intensity modulated radiation therapy (IMRT) plans, a tool optimizing leaf positions and segment weights simultaneously, was developed. This tool is called SOWAT, which is the acronym for segment outline and weight adapting tool. MATERIAL AND METHODS: The tool evaluates the effects of changing the position of each collimating leaf of all segments on the value of the objective function. Only changes that improve the value of the objective function are retained. Between December 1999 and January 2001, 30 head and neck patients were treated with IMRT. Two patient groups were distinguished: pharyngeal and laryngeal tumors (n=17) and sinonasal tumors (n=13). A specific set of physical endpoints was evaluated for each group. Dose statistics of the treatment plans without and with SOWAT were analyzed. RESULTS: When using SOWAT for the pharyngeal and laryngeal cases, the PTV dose homogeneity increased with a median of 11% (range 2-27%), while the maximum dose to the spinal cord was decreased for 14 of the 17 patients. In four plans where parotid function preservation was a goal, the parotid mean dose was lower than 26 Gy in one plan without SOWAT, and in four plans with SOWAT. For the sinonasal tumors, the PTV dose homogeneity increased with a median of 7% (range 1-14%). SOWAT lowered the mean dose to 53 of the 63 optic pathway structures (retina, optic nerve and optic chiasm). SOWAT leaves the number of segments unchanged and has little or no effect on the delivery time. CONCLUSIONS: SOWAT is a powerful tool to perform the final optimization of IMRT plans, without increasing the complexity of the plan or the delivery time.

Algorithms↗

PubMed2002

Optimal temperature input design for estimation of the square root model parameters: parameter accuracy and model validity restrictions.

As part of the model building process, parameter estimation is of great importance in view of accurate prediction making. Confidence limits on the predicted model output are largely determined by the parameter estimation accuracy that is reflected by its parameter estimation covariance matrix. In view of the accurate estimation of the Square Root model parameters, Bernaerts et al. have successfully applied the techniques of optimal experiment design for parameter estimation [Int. J. Food Microbiol. 54 (1-2) (2000) 27]. Simulation-based results have proved that dynamic (i.e., time-varying) temperature conditions characterised by a large abrupt temperature increase yield highly informative cell density data enabling precise estimation of the Square Root model parameters. In this study, it is shown by bioreactor experiments with detailed and precise sampling that extreme temperature shifts disturb the exponential growth of Escherichia coli K12. A too large shift results in an intermediate lag phase. Because common growth models lack the ability to model this intermediate lag phase, temperature conditions should be designed such that exponential growth persist even though the temperature may be changing. The current publication presents (i) the design of an optimal temperature input guaranteeing model validity yet yielding accurate Square Root model parameters, and (ii) the experimental implementation of the optimal input in a computer-controlled bioreactor. Starting values for the experiment design are generated by a traditional two-step procedure based on static experiments. Opposed to the single step temperature profile, the novel temperature input comprises a sequence of smaller temperature increments. The structural development of the temperature input is extensively explained. High quality data of E. coli K12 under optimally varying temperature conditions realised in a computer-controlled bioreactor yield accurate estimates for the Square Root model parameters. The latter is illustrated by means of the individual confidence intervals and the joint confidence region.

Bioreactors↗

PubMed2000

Application of model-predictive control based on artificial neural networks to optimize the fed-batch process for riboflavin production.

The fed-batch process for commercial production of riboflavin (vitamin B2) was optimized on-line using model-predictive control based on artificial neural networks (ANNs). The information required for process models was extracted from both historical data and heuristic rules. After each cultivation the process model was readapted off-line to include the most recent process data. The control signal (feed rate), however, was optimized on-line at each sampling interval. An optimizer simulated variations in the control signal and assessed the forecasted model outputs according to an objective function. The optimum feed profile for increasing the product yield (YB2/S) and the amount of riboflavin at the time of harvesting was adjusted continuously and applied to the process. In contrast to the control by set-point profiles, the novel ANN-control is able to react on-line to variations in the process and also to incorporate the new process information continuously. As a result, both the total amount of riboflavin produced and the product yield increased systematically by more than 10% and the reproducibility of seven subsequently optimized batches was enhanced.

Algorithms↗

PubMed2001

Application of multiple response optimization technique to extended release formulations design.

The purpose of the present study was to apply response surface methodology and multiple response optimization utilizing superimposed contour diagrams to design extended release formulations with a preplanned release profile. Bumetanide solution was layered on sugar pellets followed by coating with various coating formulations according to a central composite statistical design using a Glatt GPCG 1 Wurster Fluid Bed. The coated pellets were tested for their release profiles and the percent of drug released after 1, 4 and 8 h were used to describe and optimize the release process. Statistical models describing the percent bumetanide released after 1, 4 and 8 h were developed and the corresponding contour diagrams were superimposed to predict the coating formulation parameters expected to produce target release profile. The pellets coated with the designed coating formulation were tested for their release profiles in comparison to the target profile. According to the model-independent approach using similarity factor (F2), the dissolution profile of the designed formulation and the expected target profile were found to be similar. It was concluded that response surface methodology and multiple response optimization could be successfully used to design and optimize extended release formulations with desired preplanned release profile.

