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PubMed2003

Threshold dose of three photosensitizers in dogs with spontaneous tumors.

Photodynamic threshold doses in dogs with spontaneous tumors can be achieved through a mathematical model. For this to be clinically relevant, it is important to know the treatment parameters for tissue necrosis. The threshold dose for three photosensitizers (porfimer sodium, aluminum cholorophthalocyanine [AlClPc], and tin ethyl etiopurpurin [SnET2]) commonly used in veterinary chemotherapy protocols was evaluated in 12 dogs with spontaneous tumors. To derive the photodynamic threshold dose, the tissue optical properties of each compound were determined by diffuse reflectance and thus the light fluence rate. Uptake was measured by fluorimetry using tissue solubilization techniques. The threshold values calculated were highest for AlClPc (irradiated 48 hours after administration). The radius of necrosis (4.00 to 5.48 mm) and photosensitizer uptake (3.4 to 6.91 microg/g) were elevated after injection of porfimer sodium. The threshold dose model described here is photosensitizer dependent but independent of photosensitizer uptake and light dose. This study indicates that more photon absorption is needed for tumor necrosis with AlClPc than for either SnET2 or porfimer sodium.

Animals↗

PubMed1986

Statistical models for predicting Edgerton-Danhauer NST scores from pure-tone thresholds.

Pure-tone thresholds (PTTs) and phonemic-scored responses to the Edgerton and Danhauer (1979) Nonsense Syllable Test (NST) at 25, 35, 45, and 55 db SL re each S's SRT, were taken from 97 Ss of 4 earlier studies of Danhauer and colleagues. All studies had used the same stimuli and procedures. Among the 97 Ss were heterogeneous subpopulations of normally-hearing and sensorineural hearing-impaired Ss, aged 6-81 yrs. PTTs at octaves from .25-8 kc/s, singly and in various weighted combinations, were explored by step-wise multiple linear regression analyses for the best equation to predict an individual's NST score at each SL. Included were the two weighted PTT averages (over .5, 1, and 2 kc/s) proposed by Butts, Schoney and Ruth (Asha, 1984, 26, 64). PTT2 kc/s was the single most predictive datum. The most predictive equation at one NST SL was not necessarily the best at another SL. At each NST SL, the most predictive equation was always one or other of the equations of Butts et al, and at the higher levels the best equations incorporated in addition certain weighted PTTs at .5 and 1 kc/s. The results indicated that it is possible to predict a S's NST scores from PTTs with reasonable accuracy: from 86-91% of Ss' NST scores were predicted within +/- 10%. Further validation and refinement of these models on larger and different subject samples may result in equations predicting NST scores from PTTs with those difficult-to-test patients in whom speech recognition capacity cannot well be tested directly.

Acoustic Stimulation↗

PubMed2000

Effects of thermal conducting media on the skin surface during laser irradiation.

OBJECTIVES: To investigate the effects of thermally conductive, optically transparent media placed on skin during treatment with the flashlamp excited dye laser (FEDL). The use of higher energy densities to treat persistent cutaneous vascular lesions may result in a decrease in the number of treatment sessions. However, increased fluences can cause complications of scarring, hyperpigmentation, infection, skin texture changes, or hypopigmentation. The thermally conductive media should assist in dissipating surface thermal energy and thereby protect the skin from the complications. STUDY DESIGN: This was a prospective laboratory study using an animal model. The results were verified in a prospective, pilot, human-use trial. METHODS: The threshold for acute skin damage and measurements of the thermal transients were made using a rabbit model. The threshold for purpura was noted with and without the use of a sapphire as a thermal conductor. The thermal transients were measured with small thermocouples placed subcutaneously. On a human subject, purpura intensities were photographed and measured using computer morphometrics after treatment with the FEDL and skin surface protection with air, glass, sapphire, and diamond as conductive media. RESULTS: With the interposition of the sapphire thermal conductor during the FEDL treatment, excessive temperature increases of the epidermis were prevented during the laser pulse compared with glass and controls. Both sapphire and diamond resulted in decreased purpuric intensities with the applications of equivalent fluences. Wound recovery time for the purpura was decreased by approximately half a day when any of the surface conductors were used. CONCLUSIONS: The decreased transient temperature and decrease in purpura seen with the use of sapphire and diamond protecting the epidermis during treatment with the FEDL should result in fewer untoward effects during treatment of vascular lesions and facilitate their management.

