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PubMed2002

Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor.

N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) is a potent and selective antagonist for the CB1 cannabinoid receptor. Using the AM1 molecular orbital method, conformational analysis of 1 around the pyrazole C3 substituent identified four distinct conformations designated Tg, Ts, Cg, and Cs. The energetic stability of these conformers followed the order Tg > Cg > Ts > Cs for the neutral (unprotonated) form of 1 and Ts > Tg > Cs > Cg for its piperidine N-protonated form. Unified pharmacophore models for the CB1 receptor ligands were developed by incorporating the protonated form of 1 into the superimposition model for the cannabinoid agonists 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]perhydro-2alpha,6beta-dihydroxynaphthalene (CP55244; 2) and the protonated form of (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55212-2; 3) reported previously (Shim et al. In Rational Drug Design Symposium Series; Parrill, A. L., Reddy, M. R., Eds.; American Chemical Society: Washington, DC, 1999; pp 165-184). Values of K(i) for 1 and a series of 31 structural analogues were determined from radioligand binding analyses by competitive displacement of [3H]CP55940 from cannabinoid receptors in a rat brain membrane preparation. Comparative molecular field analysis (CoMFA) was employed to construct three-dimensional (3D)-quantitative structure-activity relationship (QSAR) models for this data set as unprotonated species assuming the Tg, Cg, and Ts conformers and for the protonated species assuming the Ts, Tg, and Cs conformers. Values of the conventional r2 and cross-validated r2 (r(cv)2) associated with these CoMFA models exceeded the threshold for statistical robustness (r2 > or = 0.90) and internal predictive ability (r(cv)2 > or = 0.50) in each of these six cases except for the protonated species assuming the Tg conformer (i.e., r2 = 0.97; r(cv)2 = 0.36). Results from conformational analyses, superimposition models, and 3D-QSAR models suggest that the N1 aromatic ring moiety of 1 dominates the steric binding interaction with the receptor in much the same way as does the C3 alkyl side chain of cannabinoid agonists and the C3 aroyl ring of the aminoalkylindole agonists. We also determined that several of the conformers considered in this study possess the proper spatial orientation and distinct electrostatic character to bind to the CB1 receptor. We propose that the unique region in space occupied by the C5 aromatic ring of 1 might contribute to conferring antagonist activity. We further propose that the pyrazole C3 substituent of 1 might contribute to conferring either neutral antagonist or inverse agonist activity, depending upon the interaction with the receptor.

Algorithms↗

PubMed1983

Iris pigmentation and AC thresholds.

Data from 160 White children were used to analyze possible associations between iris pigmentation and AC pure-tone thresholds. Iris pigmentation was graded from iris color using glass models of eyes, and AC thresholds were obtained under carefully controlled conditions. Analyses of variance using two groupings of iris color grades showed no evidence of an association between iris color grade and AC thresholds. Furthermore, inspection of arrays of the actual glass eye models, in conjunction with the order of mean thresholds at each test frequency, did not indicate the presence of an association between iris color grades and thresholds. It was concluded that while iris pigmentation may be related to some aspects of hearing ability, it does not appear to be related to AC thresholds in children.

Adolescent↗

PubMed2003

Biologically motivated computational modeling of chloroform cytolethality and regenerative cellular proliferation.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodents. As such, events related to cytotoxicity are the driving force for cancer induction. In this paper we extended an existing physiologically based pharmacokinetic (PBPK) model for chloroform to describe a plausible mechanism linking the hepatic metabolism of chloroform to hepatocellular killing and regenerative proliferation. The key aspects of this mechanism are (1) the production of damage at a rate proportional to the rate of metabolism predicted by the PBPK model, (2) the saturable repair of the damage, (3) the stimulation of the cell death rate by damage, and (4) the stimulation of the cell division rate as a function of the difference between the control and exposed numbers of cells. This extension allows the simulation of the labeling index and comparison with labeling index data. Data from a previously published chloroform-inhalation study with female B6C3F1 mice that determined cytolethality and regenerative cellular proliferation following exposures of varying concentrations and exposure durations were used for model calibration. Both threshold and low-dose linear linkages between chloroform-induced damage and cell death rate provided visually good fits to the labeling index data after formal optimization of the adjustable parameters, and there was no statistical difference between the fits of the two models to the data. Biologically motivated computational modeling of chloroform-induced cytolethality and regenerative proliferation is a necessary step in the quantitative evaluation of the hypothesis that chloroform-stimulated cell proliferation predicts the rodent tumor response.

