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PubMed1990

Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.

The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.

Animals↗

PubMed1998

Plaid slant and inclination thresholds can be predicted from components.

We investigated whether stereoscopic slant and inclination thresholds for surfaces defined by two component plaids could be predicted from the interocular differences in their individual component gratings. Thresholds were measured for binocular images defined by single sinusoidal gratings and two component plaids. In both cases thresholds showed a marked dependence on component orientation. For absolute component orientations greater than 45 deg we found that inclination thresholds were smaller than slant thresholds. However, for absolute component orientations less than 45 deg, we found a reversal: slant thresholds were smaller than inclination thresholds. We considered three models that might account for these data. One assumed that thresholds stemmed from interocular position differences of corresponding image points. The other two assumed a combination of position, orientation and/or spatial-frequency differences. The best fits were obtained from those models that explicitly represented orientation differences. From the model combining orientation and spatial-frequency differences, we estimated the relative cue sensitivity to be 1.7:1, respectively. For plaids, we found that thresholds obtained from the individual components could be used to predict thresholds for plaids, even though an additional disparity cue from the contrast beat was available.

Depth Perception↗

PubMed1995

The application of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling for exploring risk assessment approaches of chemical mixtures.

When dealing with health impacts of environmental or occupational exposure such as groundwater contamination from or remediation effort associated with hazardous waste sites, we are obviously not facing individual, single chemicals. Thus, we are immediately confronted with the following questions: (1) Is single chemical risk assessment approach applicable to the multiple chemicals in hazardous waste sites? (2) How do we handle risk assessment of chemical mixtures? Although there were pioneering and commendable efforts from the USEPA to formulate guidelines for risk assessment of chemical mixtures, these guidelines were principally based on additivity concept. As new scientific advances are made, improvement and refinement of risk assessment methodology will be anticipated. At Colorado State University (CSU), our research effort is devoted to the challenges and potential applications of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling in the risk assessment of chemical mixtures. With the ultimate goal of Predictive Toxicology, 3 specific research projects are described: (1) PBPK/PD modeling of toxicologic interactions between trichloroethylene (TCE) and 1,1-dichloroethylene (1,1-DCE) and the investigation and defining of an 'Interaction Threshold'; (2) PBPK/PD modeling of toxicologic interactions between Kepone and carbon tetrachloride (CCl4) and the coupling of Monte Carlo simulation for the prediction of acute toxicity; (3) PBPK modeling of the inhibition of pharmacokinetics and enzyme kinetics of TCE caused by low-level, repeated dosing of a chemical mixture of 7 groundwater contaminants. Since this paper is meant to be a commentary and the emphasis is on approaches for dealing with chemical mixtures, detailed presentation of data is avoided. These examples illustrate partially our ongoing research activities and the related ideas with respect to possible novel risk assessment applications to chemical mixtures.

Animals↗

PubMed2005

Setting site-specific water-quality standards by using tissue residue criteria and bioaccumulation data. Part 1. Methodology.

We have developed a method for determining site-specific water-quality standards (SSWQSs) for substances regulated based on tissue residues. The method uses a multisite regression model to solve for the conditional prior probability density function (PDF) on water concentration, given that tissue concentration equals a tissue residue threshold. The method then uses site-specific water and tissue concentration data to update the probabilities on a Monte Carlo sample of the prior PDF by using Bayesian Monte Carlo analysis. The resultant posterior PDF identifies the water concentration that, if met at the site, would provide a desired level of confidence of meeting the tissue residue threshold contingent on model assumptions. This allows for derivation of a SSWQS. The method is fully reproducible, statistically rigorous, and easily implemented. A useful property of the method is that the model is sensitive to the amount of site-specific data available, that is, a more conservative or protective number (water concentration) is derived when the data set is small or the variance is large. Likewise, as the site water concentration increases above the water-quality standard, more site-specific information is needed to demonstrate a safe concentration at the site. A companion paper demonstrates the method by using selenium as an example.

Animals↗

PubMed1999

Animal grouping strategies, sources of variation, and economic factors affecting nutrient balance on dairy farms.

