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At least 1,225 records · Page 68Linked to original sources

PubMed2004

TNF-alpha neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome.

OBJECTIVES: Neutralization of TNF-alpha with either monoclonal antibodies or soluble receptors, although not curative, has significant clinical benefit in patients with rheumatoid arthritis (RA). In contrast, blockade of TNF-alpha has little clinical benefit in the majority of patients with systemic inflammatory response syndrome (SIRS) in spite of the identification of TNF-alpha as a key factor in its pathology. It is not clear why there is such a significant difference in the responses to TNF-alpha neutralization in these two conditions. Here we use mathematical modelling to investigate this discrepancy. METHODS: Using the known pharmacokinetic and pharmacodynamic properties of TNF-alpha-blocking biological agents, we constructed a mathematical model of the biological actions of soluble(s) TNFR2, Etanercept and Infliximab. RESULTS: Our model predicts that all three inhibitors, but especially Etanercept, are effective at controlling TNF-alpha levels in RA, which we propose is a condition in which TNF-alpha production and inhibition are in equilibrium. However, when free TNF-alpha drops to a low level, as can occur in SIRS, which we propose is a non-equilibrium condition, the sequestered TNF-alpha can act as a slow-release reservoir, thereby sabotaging its effectiveness. CONCLUSIONS: These results may explain the effectiveness of TNF-alpha blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.

Antibodies, Monoclonal↗

PubMedDate not supplied

A mechanical model of tumor encapsulation and transcapsular spread.

In this paper, a mathematical modeling framework is presented which describes the growth, encapsulation, and transcapsular spread of solid tumors. The model is based on the physical forces and cellular interactions involved in tumorigenesis and is used to test and compare the active (foreign body hypothesis) and passive (expansive growth hypothesis) hypotheses of capsule formation, such investigations being ideally suited to our mechanical model. The model simulations lead us to predict that, although an active response can successfully control tumor growth via the deposition of large amounts of collagen, this alone is insufficient for capsule formation. In contrast, a solely passive responsive is capable of producing an encapsulated tumor with minimal accumulation of connective tissue within the tumor. When both responses are active, a denser capsule forms and there is a significant increase in connective tissue within the tumor. Using a modified version of the model, in which tumor cells are assumed to produce degradative proteases at a rate which depends on the pressure they experience, it is also possible to show that transcapsular spread or invasion of the tumor may be due to the production by the tumor cells of proteases and their subsequent action.

Biomechanical Phenomena↗

PubMed2004

Hormonal exposures and breast cancer in a sample of women with systemic lupus erythematosus.

OBJECTIVES: To determine if breast cancer risk in women with SLE is modified by a history of exposure to hormone replacement therapy (HRT) or oral contraceptives (OC), after adjusting for other risk factors. METHODS: Data were pooled from SLE cohorts at three centres. For each female cohort member (n = 871), the probability of developing breast cancer was estimated from factors (age, parity, age at first live birth, age of menarche, personal history of benign breast disease, family history) in the Gail model, an established tool for predicting breast cancer risk. From these probabilities, the expected number of breast cancers for the cohort was estimated. Actual occurrence of cases was determined by linkage with regional cancer registries. Standardized incidence ratios (SIRs; ratio of cancers observed to expected) were calculated, with subgroup analyses according to HRT and OC exposure. RESULTS: In the cohort, 15 breast cancers occurred vs 7.2 predicted [SIR 2.1, 95% confidence interval (CI) 1.1, 3.5]. When controlling for Gail model risk factors, estimates were similar for women never exposed to HRT vs those exposed to HRT. Adjusted SIR estimates appeared similar also for women exposed or not exposed to OC. CONCLUSIONS: Although not definitive, the data suggest that the breast cancer experience in this sample is not completely explained by factors such as reproductive and family history, or by exogenous hormonal exposures. Other determinants, including medication exposures or genetic factors (possibly related to oestrogen receptors or metabolism) may be important. Variations in these factors might explain why an elevated risk of breast cancer has not been apparent in all SLE populations.

Adult↗

PubMed2001

Discriminant analysis of minor physical anomalies as dysontogenetic markers of schizophrenia.