Adult↗

PubMed2005

Preoperative antibiotic and steroid therapy and hearing loss caused by semicircular canal transection in pseudomonas otitis media.

OBJECTIVE: The purpose of this experiment was to determine whether preoperative administration of antibiotics and corticosteroids can attenuate the severity of hearing loss (HL) with semicircular canal (SC) transection in a guinea pig model of Pseudomonas aeruginosa (PA) otitis media (OM). Study design and setting Prospective and controlled. METHODS: OM was induced in 64 pigmented guinea pigs by bilateral, transtympanic injection of PA. Two to 4 days later, 1 horizontal SC was randomly transected. In the 1st series, antibiotic therapy was initiated either immediately before or after surgery. In the 2nd series, all animals received preoperative antibiotics, and half received dexamethasone before surgery. Hearing was tested before and after surgery. RESULTS: PA was recovered in all ears. SC transection was associated with significant HL. HL was better in animals given antibiotics preoperatively (clicks, 16 versus 32 dB, P = 0.0220). Addition of preoperative steroids did not significantly further reduce HL (7 versus 14 dB for clicks, P = 0.6919). CONCLUSIONS: HL caused by SC transection in PA OM may be attenuated with preoperative antibiotic therapy in the guinea pig.

Animals↗

PubMed2001

A psychometric analysis of the measurement level of the rating scale, time trade-off, and standard gamble.

A fundamental assumption of utility-based analyses is that patient utilities for health states can be measured on an equal-interval scale. This assumption, however, has not been widely examined. The objective of this study was to assess whether the rating scale (RS), standard gamble (SG), and time trade-off (TTO) utility elicitation methods function as equal-interval level scales. We wrote descriptions of eight prostate-cancer-related health states. In interviews with patients who had newly diagnosed, advanced prostate cancer, utilities for the health states were elicited using the RS, SG, and TTO methods. At the time of the study, 77 initial and 73 follow-up interviews had. been conducted with a consecutive sample of 77 participants. Using a Rasch model, the boundaries (Thurstone Thresholds) between four equal score sub-ranges of the raw utilities were mapped onto an equal-interval logit scale. The distance between adjacent thresholds in logit units was calculated to determine whether the raw utilities were equal-interval. None of the utility scales functioned as interval-level scales in our sample. Therefore, since interval-level estimates are assumed in utility-based analyses, doubt is raised regarding the validity of findings from previous analyses based on these scales. Our findings need to be replicated in other contexts, and the practical impact of non-interval measurement on utility-based analyses should be explored. If cost-effectiveness analyses are not found to be robust to violations of the assumption that utilities are interval, serious doubt will be cast upon findings from utility-based analyses and upon the wisdom of expending millions in research dollars on utility-based studies.

Cost-Benefit Analysis↗

PubMed2005

Structures of cationized proline analogues: evidence for the zwitterionic form.

The structures of lithiated and sodiated alpha-methyl-proline (alpha-Me-Pro) and structural isomers, both with and without a water molecule, are investigated using blackbody infrared radiative dissociation (BIRD) and density functional theory. From the BIRD kinetic data measured as a function of temperature, combined with master equation modeling of these data, threshold dissociation energies for the loss of a water molecule from these clusters are obtained. These energies are 77.5 +/- 0.5 and 53 +/- 1 kJ/mol for lithiated and sodiated alpha-Me-Pro, respectively. For the nonzwitterionic isomer, proline methyl ester, these values are 3.0-4.5 kJ/mol higher. These results provide compelling experimental evidence that alpha-Me-Pro is zwitterionic in these clusters. Theory at the temperature corrected B3LYP/6-311++G**//B3LYP/6-31++G** level indicates that the salt-bridge or zwitterionic forms of lithiated and sodiated alpha-Me-Pro are between 17 and 23 kJ/mol lower in energy than the nonzwitterionic or charge-solvated forms and that attachment of a single water molecule does not significantly change the structure or the relative energies of these clusters. The proton affinity of proline is 8 kJ/mol higher than that of alpha-Me-Pro, indicating that lithiated and sodiated singly hydrated proline should also be zwitterionic.

