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PubMed1982

The dominance region and ripple noise pitch: a test of the peripheral weighting model.

An estimate of the spatial curve of pitch dominance for the repetition pitch of ripple noise was measured using the pitch strength discrimination procedure. A variety of stimulus conditions were examined. The peripheral weighting model [Yost and Hill, J. Acoust. Soc. Am. 66, 400-410 (1979)] of repetition pitch assumes a relationship between the curve of pitch dominance and the shape of the psychophysical suppression of unmasking function. Ripple noise was also used to estimate the psychophysical suppression or unmasking function. The results indicate that with the estimates of the psychophysical suppression or unmasking function the peripheral weighting model can account for the general shape of the curve of pitch dominance.

Auditory Threshold↗

PubMed2002

Can we determine a threshold level for allergenic foods by statistical analysis of published data in the literature?

BACKGROUND: The aim of this paper was to investigate whether a statistical model could be developed to estimate a "threshold" dose for foods eliciting allergic reactions in susceptible patients. The threshold dose is defined to be one that elicits allergic reactions in a given (small) proportion of susceptible patients, using data from published studies. METHODS: Based on data available from the literature, we developed a statistical model using the actual allergen content in the four foods, where data for allergen content are available (peanut, soy, egg, milk). RESULTS: The model demonstrated that the threshold doses giving a reaction of one in a million in susceptible patients were within the same order of magnitude for egg, milk and soy, but were an order of magnitude lower for peanut flour: 0.005 mg of cow's milk, 0.002 mg of fresh hen's egg, 0.0007 mg of peanut, or 0.0013 mg of soy flour. CONCLUSIONS: Although several assumptions were made in creating this statistical model, we demonstrated that the previously published differences in threshold doses for various foods can be largely eliminated by comparing actual allergen content; this may therefore serve as a model for further studies.

Allergens↗

PubMed2004

Effects of indirect and additional direct costs on the risk threshold for prophylaxis with colony-stimulating factors in patients at risk for severe neutropenia from cancer chemotherapy.

STUDY OBJECTIVES: Previous studies have used direct hospital costs to determine the threshold at which the cost of prophylactic use of colony-stimulating factor (CSF) is offset by savings from the lower risk of hospitalization for febrile neutropenia. By conducting a survey of patients in whom febrile neutropenia had developed during treatment with chemotherapy, we sought to reassess these costs by including estimates of indirect costs associated with febrile neutropenia as well as new categories of direct costs that were not previously available. Costs were included in an existing cost-minimization model, and their effect on the risk threshold at which the prophylactic use of CSF becomes cost saving was determined. PATIENTS: A sample survey of 26 patients with ovarian cancer who were treated with chemotherapy and developed febrile neutropenia. INTERVENTION: Analysis of data from patients' questionnaires containing survey items on indirect costs and additional direct costs associated with febrile neutropenia. MEASUREMENTS AND MAIN RESULTS: Estimates of indirect costs and other direct costs from the questionnaires were included in an existing cost-minimization model, and risk thresholds were recalculated. Before modification, the model showed cost neutrality for prophylactic use of CSF when the risk of hospitalization for febrile neutropenia was approximately 23%. Including previously excluded direct costs and indirect costs ranging from 1000-5000 dollars attributable to severe neutropenia in the model lowered the risk threshold for hospitalization for febrile neutropenia at which the prophylactic use of CSF becomes cost neutral to between 22% and 18%. CONCLUSION: Including additional direct as well as indirect costs associated with chemotherapy-induced neutropenia permits a more realistic assessment of the possible effect of prophylactic use of CSF from a societal perspective. Despite the limited size of the survey, this study shows a cost-benefit rationale to support prophylactic use of CSF in a greater proportion of patients treated with chemotherapy.

Antineoplastic Agents↗

PubMed1981

The genetic dynamics of disease.