Administration, Inhalation↗

PubMed2004

Differentiating acute bacterial meningitis from acute viral meningitis among children with cerebrospinal fluid pleocytosis: a multivariable regression model.

BACKGROUND: Although accurate models for predicting acute bacterial meningitis exist, most have narrow application because of the specific variables selected for them. In this study, we estimate the accuracy of a simple new model with potentially broader applicability. METHODS: On the basis of previous reports, we created a reduced multivariable logistic regression model for predicting bacterial meningitis that relies on age (years) (AGE), cerebrospinal fluid (CSF), total protein (TP) and total neutrophil count (TNC) alone. Data were from children ages 1 month-18 years diagnosed with acute enteroviral or bacterial meningitis whose initial CSF revealed >7 white blood cells/mm. A fractional polynomial model was specified and validated internally by the bootstrap procedure. The area under the receiver operating characteristic curve (discrimination: criterion standard, >0.7), the Hosmer-Lemeshow deciles-of-risk statistic (calibration: criterion standard, P > 0.05) and sensitivity-specificity pairs at prespecified probability thresholds of the model were computed. RESULTS: We identified 60 children with bacterial meningitis and 82 with enteroviral meningitis. At an area under the receiver operating characteristic curve of 0.97, our model represented by the equation: log odds of bacterial meningitis = 0.343 - 0.003 TNC - 34.802 TP + 21.991 TP - 0.345 AGE, was highly accurate when differentiating between bacterial and enteroviral meningitis. The model fit the data well (Hosmer-Lemeshow statistic; P =[r] 0.53). At probability cutoffs between 0.1 and 0.4, the model had sensitivity values between 98 and 92% and specificity values between 62 and 94%. CONCLUSIONS: Among children with CSF pleocytosis, a prediction model based exclusively on age, CSF total protein and CSF neutrophils differentiates accurately between acute bacterial and viral meningitis.

Acute Disease↗

PubMed2005

Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice.

Endothelin-1 (ET-1) exists in endothelial cells as well as a variety of other cell types. The presence of ET-1 and its receptors in neurons suggests its possible role as a neurotransmitter and/or neuromodulator. Studies utilizing exogenous ET-1 have suggested that ET-1 affects pain transmission. This study was designed to examine the possible role(s) of neuronal ET-1 in pain processing. We produced neuron-specific ET-1 knockout mice using the Cre/loxP system with a synapsin I promoter and examined the effects produced by the lack of neuronal ET-1 on pain behavior using common pain models and a model of stress-induced analgesia. In acute nociceptive pain models, paw withdrawal thresholds to radiant heat and mechanical stimuli applied with von Frey hairs were significantly lower in the knockout mice compared with control. This indicated that the absence of neuronal ET-1 leads to greater sensitivity to acute nociceptive stimuli. After inflammation was produced by intraplantar injection of carrageenan, there was a significantly greater degree of thermal hyperalgesia and mechanical allodynia in the knockout mice even after the difference in baseline values was compensated. Furthermore, in a neuropathic pain model produced by spinal nerve ligation, there was also a greater degree of mechanical allodynia in the knockout mice. Finally, in a swim-stress model, the magnitude of stress-induced analgesia was less in the knockout mice, indicating the involvement of neuronal ET-1 in stress-induced analgesia. The results suggest that there is a basal release of ET-1 from neurons that affect baseline pain thresholds as well as an additional release during persistent pain states that acts to suppress the pain. The involvement of neuronal ET-1 in stress-induced analgesia further suggests its role in endogenous pain inhibitory systems. To confirm that ET-1 is released in persistent pain states and to determine which part of the CNS is involved, we measured the concentrations of ET-1 before and after inducing peripheral inflammation in different parts of the CNS involved in endogenous pain inhibitory systems in normal mice. We found that ET-1 was increased in the hypothalamus while no significant increase was observed in the midbrain, medulla and spinal cord. The results of the present study suggest that neuronal ET-1 is involved in endogenous pain inhibitory control likely via pathways through the hypothalamus.

Acute Disease↗

PubMed1992

Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow.