Increasing environmental concerns are forcing animal industries to reevaluate current feeding practices and their relationships to nutrient excretion. Previous modeling efforts have used simple budgets of nutrient flows through animals, assuming a constant productivity level. This assumption is not valid if animals are not in a steady state. A response model of dairy cow production to levels of net energy for lactation (NEL) and crude protein (CP) was derived from an abrupt threshold and plateau model of individuals. Monte Carlo techniques were used to simulate populations of cows fed diets of various NEL and CP concentrations, to derive the optimum allocation of NEL and CP, and to estimate how the optimum is affected by herd production potential, prices of inputs, and uncertainty of parameters. The simulation showed that a 25% increase in milk production reduced N excretion per kilogram of milk produced by 8%. Improved knowledge of the biology involved and feed composition can reduce N excretion by an additional 8%. Grouping strategies and number of groups used affect optimum allocation of nutrients. An optimum of six milking groups per production unit was derived from the simulation and would reduce N excretion by 8% compared to herds fed in one group.

Agriculture↗

PubMed1998

Receptor noise as a determinant of colour thresholds.

Inferences about mechanisms at one particular stage of a visual pathway may be made from psychophysical thresholds only if the noise at the stage in question dominates that in the others. Spectral sensitivities, measured under bright conditions, for di-, tri-, and tetrachromatic eyes from a range of animals can be modelled by assuming that thresholds are set by colour opponency mechanisms whose performance is limited by photoreceptor noise, the achromatic signal being disregarded. Noise in the opponency channels themselves is therefore not statistically independent, and it is not possible to infer anything more about the channels from psychophysical thresholds. As well as giving insight into mechanisms of vision, the model predicts the performance of colour vision in animals where physiological and anatomical data on the eye are available, but there are no direct measurements of perceptual thresholds. The model, therefore, is widely applicable to comparative studies of eye design and visual ecology.

Animals↗

PubMed2006

Dental attrition models predicting temporomandibular joint disease or masticatory muscle pain versus asymptomatic controls.

AIMS: To determine whether patients with temporomandibular joint disease or masticatory muscle pain can be usefully differentiated from asymptomatic controls using multifactorial classification tree models of attrition severity and/or rates. METHODS: Measures of attrition severity and rates in patients diagnosed with disc displacement (n = 52), osteoarthrosis (n = 74), or masticatory muscle pain only (n = 43) were compared against those in asymptomatic controls (n = 132). Cross-validated classification tree models were tested for fit with sensitivity, specificity, accuracy and log likelihood accountability. RESULTS: The model for identifying asymptomatic controls only required the three measures of attrition severity (anterior, mediotrusive and laterotrusive posterior) to be differentiated from the patients with a 74.2 +/- 3.8% cross-validation accuracy. This compared with cross-validation accuracies of 69.7 +/- 3.7% for differentiating disc displacement using anterior and laterotrusive attrition severity, 68.7 +/- 3.9% for differentiating disc displacement using anterior and laterotrusive attrition rates, 70.9 +/- 3.3% for differentiating osteoarthrosis using anterior attrition severity and rates, 94.6 +/- 2.1% for differentiating myofascial pain using mediotrusive and laterotrusive attrition severity, and 92.0 +/- 2.1% for differentiating myofascial pain using mediotrusive and anterior attrition rates. The myofascial pain models exceeded the > or =75% sensitivity and > or =90% specificity thresholds recommended for diagnostic tests, and the asymptomatic control model approached these thresholds. CONCLUSION: Multifactorial models using attrition severity and rates may differentiate masticatory muscle pain patients from asymptomatic controls, and have some predictive value for differentiating intracapsular temporomandibular disorder patients as well.

Adolescent↗

PubMed1993

A natural history study of experimental Staphylococcus epidermidis endophthalmitis.