The notional principles of the genetics of disease are broadly discussed. Disease is an intrinsically vague term that represents the incongruity between the inner milieu of the organism and the environment. Its dynamics, then, cannot be reduced to naive statements about selection which may operate, and operate conflictingly, on several different levels or organization. Evolutionary selection results from the advantage of complexity, and the fundamental theorem of genetic dynamics - that mutational debts must eventually be paid in full-may be false or, at best approximate. The traditional models (mendelian, galtonian, and threshold) are set in a context that identifies certain features of disease that hitherto have been totally ignored. Neither invention nor traditional analysis has been adequate. Models should be made individually adequate for the study of diseases; the diseases should not be trimmed to fit the models.

Biological Evolution↗

PubMed1987

Mixed conductive and sensorineural hearing loss in LP/J mice.

Air and bone conduction thresholds for the detection of a compound action potential response were measured in mice of the LP/J inbred strain, which has been proposed as a possible model for human otosclerosis. Thresholds were compared with control data from CBA/Ca mice. Evidence of a mixed sensorineural and conductive hearing loss was obtained in LP/J mice. Few signs of hair cell degeneration or middle-ear bony lesions were found in 20-day old mice, although they generally showed raised thresholds to both air and bone conducted stimuli. The reason for the observed sensorineural component of the hearing loss at this age is not clear, since endocochlear potentials were normal in mice of this strain. By 225 days of age, hair cell loss was extensive and there was clearly excess bone growth in all middle-ear specimens studied, particularly on the incus and the cochlear wall facing the middle ear. Microbiological analysis of LP/J specimens revealed no evidence of a middle-ear infection specific to these mice which might explain the pathology.

Action Potentials↗

PubMed1996

Automatic liver segmentation technique for three-dimensional visualization of CT data.

PURPOSE: To develop a system for automatic segmentation of the liver from computed tomographic (CT) scans of the abdomen for three-dimensional volume-rendering displays. MATERIALS AND METHODS: An automated liver segmentation system was developed, which combined domain knowledge with analysis of a global histogram, morphologic operators, and the parametrically deformable contour model. Boundaries of the thresholded liver volume were modified section-by-section by exploiting information from adjacent sections. These boundaries were refined by optimization of the parametrically deformable contour model. Volume-rendered images were created by using the boundaries to exclude tissues outside the liver. The system was tested on CT data sets from 10 cases of potentially resectable hepatic neoplasm. RESULTS: Of the 401 sections in the 10 cases, 53 sections (13.2%) required user modifications during segmentation. The utility of the three-dimensional-rendered images with use of these liver boundaries was judged by a radiologist as being comparable to that of three-dimensional images created with manual editing. Twenty-eight of the sections were deemed imperfect by the radiologist and might need further modifications. CONCLUSION: An effective technique for automatic segmentation of the liver from CT images has been developed. This technique promises to save time and simplify the creation of three-dimensional liver images by minimizing operator intervention.

Humans↗

PubMed2001

Biological and statistical approaches to predicting human lung cancer risk from silica.

Chronic inflammation is a key step in the pathogenesis of particle-elicited fibrosis and lung cancer in rats, and possibly in humans. In this study, we compute the excess risk estimates for lung cancer in humans with occupational exposure to crystalline silica, using both rat and human data, and using both a threshold approach and linear models. From a toxicokinetic/dynamic model fit to lung burden and pulmonary response data from a subchronic inhalation study in rats, we estimated the minimum critical quartz lung burden (Mcrit) associated with reduced pulmonary clearance and increased neutrophilic inflammation. A chronic study in rats was also used to predict the human excess risk of lung cancer at various quartz burdens, including mean Mcrit (0.39 mg/g lung). We used a human kinetic lung model to link the equivalent lung burdens to external exposures in humans. We then computed the excess risk of lung cancer at these external exposures, using data of workers exposed to respirable crystalline silica and using Poisson regression and lifetable analyses. Finally, we compared the lung cancer excess risks estimated from male rat and human data. We found that the rat-based linear model estimates were approximately three times higher than those based on human data (e.g., 2.8% in rats vs. 0.9-1% in humans, at mean Mcrit lung burden or associated mean working lifetime exposure of 0.036 mg/m3). Accounting for variability and uncertainty resulted in 100-1000 times lower estimates of human critical lung burden and airborne exposure. This study illustrates that assumptions about the relevant biological mechanism, animal model, and statistical approach can all influence the magnitude of lung cancer risk estimates in humans exposed to crystalline silica.