Although clonidine analgesia appears to be mediated by the same central alpha 2-adrenoceptors that mediate its hypotensive effect, it is short-lasting when compared to the fall in blood pressure. This has been investigated by combined pharmacokinetic-pharmacodynamic analysis in 10 healthy volunteers who received (double-blind and crossover) clonidine 200 micrograms orally + placebo i.v. and clonidine orally + naloxone i.v. (2.8 mg/5 h). Analgesia was assessed by measuring the subjective (VAS) and objective (RIII) pain thresholds after transcutaneous electrical stimulations of the sural nerve; the mean arterial blood pressure (MAP), salivary flow (SF), and plasma clonidine concentrations were also monitored. A combined pharmacokinetic (first order absorption - 1 compartment) - pharmacodynamic (linear) model, including a hypothetical effect compartment with and without tolerance, were fitted to the data. Clonidine and clonidine + naloxone increased subjective and objective pain thresholds for 4 h. The concentration-effect plot for MAP showed distinct hysteresis. The t1/2s for effect compartment equilibration were 29 and 42 min for clonidine + naloxone and clonidine. The concentration-effect curves for RIII had the same shape as MAP but the starting hysteresis suddenly collapsed, suggesting acute tolerance. The best fit was obtained with a model where the linear relationship between concentration in the effect compartment and analgesia changed acutely after the third hour. The short-lived analgesia was probably related to an acute change in pain sensitivity induced by food, suggesting that it is not mediated solely by the alpha 2-adrenoceptors responsible for hypotension.

Adult↗

PubMed1991

Qualitative analysis of an HIV transmission model.

In 1988, a multiple-group model for HIV transmission with preferred mixing was proposed by Jacquez and coworkers. In the present paper, the work done by Jacquez et al. is extended. It is shown that the stability modulus of the Jacobian matrix at the no-disease equilibrium is a threshold for this model. Furthermore, if the no-disease equilibrium is unstable, the number of infected individuals will remain above a certain positive level regardless of initial levels; that is, the disease will persist uniformly. The stability of the endemic equilibrium in the case of restricted mixing is also studied. A series of sufficient conditions for local and global asymptotic stability of the endemic equilibrium are stated.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

An integrative theory of the phasic and tonic modes of dopamine modulation in the prefrontal cortex.

This paper presents a model of both tonic and phasic dopamine (DA) effects on maintenance of working memory representations in the prefrontal cortex (PFC). The central hypothesis is that DA modulates the efficacy of inputs to prefrontal pyramidal neurons to prevent interferences for active maintenance. Phasic DA release, due to DA neurons discharges, acts at a short time-scale (a few seconds), while the tonic mode of DA release, independent of DA neurons firing, acts at a long time-scale (a few minutes). The overall effect of DA modulation is modeled as a threshold restricting incoming inputs arriving on PFC neurons. Phasic DA release temporary increases this threshold while tonic DA release progressively increases the basal level of this threshold. Thus, unlike the previous gating theory of phasic DA release, proposing that it facilitates incoming inputs at the time of their arrival, the effect of phasic DA release is supposed to restrict incoming inputs during a period of time after DA neuron discharges. The model links the cellular and behavioral levels during performance of a working memory task. It allows us to understand why a critical range of DA D1 receptors stimulation is required for optimal working memory performance and how D1 receptor agonists (respectively antagonists) increase perseverations (respectively distractability). Finally, the model leads to several testable predictions, including that the PFC regulates DA neurons firing rate to adapt to the delay of the task and that increase in tonic DA release may either improve or decrease performance, depending on the level of DA receptors stimulation at the beginning of the task.

Animals↗

PubMed2005

Optimum signal in a simple neuronal model with signal-dependent noise.

How does the information about a signal in neural threshold crossings depend on the noise acting upon it? Two models are explored, a binary McCulloch and Pitts (threshold exceedance) model and a model of waiting time to exceedance--a discrete-time version of interspike intervals. If noise grows linearly with the signal, we find the best identification of the signal in terms of the Fisher information is for signals that do not reach the threshold in the absence of noise. Identification attains the same precision under weak and strong signals, but the coding range decreases at both extremes of signal level. We compare the results obtained for Fisher information with those using related first and second moment measures. The maximum obtainable information is plotted as a function of the ratio of noise to signal.

Action Potentials↗

PubMed2002

Predictors of bacteremia in febrile children with sickle cell disease.

PURPOSE: Bacteremia is an important cause of death and complications in children with sickle cell disease (SCD), yet predictors of bacteremia in these patients have not been well identified. The purpose of this study was to test whether clinical and hematologic variables commonly used to predict bacteremia in normal young children with fever could accurately predict bacteremia in febrile children with SCD. PATIENTS AND METHODS: The authors reviewed the medical records of all patients with SCD younger than 18 years of age over a 10-year period at a single institution for febrile events. They tested the univariate associations of age, height of fever, white blood cell count (WBC), absolute neutrophil count (ANC), and absolute band count (ABC) with bacteremia. Three separate multivariate analyses were performed using the predictor variables age, temperature, and one of three hematologic variables (ANC, WBC, or ABC) with the outcome bacteremia. RESULTS: There were 175 evaluable febrile events, of which 8 (4.6%) were associated with bacteremia. In the multivariate analyses, all hematologic variables, but not age or height of fever, retained significant associations with bacteremia. CONCLUSIONS: In febrile children with SCD, WBC, ANC, and ABC are all independently associated with bacteremia when adjusting for height of fever and age. Hematologic variables may be useful in developing prediction algorithms to identify febrile patients with SCD at higher risk of bacteremia. These data emphasize the need for a national trial to develop a predictive model with defined thresholds.