AIM: The aim of the study was to evaluate the predictive value of minor physical anomalies in the binomial model schizophrenic patient-mentally healthy subject as an index of developmental origin of schizophrenia. MATERIAL AND METHODS: Sixty-eight schizophrenic patients (38 males and 30 females) and 69 mentally healthy subjects (36 males and 33 females) of Bulgarian ancestry were examined for minor physical anomalies using the Waldrop Physical Anomaly Scale. The predictive value of minor physical anomalies for schizophrenia was determined by discriminant analysis. RESULTS: The two-group discriminant analysis distinguishes well the schizophrenic patients from the controls with 6 predictive variables. The variables with significant contribution to prediction of the patient-control status are fine electric hair (p < 0.001), gap between I and II toes (p < 0.001), epicanthus (p < 0.001), high/steepled palate (p < 0.001), tongue with rough/smooth spots (p < 0.001), III toe > or = II toe (p < 0.001). The model overall correct classification is 78.63%, predicting slightly better the schizophrenics than the controls (79.7% vs. 77.4%). CONCLUSIONS: The constellation of variables entered into the discriminant analysis model confirms the hypothesis that at least in one subpopulation of schizophrenic patients the minor physical anomalies reflect early developmental processes determining occurrence of the disease in later periods of life.

Adult↗

PubMed1985

Verification of a model for the mechanisms controlling expiratory duration in rabbits under various conditions.

A mathematical model for the mechanisms controlling expiratory (E) duration was verified through comparison of its prediction with the relationships between TE and waveform parameters of various input patterns obtained by bilateral, simultaneous electrical stimulation of the largest vagal afferent fibers in vagotomized, paralyzed rabbits at normal or elevated chemical drive under light or deep barbiturate anesthesia. The model accurately reproduced experimental results in each animal and condition; it suggests that in the absence of vagal input (v.i.) an exponentially decaying central activity (phi) prevents inspiratory (I) onset until a time independent threshold (phi thr) is reached; the vagal component of phi results from fixed gain, long time constant (tau = 1.07 +/- 0.03 sec; mean +/- SE for N = 37 for N = 37 animals) temporal summation of expiratory v.i., being unaffected by inspiratory v.i.; central and vagal components share a common mechanism, the same value of tau applying to v.i. integration and to phi decay in the absence of v.i. under all conditions; the amplitude of the central component is proportional to tidal changes in central I activity, independently of the condition studied; and phi thr increases at elevated chemical drive, is unaffected by v.i., and decreases under deep anesthesia.

Anesthesia, General↗

PubMed1983

Viscosity dependence of the kinetics of the diffusion-controlled reaction of carbon monoxide with the separated alpha and beta chains of hemoglobin.

The kinetics of the recombination reaction of carbon monoxide with the isolated alpha and beta chains of human hemoglobin have been examined by laser flash photolysis in glycerol-water as a function of temperature and solvent viscosity. The second-order recombination rate constant is inversely proportional to viscosity raised to the 0.5 power--paralleling that predicted for the CO diffusion coefficient. This viscosity exponent is independent of the protein. These results are consistent with the reaction kinetics being essentially diffusion controlled in the high viscosity glycerol-water. For the alpha and beta chains, respectively, the diffusion-controlled rate constant is 0.003 and 0.002 of that predicted from the simple von Smoluchowski model based on the diffusion coefficients and molecular sizes of uniformly reactive spherical molecules. Several models incorporating steric requirements are used to rationalize the results. These models indicate that steric requirements for reaction in the diffusion-controlled limits are not greatly different in the alpha and beta chains and are only slightly less stringent than for myoglobin.

Carbon Monoxide↗

PubMed1997

Nosocomial infections in surgical patients: comparison of two measures of intrinsic patient risk.

OBJECTIVE: To compare, in subjects undergoing general surgery, two measures of intrinsic patients risk for nosocomial infection: the Study on the Efficacy of Nosocomial Infection Control (SENIC) index and the National Nosocomial Infection Surveillance (NNIS) System index. DESIGN: Prospective cohort study, with follow-up for 1 month after hospital discharge. SETTING: The general surgery service of a tertiary hospital. MAIN OUTCOME MEASURE: Surgical-site infection. PATIENTS: 1,483 subjects aged 10 to 92 years. RESULTS: During follow-up, 155 patients developed nosocomial infection, yielding a cumulative incidence of 10.5%. The NNIS index showed a linear trend with both crude and adjusted (for SENIC index) rates of surgical-wound infection. The SENIC index did not exhibit any linear trend with adjusted (for NNIS index) rates of surgical-wound infection. To delineate whether the SENIC index added explanatory information to the NNIS index (or vice versa), we regressed each variable on the other. Logistic regression analyses confirmed the results of stratified analysis: residuals of the NNIS index added discriminating ability to the SENIC index, whereas residuals of the SENIC index did not improve the predictive power of the NNIS index. CONCLUSIONS: The NNIS index had a better ability than the SENIC index for discriminating and predicting risk of surgical-wound infection.