Bumetanide↗

PubMed1999

GLLS for optimally sampled continuous dynamic system modeling: theory and algorithm.

The original generalized linear least squares (GLLS) algorithm was developed for non-uniformly sampled biomedical system parameter estimation using finely sampled instantaneous measurements (D. Feng, S.C. Huang, Z. Wang, D. Ho, An unbiased parametric imaging algorithm for non-uniformly sampled biomedical system parameter estimation, IEEE Trans. Med. Imag. 15 (1996) 512-518). This algorithm is particularly useful for image-wide generation of parametric images with positron emission tomography (PET), as it is computationally efficient and statistically reliable (D. Feng, D. Ho, Chen, K., L.C. Wu, J.K. Wang, R.S. Liu, S.H. Yeh, An evaluation of the algorithms for determining local cerebral metabolic rates of glucose using positron emission tomography dynamic data, IEEE Trans. Med. Imag. 14 (1995) 697-710). However, when dynamic PET image data are sampled according to the optimal image sampling schedule (OISS) to reduce memory and storage space (X. Li, D. Feng, K. Chen, Optimal image sampling schedule: A new effective way to reduce dynamic image storage space and functional image processing time, IEEE Trans. Med. Imag. 15 (1996) 710-718), only a few temporal image frames are recorded (e.g. only four images are recorded for the four parameter fluoro-deoxy-glucose (FDG) model). These image frames are recorded in terms of accumulated radio-activity counts and as a result, the direct application of GLLS is not reliable as instantaneous measurement samples can no longer be approximated by averaging of accumulated measurements over the sampling intervals. In this paper, we extend GLLS to OISS-GLLS which deals with the fewer accumulated measurement samples obtained from OISS dynamic systems. The theory and algorithm of this new technique are formulated and studied extensively. To investigate statistical reliability and computational efficiency of OISS-GLLS, a simulation study using dynamic PET data was performed. OISS-GLLS using 4-measurement samples was compared to the non-linear least squares (NLS) method using 22-measurement samples, GLLS using 22-measurement samples and OISS-NLS using 4-measurement samples. Results demonstrated that OISS-GLLS was able to achieve parameter estimates of equivalent accuracy and reliability in comparison to NLS or GLLS using finely sampled measurements (22-measurement samples), or OISS-NLS using optimally sampled measurements (4-measurement samples). Further more, as fewer measurement samples are used in OISS-GLLS, this algorithm is computationally faster than NLS or GLLS. Therefore, OISS-GLLS is well-suited for image-wide parameter estimation when PET image data are recorded according to the optimal image sampling schedule.

Algorithms↗

PubMed2003

Neural network based optimization of drug formulations.

A pharmaceutical formulation is composed of several formulation factors and process variables. Several responses relating to the effectiveness, usefulness, stability, as well as safety must be optimized simultaneously. Consequently, expertise and experience are required to design acceptable pharmaceutical formulations. A response surface method (RSM) has widely been used for selecting acceptable pharmaceutical formulations. However, prediction of pharmaceutical responses based on the second-order polynomial equation commonly used in an RSM, is often limited to low levels, resulting in poor estimations of optimal formulations. The purpose of this review is to describe the basic concept of the multi-objective simultaneous optimization technique, in which an artificial neural network (ANN) is incorporated. ANNs are being increasingly used in pharmaceutical research to predict the nonlinear relationship between causal factors and response variables. Superior function of the ANN approach was demonstrated by the optimization for typical numerical examples.

Chemistry, Pharmaceutical↗

PubMed1985

An adjustment error in optimization of taste intensity.

In a currently popular method of adjustment for assessing optimal preferred levels of tastants in foods, a robust perceptual error was observed. When subjects concentrated a dilute beverage to optimal taste, the final (adjusted) concentration of the added tastant was reliably lower than when diluting a concentrated beverage. This discrepancy between ascending and descending runs was observed for both adjusted sucrose in a fruit beverage and for adjusted NaCl in tomato juice. The premature shift in perception from non-optimal to optimal judgment resembles the "error of anticipation" in the classical method of limits. The effect could not be attributed to sensory adaptation or perceptual insensitivity, and it persisted even when subjects were told to be sure to reach the same level in both directions of adjustment. The magnitude of the error was diminished by interweaving of ascending and descending trials, which altered the immediate stimulus context, and by enhancing the motivational level of subjects (through reward) to try to reach the same concentration in both ascending and descending adjustments.

Adult↗