Age Factors↗

PubMed1995

Hemodynamics of stenotic infrainguinal vein grafts: theoretic considerations.

We developed a theoretic model of arterial stenosis to study the relationship between perfusion pressure and regional hemodynamics in stenotic infrainguinal vein grafts in an attempt to identify grafts at high risk for failure. Our model was based on the concept of energy and mass conservation of the flowing blood. We used the modified Bernoulli equation (delta P = 4 delta V2) to calculate the maximum possible intrastenotic peak systolic velocity (PSV) from the systolic blood pressure. PSV was measured by means of duplex ultrasonography in infrainguinal bypasses up to the time of revision (nine grafts) or spontaneous thrombosis (two grafts). We related arm systolic blood pressure, intrastenotic PSV, and prestenotic PSV obtained from duplex examinations conducted prior to graft thrombosis or revision and applied our model to these stenotic vein grafts. Intrastenotic PSV was consistently lower than maximum PSV predicted from the Bernoulli equation. The highest measured intrastenotic PSV of 600 cm/sec would require a minimum perfusion pressure of 144 mm Hg. The lowest measured PSV (20 cm/sec) was considered the minimum "thrombotic threshold velocity." This model predicts that for parabolic profile flow in an 80% diameter-reducing axisymmetric stenosis (96% cross-sectional area reduction), a prestenotic PSV of 20 cm/sec would produce an intrastenotic PSV of 500 cm/sec requiring the equivalent potential energy of 100 mm Hg systolic blood pressure. Our theory implies that in patients with nocturnal hypotension thrombosis of stenotic vein grafts may occur.

Blood Flow Velocity↗

PubMed2006

A bifurcation analysis of a differential equations model for mutualism.

We develop from basic principles a two-species differential equations model which exhibits mutualistic population interactions. The model is similar in spirit to a commonly cited model [Dean, A.M., Am. Nat. 121(3), 409-417 (1983)], but corrects problems due to singularities in that model. In addition, we investigate our model in more depth by varying the intrinsic growth rate for each of the species and analyzing the resulting bifurcations in system behavior. We are especially interested in transitions between facultative and obligate mutualism. The model reduces to the familiar Lotka-Volterra model locally, but is more realistic for large populations in the case where mutualist interaction is strong. In particular, our model supports population thresholds necessary for survival in certain cases, but does this without allowing unbounded population growth. Experimental implications are discussed for a lichen population.

Lichens↗

PubMed1983

Visual search and selection of natural stimuli in the pigeon: the attention threshold hypothesis.

During visual search for samples of varying proportions of familiar, natural food grains displayed against a complex gravel background, pigeons exhibited "matching selection," a tendency to overselect the more common grain. The matching-selection effect was decreased at low levels of stimulus/background contrast and reversed when the grains were highly conspicuous. The results were consistent with the hypothesis that stimulus detectability should be enhanced by recent experience with a particular grain type, but they showed no convincing indications of a corresponding effect on the response criterion. An explanatory model, termed the attention threshold hypothesis, argues that the mean latency of discovery can be minimized by selectively attending to one stimulus type at a time and switching to a more generally receptive state when the rate of discovery falls below a threshold value. The model appears to account for the fact that the response rate was highest toward samples containing a single grain type and decreased as the relative proportions approached equality. Additional consequences of the adoption of this theoretical perspective were explored in some detail. Among other results, the evidence suggests that the switching threshold might be chosen so as to optimize the rate of food discovery.

Animals↗

PubMed2006

Modeling psychometric functions in R.

We demonstrate some procedures in the statistical computing environment R for obtaining maximum likelihood estimates of the parameters of a psychometric function by fitting a generalized nonlinear regression model to the data. A feature for fitting a linear model to the threshold (or other) parameters of several psychometric functions simultaneously provides a powerful tool for testing hypotheses about the data and, potentially, for reducing the number of parameters necessary to describe them. Finally, we illustrate procedures for treating one parameter as a random effect that would permit a simplified approach to modeling stimulus-independent variability due to factors such as lapses or interobserver differences. These tools will facilitate a more comprehensive and explicit approach to the modeling of psychometric data.