Adolescent↗

PubMed1991

Prediction of gas chromatographic relative retention times of stimulants and narcotics.

The ADAPT software system was used to create models for the prediction of gas chromatographic relative retention times (RRTs) of stimulants and narcotics that are analyzed in doping control of athletes. The two main methods that were followed for building the models were the quantitative structure-retention relationship (QSRR) and multiple linear regression analysis. The main proposed model for the entire data set had a multiple correlation coefficient R = 0.991 and standard error s = 0.046 or approximately 4.5%. Because of the relatively high standard error of the main model, a second model was built on a subset of compounds with R = 0.982 and s = 0.027 or approximately 2.5%.

Central Nervous System Stimulants↗

PubMed1987

A model for emmetropization: predicting the progression of ametropia.

The response of a second-order feedback system is used to describe the controlling process that regulates the refraction of the human eye to achieve optimal visual acuity over the years (emmetropization). From data collected in past refractions, the equation of the feedback system has been derived for individual eyes and used to predict changes in their refraction with age with an accuracy of 0.50 diopters for 89.1% of the eyes tested. If the model is applied to other populations, the root mean square error of prediction will be between 0.20 and 0.36 diopters with a 95% degree of confidence. The model indicates that corrective lenses applied to the eyes, especially in the early years of life, will cheat the servo system and defeat the emmetropization process.

Adolescent↗

PubMed1992

Internal-external control and temporal orientation among southeast Asians and white Americans.

This study examined ethnic group differences with the use of the Model of Human Occupation (Kielhofner, 1985b). Three groups--immigrants from Thailand, immigrants from Cambodia, and white Americans--were contrasted on two constructs--internal versus external control and temporal orientation. The study attempted to identify whether nonpatient subjects have an internal locus of control and a strong future orientation, as the Model of Human Occupation would predict. No differences were found with the use of the Internal-External Scale (Rotter, 1966). The Thai and white Americans differed significantly on the Time Reference Inventory (Roos & Albers, 1965b). The Thai selected more items referring to the past, and the white Americans chose more statements applying to the present. There were no differences for past or future time extensions between groups. All the groups had a greater past extension than future extension. It was proposed that a larger future time perspective was not a requisite for functional temporal adaptation.

Adult↗

PubMed2002

Adaptation of reflexive feedback during arm posture to different environments.

In this study we have examined the ability of the central nervous system (CNS) to use spinal reflexes to minimize displacements during postural control while continuous force perturbations were applied at the hand. The subjects were instructed to minimize the displacements of the hand from a reference position that resulted from the force perturbations. The perturbations were imposed in one direction by means of a hydraulic manipulator of which the virtual mass and damping were varied. Resistance to the perturbations came from intrinsic and reflexive stiffness, and from the virtual environment. It is hypothesized that reflexive feedback during posture maintenance is optimally adjusted such that position deviations are minimal for a given virtual environment. Frequency response functions were estimated, capturing all mechanical properties of the arm at the end point (hand) level. Intrinsic and reflexive parameters were quantified by fitting a linear neuromuscular model to the frequency responses. The reflexive length feedback gain increased strongly with damping and little with the eigenfrequency of the total combined system (i.e. arm plus environment). The reflexive velocity feedback gain decreased slightly with relative damping at the largest eigenfrequency and more markedly at smaller eigenfrequencies. In the case of highest reflex gains, the total system remained stable and sufficiently damped while the responses of only the arm were severely underdamped and sometimes even unstable. To further analyse these results, a model optimization was performed. Intrinsic and reflexive parameters were optimized such that two criterion functions were minimized. The first concerns performance and penalized hand displacements from a reference point. The second one weights afferent control effort to avoid inefficient feedback. The simulations showed good similarities with the estimated values. Length feedback was adequately predicted by the model for all conditions. The predicted velocity feedback gains were larger in all cases, probably indicating a mutual gain limiting relation between length and velocity afferent signals. The results suggest that both reflex gains seem to be adjusted by the CNS, where in particular the length feedback gain was optimal so as to maximize performance at minimum control effort.

Adult↗

PubMed1997

Mathematical model of progressive renal disease.