The purpose of this study was to find a "threshold" quantity of organisms (i.e. inoculum) to produce clinical endophthalmitis and determine the natural course of intravitreal bacterial counts following inoculation in a rabbit model of Staphylococcus epidermidis endophthalmitis. S. epidermidis endophthalmitis was induced experimentally in 18 New Zealand white rabbits. Eyes were injected with 2.0 x 10(3) (Group I: n = 3), 2.0 x 10(4) (Group II: n = 3), 3.0 x 10(5) (Group III: n = 3), 3.0 x 10(6) (Group IV: n = 3), 3.0 x 10(7) (Group V: n = 3), or 3.0 x 10(8) (Group VI: n = 3) organisms. Serial quantitative bacterial cultures (colony counts) were performed on the vitreous every eight hours for 9 days. All eyes in Groups I and II became culture negative by 24-64 hours post-inoculation (PI). All eyes in Groups III-VI remained culture positive [approximately 600-4000 colony forming units (CFU) per cm3] at 48 to 72 hours PI and were stable for the remainder of the nine day study period. Previous work suggests that the host's inflammatory response is more important than had been recognized. Previous rabbit models of infectious endophthalmitis are known to become culture negative ("autosterilized") despite continued intraocular inflammation. This rabbit model demonstrates a "threshold" of infection where the host's immune response is overwhelmed and "autosterilization" does not occur. When inoculated with 3.0 x 10(5) or greater S. epidermidis organisms of this strain, continued active bacterial replication can now be studied in the rabbit.

Animals↗

PubMed1999

Models of intervention in menopause: proposal of a holistic or integral model.

OBJECTIVE: On the threshold of the third millennium, menopause has become a crucial social and health problem in developed countries. In the present work, we analyze possible healthcare strategies, describing their advantages and disadvantages within the context of different underlying conceptions of menopause. DESIGN: We have considered three theoretical frameworks or "menopause models": the biological model, the psychosocial model, and the holistic or integral model. Each model is examined under three subheadings: concept, contributions, and criticisms. RESULTS: The holistic model is proposed and defended as a valid option for the management of menopause. CONCLUSIONS: Adoption of the holistic model by health personnel may improve the attention given to menopausal women. As characteristics of such a model, the following are important: (1) The positive vision of the climacteric transition as an opportunity for personal growth, (2) the biopsychosocial perspective of the phenomena responsible for the different effects on the level of health and quality of life of women, (3) the development of health policies focused on health promotion, (4) the protagonism of women through strategies based on self-care and self-help groups, and (5) individualized use of hormone replacement therapy.

Aged↗

PubMed2005

Relationship between oral sensory thresholds and depressive moods.

AIMS: The aims were to compare the sensory thresholds on the tip of the tongue with on the dorsum of the hand, and to investigate the relationship between the sensory threshold and depressive mood with volunteers whose psychological conditions were normal. METHODS: Fifty-five subjects (28 women, 27 men) took psychiatric structured diagnostic interview and Self-rating Depression Scale (SDS). In the next step, the quantitative sensory tests (light touch sensation and thermal sensory test) were carried out on the tongue and the hand. Then we investigated the relationship between depressive moods and sensory thresholds on the tongue and the hand using logistic regression model. RESULT: The sensory thresholds on the tip of the tongues were significantly different from those on the dorsum of the hands. Only on tongue tip, increment of SDS had relation to the thresholds of innoxious thermal stimulation (OR=0.152, 95% CI. 0.049-0.478) and noxious heat stimulation (OR=0.352, 95% CI. 0.169-0.734). CONCLUSION: This finding might support for the idea that depressive mood had closer association with the tongue of the orofacial areas than the dorsum of the hand.

Adolescent↗

PubMed1995

Temporal thresholds of reperfusion in the middle cerebral artery occlusion model in rats.

In this study, the middle cerebral artery (MCA) of adult male Sprague-Dawley rats was occluded by the modified Koizumi method to determine the temporal thresholds of reperfusion for the treatment of cerebral embolism. Regional cerebral blood flow (rCBF) and pathological findings were measured at 1 and 2 h of ischemia and after 24 h and 7 days of reperfusion following 1 or 2 h of ischemia. rCBF was decreased the most (less than 10% of control CBF) in the parietal cortex (Pcor) and the lateral caudoputamen (Lcp) at both 1 and 2 h of ischemia. There was no significant difference in rCBF in these areas between the 2 ischemic groups. The 2 h ischemia group clearly showed infarction in the area perfused by the middle cerebral artery (including the Pcor and Lcp) after 24 h and 7 days of reperfusion, while the 1 h ischemia group showed only slight infarction. These findings suggest that temporal thresholds of reperfusion in this model exist between 1 and 2 h of ischemia, and that rCBF levels during ischemia and the duration of ischemia are the most important factors in producing brain infarction.