Anions↗

PubMed1994

Threshold conditions for the spread of the HIV infection in age-structured populations of homosexual men.

The age-structure of a population, and the distribution of sexual behavior according to age, are significant factors determining the spread of the AIDS epidemic. The threshold conditions for age-structured models account for life-history information, and thus differ significantly from their age-independent counterparts. We examine the threshold conditions for four general age-structured models of the spread of HIV in a homosexual population: three with random partner selection and one with biased partner selection. We consider both discrete and continuous risk groups, and the duration of infection. Susceptibility and infectiousness are treated separately, and the infectivity varies with duration of infection. Through specific examples, we examine the sensitivity of the threshold conditions to the population age-structure and the shape of the infectivity profile. The effects of each are of the same order of magnitude.

Adult↗

PubMed2003

A diminished rate of "physiological decay" at noise offset contributes to age-related changes in temporal acuity in the CBA mouse model of presbycusis.

The persistence of afferent activity at stimulus offset was examined in mice as a function of age (experiment 1) and noise level (experiment 2), using a procedure devised by von Bekesy to study the physiological decay of afferent activity. Noise offset was presented from 1 to 10 ms (the temporal gap) prior to an acoustic startle stimulus, with an abrupt edge or a linear ramp having the duration of the gap. Noise offset inhibited the startle reflex, this effect declining with age. For young (2-3 months old) and "young-old" mice (18-19 months old), the abrupt offset was always more inhibitory than the ramp, even for the one millisecond gap. In "old-old" mice (24-26 months old) abrupt and ramped offsets were not different until the gap exceeded 4 ms. The behavioral difference between abrupt and ramped decay times did not depend on noise level in young mice (4-5 months old), though overall inhibition increased with level. These data indicate that temporal acuity as measured by this gap detection method is limited in very old mice by their reduced ability to follow the abrupt change in noise level at the beginning of the gap.

Acoustic Stimulation↗

PubMed1990

Surface characterizations of color thresholds.

We evaluate how well three different parametric shapes, ellipsoids, rectangles, and parallelograms, serve as models of three-dimensional detection contours. We describe how the procedures for deriving the best-fitting shapes constrain inferences about the theoretical visual detection mechanisms. The ellipsoidal shape, commonly assumed by vector-length theories, is related to a class of visual mechanisms that are unique only up to orthogonal transformations. The rectangle shape is related to a unique set of visual mechanisms, but since the rectangle is not invariant with respect to linear transformations the estimated visual mechanisms are dependent on the stimulus coordinate frame. The parallelogram is related to a unique set of visual mechanisms and can be derived by methods that are independent of the stimulus coordinate frame. We evaluate how well these shapes approximate detection contours, using 2-deg test fields with a long (1-sec) Gaussian time course. Two statistical tests suggest that the parallelogram model is too strong. First, we find that the ellipsoid and rectangle shapes fit the data with the same precision as the variance in repeated threshold measurements. The parallelogram model, which has more free parameters, fits the data with more precision than the variance in repeated threshold measurements. Second, although the parallelogram model provides a slightly better fit of our data than the other two shapes, it does not serve as a better guide than the ellipsoidal model for interpolating from the measurements to thresholds in novel color directions.

Calibration↗

PubMed1999

Models for the description of angioscotomas.

To describe small scotomas in visual field examinations several statistical models are proposed and applied to the evaluation of angioscotoma in 13 ophthalmologically normal subjects. A special perimetric grid is used where thresholds can be estimated along a line of narrow-spaced test points which crosses the predicted location of the retinal vessel. A two-stage analysis employs single estimations to fit a threshold curve by means of a special parametric description of the luminance difference sensitivity threshold as a function of stimulus position. An alternative model incorporates the threshold as a function of position into the probabilistic description of the binary response (stimulus seen/not seen).

Adult↗

PubMed2006

Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression.

The aim of the present study was to examine the effect of the selective 5-HT7 receptor antagonist SB 269970 (0.25-20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1-20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT7 receptor antagonists may play a role in the therapy of both anxiety and depression.

Analysis of Variance↗

PubMed2005

Weak and strong chaos in Fermi-Pasta-Ulam models and beyond.