Air Pollutants, Occupational↗

PubMed1999

Cardiovascular and neuronal responses to head stimulation reflect central sensitization and cutaneous allodynia in a rat model of migraine.

Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. One conclusion of these studies was that when low- and high-intensity stimuli induce responses of similar magnitude in nociceptive neurons, low-intensity stimuli must be as painful as the high-intensity stimuli. The present study investigates in anesthetized rats the significance of the changes in the responses of central trigeminal neurons (i.e., in nucleus caudalis) by correlating them with the occurrence and type of the simultaneously recorded cardiovascular responses. Before chemical stimulation of the dura, simultaneous increases in neuronal firing rates and blood pressure were induced by dural indentation with forces >/= 2.35 g and by noxious cutaneous stimuli such as pinching the skin and warming > 46 degrees C. After chemical stimulation, similar neuronal responses and blood pressure increases were evoked by much smaller forces for dural indentation and by innocuous cutaneous stimuli such as brushing the skin and warming it to >/= 43 degrees C. The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine.

Animals↗

PubMedDate not supplied

Boiling nucleation on melanosomes and microbeads transiently heated by nanosecond and microsecond laser pulses.

Selective tissue damage on the cellular level can be achieved by microbubble formation around laser-heated intracellular pigments. To acquire a more detailed understanding of the laser tissue interaction in the highly pigmented retinal pigment epithelium (RPE), we irradiate aqueous suspensions of absorbing microparticles by short pulsed laser irradiation (12 ns, 240 ns, and 1.8 micros). Porcine retinal pigment epithelial melanosomes, gold beads, and magnetic silica beads are used as absorbers. Pulsed laser heating of the particles leads to vaporization of the surrounding liquid. The resulting transient microbubbles on the particle surface are imaged directly on a microscopic level by fast flash light photography. Furthermore, the bubble dynamics is probed by a low power laser. Threshold radiant exposures for bubble formation and nucleation temperatures are experimentally determined. Superheating of the surrounding water to 150 degrees C for melanosomes and to more than 200 degrees C for magnetic silica beads (psi = 3 microm) and gold beads (psi = 500 nm) is achieved. With these data, the absorption coefficient of a melanosome is calculated by thermal modeling of the experimental thresholds for bubble formation.

Absorption↗

PubMed1999

Utilization of a model lung system to assess the effects of an inspiratory impedance threshold valve on the relationship between active decompression and intra-thoracic pressure.

Use of an inspiratory impedance valve has recently been shown to increase the efficacy of standard and active compression-decompression cardiopulmonary resuscitation. We evaluated the effects of a prototypic impedance valve on the relationship between the active decompression and intra-thoracic pressure using a mechanical model lung system. Intermittent impedance to inspiratory flow of respiratory gases during the decompression phase of active compression-decompression cardiopulmonary resuscitation significantly decreased the intra-thoracic pressure, while the pressure was almost zero cm H2O during the cardiopulmonary resuscitation cycle when the impedance threshold valve was not functioning. Thus, this mechanical model will help in evaluating the valve as well as in optimizing its function by simulating various forms of lung disease.

Cardiopulmonary Resuscitation↗

PubMed2001

Characterisation of hoxa gene expression in the chick limb bud in response to FGF.

We tested a diffusion gradient model for setting up overlapping domains of Hoxa gene expression in the chick limb bud. The model is based on morphogen production at the limb bud tip where the apical ridge is located and assumes that cells respond to a series of concentration thresholds. Consistent with the model, Hoxa13 gene expression rapidly switches off when the ridge is removed from stage 21/22 buds, while Hoxa11 and Hoxa10 expression is stable; Hoxa13 expression can be initiated and maintained in absence of the ridge by FGF soaked beads; the Hoxa13 domain first expands quickly and then slows up and the size is related to the dose of FGF4. Contrary to the model, addition of FGF4 to early limb buds does not activate Hoxa13 prematurely nor extend the Hoxa13 expression domain proximally. Therefore FGF4 signalling is necessary but not sufficient for Hoxa gene expression in the limb bud.

Animals↗

PubMed1996

Allometry and simple epidemic models for microparasites.