Animals↗

PubMed2002

Ozone interactions with carpet: secondary emissions of aldehydes.

Ozone-induced formation of aldehydes was studied on the surface and in the gas phase above carpets and on carpet components. Samples of four carpets were exposed to 100 ppb ozone. Emission rates of aldehydes and other organic compounds were measured from exposed and unexposed samples. Surface interactions of ozone with carpets produced C1-C13 n-aldehydes and several unsaturated aldehydes. Total aldehyde emission rates increased markedly with ozone exposure, from 1 to 70 microg m(-2) h(-1) for unexposed samples, to 60-800 microg m(-2) h(-1) during exposure. One exposed sample emitted large amounts of 2-nonenal (180-230 microg m(-2) h(-1)), a compound with a low odor threshold. Material balance modeling of a residence with this high emitting carpet suggests (1) that the concentration of 2-nonenal would be well above its odor threshold even in areas with only moderate ambient ozone levels and (2) that odorous levels of 2-nonenal could persist for years. Reactions of ozone with gas-phase primary emissions from carpet significantly reduced the levels of 4-phenylcyclohexene and produced small amounts of branched ketones. Separately measured patterns of aldehyde emissions from ozone exposure of linseed and tung oils were similar but not identical to those observed from ozone-exposed carpets.

Air Pollution, Indoor↗

PubMed1984

Behaviour of some models of myelinated axons.

In this paper we discuss several approaches to modelling myelinated axons and examine the qualitative behaviour of the models. To facilitate our goal of understanding in detail the differences in mechanisms modelling myelination, we impose at the nodes the simplest nonlinear current-voltage relation which allows the models to possess appropriate threshold behaviour and propagating action potentials (travelling waves). Our type of model is a nonlinear differential-difference system and the resulting travelling wave must satisfy a nonlinear delay-differential equation of mixed type. Another type of model is a diffusion equation coupled nonlinearly to ordinary differential systems whose solutions represent boundary data for the diffusion equation. We give some threshold results and derive a relationship between conduction speed and various model parameters for a few classes of these models.

Animals↗

PubMed1999

An empirically based model of the electrically evoked compound action potential.

The relationship between electrically evoked single-fiber action potentials and the electrically evoked compound action potential of the auditory nerve is of interest to those attempting to model such responses with computational techniques. It also relates to efforts to exploit the gross potentials that can now be recorded by some implantable cochlear prostheses. In this paper, we develop a computational model of the auditory nerve response to single, pulsatile, electrical stimuli based upon the response characteristics obtained from 230 single fibers of 13 cats. These fibers were stimulated by brief (39s) monophasic cathodic stimuli delivered by a monopolar intracochlear electrode. The data were pooled to obtain an estimate of the distribution of fiber thresholds. Post-stimulus time histograms were modeled using Poisson functions and adjusted to account for empirically determined latency and jitter characteristics. The probabilistic nature of single-fiber input-output functions (i.e. Verveen's (1961) 'relative spread') was also modelled. PST histograms from 5000 modelled fibers were then summed and convolved with an estimated 'unit potential' following the method of Goldstein and Kiang (1958). This convolution produced modelled compound action potentials, which were then compared with experimentally obtained data. Manipulations of model parameters affecting threshold, jitter, and relative spread suggest that the most important determinant of the shape of the EAP amplitude-level function is the threshold distribution. A model based solely on threshold distribution produces an EAP input-output function similar to one that accounts for probabilistic single-fiber input-output functions. Discrepancies between these two models do occur if the threshold distribution function is compressed significantly, as might be the case in pathological cochleae with altered distributions or numbers of nerve fibers.

Algorithms↗

PubMedDate not supplied

[Dependence of the nerve pulse generation threshold on the ability of forming an input signal based on the Hodgkin-Huxley model].

Different methods of definition of the threshold of the action potential (AP) generation were considered. It was established that the threshold defined as a difference between the critical value of the membrane depolarization and the resting potential was practically independent of the value and duration of an input signal which was given as a stepped function. It was shown that the critical values of the membrane depolarization could be defined by the point of bend, as well as by the point of maximum of the curve curvature on the frontal part of AP.