A simple mathematical model is proposed that predicts the dynamics of chronic progressive renal disease. The model consists of coupled linear differential equations formed from three state variables, four control parameters, and three parameters related to initial conditions. All have straightforward physical interpretations. Applied to a population of nephrons, the model predicted the hypertrophic and sclerotic features of parenchyma progressing towards end-stage renal disease. Simulation results compared favorably with measurements obtained from the literature involving the subtotal nephrectomy rat model for renal disease. The time course of disease progression and treatment were considered. Also, the implications of the model for designing new diagnostic techniques using ultrasonic analysis are discussed.

Disease Progression↗

PubMed1991

The combination of symbolic and numerical computation for three-dimensional modeling of RNA.

Three-dimensional (3-D) structural models of RNA are essential for understanding of the cellular roles played by RNA. Such models have been obtained by a technique based on a constraint satisfaction algorithm that allows for the facile incorporation of secondary and other structural information. The program generates 3-D structures of RNA with atomic-level resolution that can be refined by numerical techniques such as energy minimization. The precision of this technique was evaluated by comparing predicted transfer RNA loop and RNA pseudoknot structures with known or consensus structures. The root-mean-square deviation (2.0 to 3.0 angstroms before minimization) between predicted and control structures reveal this system to be an effective method in modeling RNA.

Algorithms↗

PubMed1987

Simulation of genetic control of reproduction in beef cows. I. Simulation model.

A stochastic computer simulation model was constructed to predict the reproductive performance of beef cows as a function of the postpartum interval from calving to first estrus and the single-service conception rate. Phenotypic values for single-service conception rate were obtained by truncation of an assumed underlying normal phenotypic distribution at a point corresponding to a cumulative frequency of conception of .70. The underlying phenotypic distribution was derived as the sum of independent, normally-distributed additive genetic, permanent environmental and temporary environmental effects. The phenotypic frequency distribution for postpartum interval has been shown to be skewed toward large intervals. This distribution was simulated by combining normal distributions of additive genetic and permanent environmental effects with a strongly skewed Pearson III gamma distribution of temporary environmental effects. The simulated management system involved a 63-d breeding season, thereby allowing females up to three opportunities to conceive. The reproductive outputs that were simulated from postpartum interval and single-service conception rate included date of first service, first-service conception rate, number of services received, annual conception rate, calving date and postpartum interval. A normally-distributed 205-d weaning weight was also simulated and converted to an actual weaning weight by adjustment for calving date. General simulation results in terms of frequencies, means and standard deviations were compared with values found in the literature and found to provide a reasonable model of bovine reproductive performance.

Animals↗

PubMed1997

Use of a clinical sepsis score for predicting bacteremia in neonatal dairy calves on a calf rearing farm.

In human, equine, and bovine neonates, early diagnosis of bacteremia remains a challenge for the internist. The objective of this study was to develop a predictive model for risk of bacteremia, based on a clinical evaluation system called the clinical sepsis score. Blood from 90 ill calves, 1- to 14-days-old from a calf-raising farm in the San Joaquin Valley of California was cultured. The calves were also scored according to a clinical score for hydration status, fecal appearance, general attitude, appearance of scleral vessels, and umbilical abnormality. Age, rectal temperature, heart rate, respiratory rate, and presence or absence of a focal site of infection were recorded. Prevalence of bacteremia was 31% (28/90). A logistic regression model indicated that high clinical score, presence of a focal infection, and increased age were associated with an increased risk of bacteremia in ill calves (P < 0.06). Calves for which the model predicted bacteremia with a probability > or = 40.8% were considered bacteremic, yielding acceptable sensitivity (75%) and specificity (71%) estimates. The predictive model was validated through a 2nd sampling of 100 calves (79 ill calves and 21 controls), of which 17 calves were bacteremic. The classification was 75% correct using the model, with an estimated sensitivity of 76% and specificity of 75%. Overall, results indicated that the model could be a useful tool for predicting bacteremia in ill calves in a clinical setting.

Aging↗

PubMed2000

Large-scale prediction of phenotype: concept.