We briefly review some of the most relevant results that our group obtained in the past, while investigating the dynamics of the Fermi-Pasta-Ulam (FPU) models. The first result is the numerical evidence of the existence of two different kinds of transitions in the dynamics of the FPU models: (i) A stochasticity threshold (ST), characterized by a value of the energy per degree of freedom below which the overwhelming majority of the phase space trajectories are regular (vanishing Lyapunov exponents). It tends to vanish as the number N of degrees of freedom is increased. (ii) A strong stochasticity threshold (SST), characterized by a value of the energy per degree of freedom at which a crossover appears between two different power laws of the energy dependence of the largest Lyapunov exponent, which phenomenologically corresponds to the transition between weak and strong chaotic regimes. It is stable with N. The second result is the development of a Riemannian geometric theory to explain the origin of Hamiltonian chaos. Starting this theory has been motivated by the inadequacy of the approach based on homoclinic intersections to explain the origin of chaos in systems of arbitrarily large N, or arbitrarily far from quasi-integrability, or displaying a transition between weak and strong chaos. Finally, the third result stems from the search for the transition between weak and strong chaos in systems other than FPU. Actually, we found that a very sharp SST appears as the dynamical counterpart of a thermodynamic phase transition, which in turn has led, in the light of the Riemannian theory of chaos, to the development of a topological theory of phase transitions.

Kinetics↗

PubMed2004

The reinfection threshold promotes variability in tuberculosis epidemiology and vaccine efficacy.

Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control.

BCG Vaccine↗

PubMed2005

Low-level integration of auditory and visual motion signals requires spatial co-localisation.

It is well known that the detection thresholds for stationary auditory and visual signals are lower if the signals are presented bimodally rather than unimodally, provided the signals coincide in time and space. Recent work on auditory-visual motion detection suggests that the facilitation seen for stationary signals is not seen for motion signals. We investigate the conditions under which motion perception also benefits from the integration of auditory and visual signals. We show that the integration of cross-modal local motion signals that are matched in position and speed is consistent with thresholds predicted by a neural summation model. If the signals are presented in different hemi-fields, move in different directions, or both, then behavioural thresholds are predicted by a probability-summation model. We conclude that cross-modal signals have to be co-localised and co-incident for effective motion integration. We also argue that facilitation is only seen if the signals contain all localisation cues that would be produced by physical objects.

Acoustic Stimulation↗

PubMed2004

A response time model for judging order relationship between two symbolic stimuli.

The response time to judge the order relationship between two symbolic stimuli is frequently modeled as the time spent in a (constant-rate) accumulative sampling process until a threshold is reached. We will show that empirical descriptions of observed effects in number comparisons suggest an accrual process that reaches the threshold at an exponential rate. The model accrual equations and stopping conditions have an immediate interpretation in terms of a simple quantitative connectionist network. The encoded stimuli and thresholds are inputs to the network. The former are considered to result from the participant's learning history, and the latter modulate the rearrangement of the network parts; each arrangement models a different task. We have found a good correlation between model predictions and other authors' experimental data, both in number comparisons and in experiments in which the ordering of the symbolic stimuli has been artificially induced. Incorrect answers are discussed, and predictions are compared with data. We will explore differences and similarities with other approaches, such as random walk and the symbolic comparison model. In a limit case, our model becomes identical to the discriminability model.

Humans↗

PubMed1989

A model of propagating calcium-induced calcium release mediated by calcium diffusion.

The effect of sudden local fluctuations of the free sarcoplasmic [Ca++]i in cardiac cells on calcium release and calcium uptake by the sarcoplasmic reticulum (SR) was calculated with the aid of a simplified model of SR calcium handling. The model was used to evaluate whether propagation of calcium transients and the range of propagation velocities observed experimentally (0.05-15 mm s(-1)) could be predicted. Calcium fluctuations propagate by virtue of focal calcium release from the SR, diffusion through the cytosol (which is modulated by binding to troponin and calmodulin and sequestration by the SR), and subsequently induce calcium release from adjacent release sites of the SR. The minimal and maximal velocities derived from the simulation were 0.09 and 15 mm s(-1) respectively. The method of solution involved writing the diffusion equation as a difference equation in the spatial coordinates. Thus, coupled ordinary differential equations in time with banded coefficients were generated. The coupled equations were solved using Gear's sixth order predictor-corrector algorithm for stiff equations with reflective boundaries. The most important determinants of the velocity of propagation of the calcium waves were the diastolic [Ca++]i, the rate of rise of the release, and the amount of calcium released from the SR. The results are consistent with the assumptions that calcium loading causes an increase in intracellular calcium and calcium in the SR, and an increase in the amount and rate of calcium released. These two effects combine to increase the propagation velocity at higher levels of calcium loading.