Simple mathematical models for microparasites offer a useful way to examine the population dynamics of different viral and bacterial pathogens. One constraint in applying these models in free-living host populations is the paucity of data with which to estimate transmission rates. Here we recast a standard epidemiological model by setting the birth and death rates of the host population and its density as simple allometric functions of host body weight. We then use standard threshold theorems for the model in order to estimate the minimum rate of transmission for the parasite to establish itself in a mammalian host population. Transmission rates that produce different comparable values of the parasites' basic reproductive number, RO, are themselves allometric functions of host body size. We have extended the model to show that hosts having different body sizes suffer epidemic outbreaks whose frequency scales with body size. The expected epidemic periods for pathogens in different mammalian populations correspond to cycles observed in free-living populations.

Animals↗

PubMed1998

Extracting isovolumes from three-dimensional torso geometry using PROLOG.

Three-dimensional (3-D) finite element torso models are widely used to simulate defibrillation field quantities, such as potential, gradient, and current density. These quantities are computed at spatial nodes that comprise the torso model. These spatial nodes typically number between 10(5) and 10(6), which makes the comprehension of torso defibrillation simulation output difficult. Therefore, the objective of this study is to rapidly prototype software to extract a subset of the geometric model of the torso for visualization in which the nodal information associated with the geometry of the model meets a specified threshold value (e.g., minimum gradient). The data extraction software is implemented in PROLOG, which is used to correlate the coordinate, structural, and nodal data of the torso model. A PROLOG-based environment has been developed and is used to rapidly design and test new methods for sorting, collecting, and optimizing data extractions from defibrillation simulations in a human torso model for subsequent visualization.

Algorithms↗

PubMed1998

Sensitivity to changes in level and envelope patterns across frequency.

In the first experiment, two measurements were compared--sensitivity to across-frequency changes in level and sensitivity to across-frequency changes in the modulation phase of SAM tones. For the level task, multi-tone stimuli composed of 2-80 tones ranging in frequency from 200 to 5000 Hz were used. For the phase task, the same frequency range was used, and 2-80 SAM tones were tested. For the level task, observers discriminated between a multi-tone, equal-amplitude standard and one of two signals--a one-step or an up-down signal. The one-step signal had higher levels at low frequencies and lower levels at high frequencies. The up-down signal had components with levels that varied high-low-high-low. For the phase task, the standard was the sum of SAM tones with identical modulator phases across frequency. The one-step signal had a common modulator phase at low frequencies and a different common modulator phase at high frequencies. The up-down signal had modulator phases that varied lag-lead-lag-lead. The results suggest that sensitivity to across-frequency changes in level and modulation phase reflect similar initial processing stages. In a second experiment, SAM tones were used, and psychometric functions were measured for the level task, the phase task, and a condition in which changes in level and modulator phase were both present. The standard was "flat," and an up-down signal was to be detected. For one observer, the data suggest that level and phase information are independently represented. For the other two observers, interactions between the two features of the stimuli are apparent. A multiple-looks model was moderately successful in accounting for the data.

Auditory Perception↗

PubMed1998

Computational models of thalamocortical augmenting responses.

Repetitive stimulation of the dorsal thalamus at 7-14 Hz produces an increasing number of spikes at an increasing frequency in neocortical neurons during the first few stimuli. Possible mechanisms underlying these cortical augmenting responses were analyzed with a computer model that included populations of thalamocortical cells, thalamic reticular neurons, up to two layers of cortical pyramidal cells, and cortical inhibitory interneurons. Repetitive thalamic stimulation produced a low-threshold intrathalamic augmentation in the model based on the deinactivation of the low-threshold Ca2+ current in thalamocortical cells, which in turn induced cortical augmenting responses. In the cortical model, augmenting responses were more powerful in the "input" layer compared with those in the "output" layer. Cortical stimulation of the network model produced augmenting responses in cortical neurons in distant cortical areas through corticothalamocortical loops and low-threshold intrathalamic augmentation. Thalamic stimulation was more effective in eliciting augmenting responses than cortical stimulation. Intracortical inhibition had an important influence on the genesis of augmenting responses in cortical neurons: A shift in the balance between intracortical excitation and inhibition toward excitation transformed an augmenting responses to long-lasting paroxysmal discharge. The predictions of the model were compared with in vivo recordings from neurons in cortical area 4 and thalamic ventrolateral nucleus of anesthetized cats. The known intrinsic properties of thalamic cells and thalamocortical interconnections can account for the basic properties of cortical augmenting responses.