Computer Simulation↗

PubMed2000

Spatial color contrast matching: broad-bandpass functions and the flattening effect.

The contrast matching function (CMF) is the reciprocal of test contrast that perceptually matches the contrast of standard pattern, measured as a function of test spatial frequency (SF). Achromatic CMFs usually flatten as the contrast of the standard is raised, and are broader than the achromatic, bandpass, contrast sensitivity function (CSF). This report investigates whether chromatic CMFs have similar characteristics. For this purpose, the red-green color channel was defined using minimum flicker and hue cancellation techniques. Spatially localized (D6), vertical, equiluminant patterns (SFs: 0.063-8 cpd; contrast: 3-80%) were used to measure the CSF and CMF of isoluminant patterns presented with a temporal Gaussian envelope. CMFs were measured using a randomized double-staircase procedure and the two-interval forced choice technique. Two color-normal observers, whose task was to select the interval that had higher color contrast, participated in experiments. Results show that: (a) the color CMFs are lowpass functions of SF at low standard contrasts (3-12.5%), broad-bandpass at intermediate contrasts (6.25-60%), and near-flat at high contrasts (80%); and (b) isoluminant CMFs have higher upper cut-off frequencies than isoluminant CSFs. It is concluded that: (i) color-contrast-constancy (CMF independent of SF) is partly achieved at high contrasts because color CMFs flatten as contrast increases; (ii) the information processing at suprathreshold levels is different from that at the threshold levels; and (iii) the model that explained achromatic CMFs using achromatic threshold mechanisms could not explain chromatic CMFs using chromatic threshold mechanisms.

Adult↗

PubMed1997

Comparison of a mathematical model to predict 10-km performance from the Conconi test and ventilatory threshold measurements.

The purpose of this study was to validate a mathematical model (MM) that evaluates the Conconi test and predicts 10-km race time. In addition, the relationship between ventilatory threshold (Tvent) determined from a laboratory test and heart rate deflection (HRd) from the Conconi test were examined. Seventeen trained runners performed the Conconi test, and performance times were predicted using a MM based on a logistics function. A correlational analysis indicated a highly significant relationship (r = .98, p < .01) between MM predicted time and actual time. Significant relationships were found between velocity at Tvent and HRd (r = .95, p < .01), and predicted times from each method (r = .96, p < .01). Heart rates from Tvent and HRd were also related (r = .79, p < .01). These results suggest that a MM of the Conconi test is a valid method of predicting 10-km performance and is closely related to traditional laboratory measures.

Adult↗

PubMed2002

Time-dependent extinction rate and species abundance in a tangled-nature model of biological evolution.

We present a model of evolutionary ecology consisting of a web of interacting individuals, a tangle-nature model. The reproduction rate of individuals characterized by their genome depends on the composition of the population in genotype space. Ecological features such as the taxonomy and the macroevolutionary mode of the dynamics are emergent properties. The macrodynamics exhibit intermittent two-mode switching with a gradually decreasing extinction rate. The generated ecologies become gradually better adapted as well as more complex in a collective sense. The form of the species abundance curve compares well with observed functional forms. The model's error threshold can be understood in terms of the characteristics of the two dynamical modes of the system.

Biological Evolution↗

PubMed1982

Multiplication noise in the human visual system at threshold: 2. Probit estimation of parameters.

A mathematical technique is described that relates detection model parameters to stimulus magnitude and experimental probability of detection. The normalizing transform is used to make the response statistics approximately Gaussian. Conventional probit analysis is then applied. From measurements at M stimulus levels, a system of M equations is solved and estimates of M unknown parameters of the detection model are obtained. The technique is applied to a threshold vision model based on additive and multiplicative Poisson noise. Results are obtained for the parameter estimates for individual subjects, and for the standard deviation of the estimates, for various values of the stimulus energy and number of trials. A frequency-of-seeing experiment is performed using a point-source stimulus that randomly assumes 3 energy levels with 200 trials per level. With a central efficiency of 50%, the estimated ocular quantum efficiency for our four subjects lies between 12% and 23%, the average dark count at the retina lies between 8 and 36 counts, and the threshold count for our (low false-report rate) data lies between 11 and 32. The theoretical results reduce to those obtained by Barlow (J. Physiol. London 160, 155-168, 1962), in the absence of dark light and multiplication noise.

Humans↗