Action Potentials↗

PubMed2005

Breakdown of accommodation in nerve: a possible role for persistent sodium current.

BACKGROUND: Accommodation and breakdown of accommodation are important elements of information processing in nerve fibers, as they determine how nerve fibers react to natural slowly changing stimuli or electrical stimulation. The aim of the present study was to elucidate the biophysical mechanism of breakdown of accommodation, which at present is unknown. RESULTS: A model of a space-clamped motor nerve fiber was developed. It was found that this new model could reproduce breakdown of accommodation when it included a low-threshold, rapidly activating, persistent sodium current. However, the phenomenon was not reproduced when the persistent sodium current did not have fast activation kinetics or a low activation threshold. CONCLUSION: The present modeling study suggests that persistent, low-threshold, rapidly activating sodium currents have a key role in breakdown of accommodation, and that breakdown of accommodation can be used as a tool for studying persistent sodium current under normal and pathological conditions.

Animals↗

PubMed2003

Afferent response parameters derived from postmasker probe-detection thresholds: 'the decay of sensation' revisited.

The classical model of forward masking postulates that the detection threshold for a tone probe that follows a stimulus of similar frequency content is elevated relative to the quiet threshold because the probe must evoke a just-detectable increment in a decaying postmasker sensation. That postmasker decay is charted by probe-detection thresholds if the sensation increment is small and constant. This model was examined for a 2-kHz Gaussian-shaped probe and a 2-kHz forward masker, based on the model's assumption that a just-detectable increment in sensation results from a just-detectable increment in level. Psychometric functions for detection were obtained at 2.5-30 ms postmasker. Their means and standard deviations generally decreased with delay. It was assumed that standard deviation is related to the putative just-detectable level increment by a simple monotonic transformation. Thus, if the standard deviation of the psychometric function for probe detection is neither small nor constant, then the corresponding just-detectable increment in level is neither small nor constant, and the just-detectable increment in sensation is neither small nor constant. The classical model also fails to allow for the variability of internal events. The concept of detection threshold as a sensation increment was preserved in a Signal Detection model, that does allow for internal variability. In this model the postmasker residual is the input to a probe detector. The new model produces an equation for the just-detectable level increment as a function of probe delay. Comparison data were generated by again assuming some relation between the standard deviation of the psychometric function for detection, and the just-detectable increment in level. The fit of equation to data yields robust values for the probe detector's maximum firing rate, dynamic range, and spike-counting time. All that is required to account for the decay of sensation, for a pure tone, is a single neuron operating at some higher center.

Animals↗

PubMed2002

Redistribution of synaptic efficacy supports stable pattern learning in neural networks.

Markram and Tsodyks, by showing that the elevated synaptic efficacy observed with single-pulse long-term potentiation (LTP) measurements disappears with higher-frequency test pulses, have critically challenged the conventional assumption that LTP reflects a general gain increase. This observed change in frequency dependence during synaptic potentiation is called redistribution of synaptic efficacy (RSE). RSE is here seen as the local realization of a global design principle in a neural network for pattern coding. The underlying computational model posits an adaptive threshold rather than a multiplicative weight as the elementary unit of long-term memory. A distributed instar learning law allows thresholds to increase only monotonically, but adaptation has a bidirectional effect on the model postsynaptic potential. At each synapse, threshold increases implement pattern selectivity via a frequency-dependent signal component, while a complementary frequency-independent component nonspecifically strengthens the path. This synaptic balance produces changes in frequency dependence that are robustly similar to those observed by Markram and Tsodyks. The network design therefore suggests a functional purpose for RSE, which, by helping to bound total memory change, supports a distributed coding scheme that is stable with fast as well as slow learning. Multiplicative weights have served as a cornerstone for models of physiological data and neural systems for decades. Although the model discussed here does not implement detailed physiology of synaptic transmission, its new learning laws operate in a network architecture that suggests how recently discovered synaptic computations such as RSE may help produce new network capabilities such as learning that is fast, stable, and distributed.

Algorithms↗