Animals↗

PubMed2001

Cost-efficient vaccination of foxes (Vulpes vulpes) against rabies and the need for a new baiting strategy.

In this study, ecological models, optimisation algorithms and threshold analysis were linked to develop oral-vaccination strategies against rabies in fox populations. It is important that such strategies are cost-efficient and resistant to environmental conditions which would lessen their success. The model validation shows that the ecological models used are suited to predict the proportion of tetracycline- (TC) marked foxes in the course of time. This figure indicates the proportion of foxes which had at least one contact to vaccine baits, and is based on the design of the vaccination strategy (i.e. the number and timing of vaccination campaigns and the number of baits used per square kilometre and campaign). The design of a vaccination strategy also determines the costs. It is the combination of ecological models and optimisation algorithms that helped us to design a vaccination strategy which is capable of achieving a continuous rate of >70% of TC-marked foxes within an analytical horizon of 3 years at low costs. Compared to the standard strategy (baseline comparator), the improved strategy incurs just over half of the cost while almost doubling the number of weeks during which the proportion of TC-marked foxes is >70%. In the improved strategy, June is recommended as the time for bait distribution. The standard strategy, however, avoids summer months (because high temperatures reduce the durability of the baits) which again leads to a reduction of the bait intake by the foxes. Using threshold analysis, we examined the effect of a reduced durability of the baits on the design of the improved vaccination strategy. We concluded that distribution of baits in June was optimal given that the durability of baits is above a threshold of 7 days.

Administration, Oral↗

PubMed2006

Frequency doubling illusion VEPs and automated perimetry in multiple sclerosis.

We examined frequency doubling (FD) illusion based automated perimetry (FDT) and dichoptic FD multifocal visual evoked potentials (FDmfVEPs) in Normal and multiple sclerosis (MS) subjects. Contrast thresholds were determined at 17 visual field locations using an FDT perimeter. The stimuli presented to each location were 0.25 cpd gratings presented with rapid (25 Hz) counterphase flicker and thus displayed the spatial FD illusion. Dichoptic mfVEPs were recorded by concurrently stimulating eight regions/eye with FD stimuli presented at 95% contrast. Recordings were obtained from 27 Normal subjects, 26 MS patients who had experienced Optic Neuritis (MSON) and 24 MS patients without a history of ON (MSNON). The FDT thresholds showed enhanced contrast sensitivity for MSON patients (P < 0.0001) but not for MSNON patients. Response amplitudes for the central four regions of the mfVEP stimulus were reduced in both patient groups (P < 0.005). A classification model based upon the FDT thresholds performed at a specificity of 96% for a sensitivity of 97% in MSON patients, but the accuracy (simultaneously largest sensitivities and specificities) was poor (approximately 60%) in MSNON patients. Discriminant models based on the FDT thresholds and FDmfVEPs were able to diagnose more that 90% MSON patients but performed poorly for MSNON patients.

Adult↗

PubMed1991

Hysteresis in the excitability of isolated guinea pig ventricular myocytes.

Hysteresis phenomena were demonstrated in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current-clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:1) and nonexcitation (1:0) patterns depending on current strength. However, transition between patterns depended on the direction of current strength change, and stable hysteresis loops were obtained in stimulus-response pattern versus current strength plots in 31 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. In addition, at the abrupt transitions from 1:0 to 1:1 patterns, a latency adaptation phenomenon was consistently observed. Bath application of tetrodotoxin (30 microM) produced no change of hysteresis, whereas hysteresis was substantially decreased in cobalt (2 mM) superfusion experiments. Analysis of the changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting and threshold potentials. We therefore modeled the dynamic behavior of the single cells, using an analytical solution aimed at calculating the recovery of activation latency as a function of diastolic membrane resistance. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. The effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes is responsible for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels.

Adaptation, Physiological↗