The capability to gather organism wide data has far outstripped the ability to understand it. Transforming large-scale data into a "better" cell requires tools that integrate physiology with its environment. One such tool is large-scale mathematical models that marry stoichiometry and kinetics with metabolic regulation and control. It is straightforward to determine stoichiometry (at least for central pathways), and kinetics can be roughly approximated where need be. However, the molecular details of the "metabolic wiring" managing the cell are often missing. Presented here is a surrogate for these missing details based on a simple premise; over evolutionary time, biological systems have developed objective-based programs that frugally manage gene expression and enzyme activity. Mathematically, this notion can be represented as sets of nonlinear control or "management" problems which, when solved in parallel with the model balances, offer a prediction of how gene expression and enzyme activity are modulated, in the absence of specific mechanistic details. We present a model of Escherichia coli central carbon metabolism, describing batch aerobic growth on glucose, in which transcription, translation, and activity of the gene products of 45 genes is "managed" using this approach. The model consists of 122 species (metabolites, enzymes, mRNA pools, and biomass) and describes 46 reactions (17 reversible). The model is identified (kinetic parameters as well as management structure) from metabolic flux ratio (METAFoR) analysis and physiological measurements. Simulations of a pyruvate kinase knockout strain are compared with experiments and it is shown the model is capable of accurately capturing the metabolic reprogramming resulting from the deletion. Analysis of the mRNA expression pattern, translational pattern and enzyme activity pattern of the wild-type versus mutant indicates a combination of expression and specific activity shifts are responsible for observed differences. While being only a first step toward large-scale physiological modeling, this work is important in two ways. First, it strengthens the hypothesis that unknown mechanism can be reasonably approximated using objective-based management criteria. Second, it provides a dynamic means to couple large-scale analysis technologies with physiology at the single-gene, single-protein level.

Carbon↗

PubMed1999

Monte Carlo based protocol for cell survival and tumour control probability in BNCT.

A mathematical model to calculate the theoretical cell survival probability (nominally, the cell survival fraction) is developed to evaluate preclinical treatment conditions for boron neutron capture therapy (BNCT). A treatment condition is characterized by the neutron beam spectra, single or bilateral exposure, and the choice of boron carrier drug (boronophenylalanine (BPA) or boron sulfhydryl hydride (BSH)). The cell survival probability defined from Poisson statistics is expressed with the cell-killing yield, the 10B(n,alpha)7Li reaction density, and the tolerable neutron fluence. The radiation transport calculation from the neutron source to tumours is carried out using Monte Carlo methods: (i) reactor-based BNCT facility modelling to yield the neutron beam library at an irradiation port; (ii) dosimetry to limit the neutron fluence below a tolerance dose (10.5 Gy-Eq); (iii) calculation of the 10B(n,alpha)7Li reaction density in tumours. A shallow surface tumour could be effectively treated by single exposure producing an average cell survival probability of 10(-3)-10(-5) for probable ranges of the cell-killing yield for the two drugs, while a deep tumour will require bilateral exposure to achieve comparable cell kills at depth. With very pure epithermal beams eliminating thermal, low epithermal and fast neutrons, the cell survival can be decreased by factors of 2-10 compared with the unmodified neutron spectrum. A dominant effect of cell-killing yield on tumour cell survival demonstrates the importance of choice of boron carrier drug. However, these calculations do not indicate an unambiguous preference for one drug, due to the large overlap of tumour cell survival in the probable ranges of the cell-killing yield for the two drugs. The cell survival value averaged over a bulky tumour volume is used to predict the overall BNCT therapeutic efficacy, using a simple model of tumour control probability (TCP).

Boron Neutron Capture Therapy↗

PubMed2004

Contrasting effects of dopamine and glutamate receptor antagonist injection in the nucleus accumbens suggest a neural mechanism underlying cue-evoked goal-directed behavior.

Discriminative stimuli (DSs) inform animals that reward can be obtained contingent on the performance of a specific behavior. Such stimuli reinstate drug-seeking behavior, evoke dopamine release in the nucleus accumbens (NAc) and excite and inhibit specific subpopulations of NAc neurons. Here we show in rats that DSs can reinstate food-seeking behavior. In addition, we compare the effects of injecting dopamine receptor antagonists into the NAc with those of general NAc inactivation on the performance of a DS task. Selective antagonism of D1 receptors reduced responding to the DS and increased the latency to respond, whereas general inactivation of NAc neuronal activity increased the latency to respond to the DS and increased behaviors extraneous to the task, such as responding in the absence of cues and responding on the inactive lever. Based on these results and our previous findings that NAc neuronal responses to DSs are dependent on the ventral tegmental area, we propose a model for the functional role of NAc neurons in controlling behavioral responses to reward-predictive stimuli.

Animals↗