Calcium↗

PubMed2004

Epilepsy induced by extended amygdala-kindling in rats: lack of clear association between development of spontaneous seizures and neuronal damage.

Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus, amygdala, and parahippocampal regions. Hippocampal damage in patients with TLE is characterized by extensive neuronal loss in the CA3 and CA1 sectors and the hilus of the dentate gyrus. There is a long and ongoing debate on whether this type of hippocampal damage, referred to as hippocampal sclerosis, is the cause or consequence of TLE. Furthermore, hippocampal damage may contribute to the progressive features of TLE. The present study was designed to determine whether development of spontaneous recurrent seizures (SRS) after extended kindling of the amygdala in rats is associated with neuronal damage. The kindling model of TLE was chosen because previous studies have shown that only part of the rats develop SRS after extended kindling, thus allowing to compare the brain pathology of rats that received the same number of amygdala stimulation but did or did not develop SRS. For extended kindling, rats were stimulated twice daily 3-5 days a week for up to about 280 stimulations. During long-term EEG/video monitoring, SRS were observed in 50% of the rats over the period of extended kindling. SRS often started with myoclonic jerks or focal seizures and subsequently progressed into secondarily generalized seizures, so that the development of SRS recapitulated the earlier kindling of elicited seizures. No obvious neurodegeneration was observed in the CA1 and CA3 sectors of the hippocampus, the amygdala, parahippocampal regions or thalamus. A significant bilateral reduction in neuronal density was determined in the dentate hilus after extended kindling, but this reduction in hilar cell density did not significantly differ between rats with and without observed SRS. Determination of the total number of hilar neurons and of hilar volume indicated that the reduced neuronal density in the dentate hilus was due to expansion of hilar area but not to neuronal damage. The data demonstrate that extended kindling does not cause any hippocampal damage resembling hippocampal sclerosis, but that SRS develop in the absence of such damage.

Amygdala↗

PubMed2005

Comparison of the relative sensitivity of human lymphocytes and mouse splenocytes to two spindle poisons.

Aneugenic compounds act on non-DNA targets to exert genotoxicity via an indirect mechanism. In contrast to DNA-binding agents, these compounds are expected to possess threshold levels of activity. Therefore, the risk for adverse effects following human exposure to an aneugen could be minimal, if the threshold of activity has been clearly determined in vivo and in vitro and providing the human exposure level is below this threshold. Thus, the development of a single-cell model to allow comparisons between in vitro and in vivo threshold values for aneugenic compounds is of importance. The in vivo micronucleus test is one of the main assays used in genetic toxicology, and is often performed in the mouse. Thus, an extensive database is available in the literature. However, there are only few data concerning the in vitro micronucleus assay using mouse cells, as the majority of in vitro micronucleus assays have been performed using human lymphocytes. In addition, there is a lack of data concerning thresholds for any compound using this model. First, we evaluated whether the use of mouse splenocytes would be an acceptable alternative to that of human lymphocytes to identify aneugens. To allow valid comparisons, the two protocols were first harmonized. Thus, phytohemagglutinin (PHA) and concanavalin A were used as specific mitogens for human lymphocytes and mouse splenocytes, respectively, in order to achieve similar cell-proliferation rates. To achieve similar and sufficient numbers of binucleated cells, cytochalasin B was added 44 and 56 h after culture initiation of the human and mouse cells, respectively. Second, we compared the sensitivity of the mouse protocol with that of the human protocol by exposing the cells to the aneugens nocodazole and paclitaxel. There was good reproducibility of the cytotoxic/genotoxic responses of the two cell models following exposure to the aneugens. The sensitivity of the mouse splenocytes to paclitaxel was higher than that of the human lymphocytes. The two cell types were equally sensitive to nocodazole.

Aneugens↗