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PubMed1998

Anticonvulsant drug effects in the direct cortical ramp-stimulation model in rats: comparison with conventional seizure models.

A modified cortical ramp stimulation (CRS) model has been developed allowing repeated determinations of seizure threshold at short time intervals in individual rats without inducing postictal threshold increases. Anticonvulsant potency of the standard antiepileptic drugs carbamazepine, phenytoin, phenobarbital, valproate, diazepam and ethosuximide in the CRS model was compared with respective drug potencies in two more traditional seizure models with transcorneal stimulus application, i.e., the minimal electroshock seizure threshold (minEST) and the maximal electroshock seizure threshold (maxEST). In the CRS model, two different types of threshold were determined, the threshold for localized seizures (TLS) and the threshold for generalized seizures (TGS). When screw electrodes were implanted over the primary motor cortex, TLS was characterized by unilateral forelimb clonus, tonic abduction of contralateral forelimb, and head adversion. When ramp-shaped stimulation was continued above the TLS current, bilateral clonic forelimb seizures with loss of posture developed, which was defined as TGS. In contrast to TLS, TGS could not be repeatedly determined at short time intervals because of postictal threshold increase. TLS was dose-dependently increased by carbamazepine, phenobarbital, valproate and diazepam, although phenytoin showed a truncated dose-response, and ethosuximide was ineffective. In comparison to TLS, drug-induced increases in TGS were more marked. All drugs dose-dependently increased minEST and, except ethosuximide, maxEST. For comparison of drug potencies, doses increasing seizure thresholds by 20 or 50% were calculated from dose-response curves. Respective comparisons showed marked differences in drug potencies between models, indicating that the CRS method presents a model of another, more pharmacoresistant seizure type than seizure types induced in traditional models, such as transcorneal electroshock. Based on the location of electrodes in the frontal neocortex, the characteristic seizure pattern, and the low pharmacological sensitivity of the seizures to standard antiepileptics, the modified CRS model most likely represents a new model of localization-related seizures occurring in frontal lobe epilepsy and may thus be used in the search for novel drugs with higher efficacy against this difficult-to-treat type of epilepsy.

Animals↗

PubMed2004

Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis.

PURPOSE: Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL. PATIENTS AND METHODS: Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 microg/L, and cTnI < 0.1 microg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively. RESULTS: Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively. CONCLUSION: Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.

Adult↗

PubMed2005

Areawide models comparing synchronous versus asynchronous treatments for control of dispersing insect pests.

Integrated pest management (IPM) has the goal of combining several control methods that reduce populations of pest insects and their damage to tolerable levels and thereby reduce the use of costly pesticides that may harm the environment. Insect populations can be monitored during the season to determine when the densities exceed an economic threshold that requires treatment, often as an insecticide application. We developed a simulation model where insect populations varied in exponential growth in fields and dispersed to adjacent fields each day of a season. The first model monitored populations of individual fields in a grid of fields and treated any field with insecticide if it exceeded a threshold population (asynchronous model) as done in traditional IPM. The second model treated the entire grid of fields with insecticide when the average population of all fields exceeded the threshold (synchronous model). We found that the synchronous model at all growth and dispersal rates tested had average field populations during a season that were significantly lower and required fewer treatments than the asynchronous method. Parameters such as percentage of fallow fields, number of fields, and treatment threshold had little affect on relative differences between the two models. The simulations indicate that cooperation among growers in areawide monitoring of fields to obtain an average population estimate for use in treatment thresholds would result in significantly less insect damage and fewer insecticide treatments. The synchronous method is more efficient because population refugia are precluded from which dispersal could reintroduce insects.

Animals↗

PubMed2004

Influences of motor instructions on the reaction times of saccadic eye movements.

When a gap period is inserted between the fixation point extinction and the target presentation, the distribution of saccadic reaction times has two distinct peaks: one at 150-250 ms (ordinary saccades) and another at approximately 100 ms (express saccades). The distribution of saccadic reaction times can be explained by the linear approach to threshold with ergodic rate (LATER) model, in which the value of a decision signal increases linearly from a start level to initiate a saccade when the signal value reaches a threshold. We hypothesized that a gap period and/or an instruction signal can modulate the parameters of the model to determine when a saccade is initiated. Two reciprobit plots of reaction times, one for ordinary and the other for express saccades, for a task with both a gap period and visuospatial instruction, were constrained by a common infinite-time intercept, although no such constraint was observed during task performance without a visuospatial instruction. We interpreted the results that either the threshold, the start level, or the rate of increase of the decision signal of the model was switched in a bistable manner by both the visuospatial instruction and a gap period, but not by the gap period alone.

Adult↗

PubMed1995

Reduced tumorigenicity of threshold syngeneic tumor inocula in xid-bearing mice treated with natural antibodies.

Several correlative experimental approaches have provided evidence that polyclonal serum natural antibodies (NAb) participate in the defense against small syngeneic tumor foci in vivo. The threshold subcutaneous tumor inoculum model of incipient neoplasia has consistently revealed an inverse relationship between tumorigenicity in vivo and the NAb binding capacity of the tumor injected or the anti-tumor NAb levels of the recipient animals, including B cell-deficient mice bearing the xid mutation of the CBA/N mouse strain. Now passive i.v. administration of whole normal syngeneic serum NAb in bolus injections, given I each day beginning on day -2, -1 or 0 prior to the threshold s.c. challenge of xid-bearing CBA/N or male (CBA/N x CBA/J)F1 mice with syngeneic RI-28 lymphoma cells, consistently and significantly reduced their tumorigenicity assayed as tumor appearance and latency. Three similar injections of an ammonium sulfate-precipitated fraction of whole serum NAb also reduced tumor frequency and latency, while a combination of purified IgG and IgM NAb reduced the appearance of tumors slightly and increased the survival of recipients. The reconstitution of the xid-defect in anti-tumor NAb provides more direct evidence to substantiate a role for NAb in the defense against early tumor development in vivo and establishes a model for the dissection of the in vivo mechanisms of the NAb anti-tumor activity.

Animals↗

PubMed1995

[Current trends in the use of statistics in medicine. A study of original articles published in the Medicina Clínica (1991-1992)].

BACKGROUND: In recent years there has been a notable increase in the use of statistical techniques in biomedical journals. Furthermore, the complexity of statistical analysis has increased because of data processing. In this study statistical accessibility is quantified and the types of statistical analysis performed in all the articles published under the section of original articles in the journal Medicina Clínica from 1991 to 1992 (volumes 96 to 99). METHODS: One reviewer analyzed a total of 264 original articles. The statistical analyses were classified according to a list with 18 categories. The quantification of accessibility was obtained from the order of the 18 categories with bivariate statistics (up to simple regression), being used as the reference threshold. Intrareviewer concordance was 97%. RESULTS: Eighty-one percent of the 264 originals used categories of statistical analysis beyond that of descriptive statistics (inferential methods). The originals used bivariate tables (49.2%) and t and z tests (33.3%) most frequently. In 1992 the use of variance analysis and survival analysis increased notably (from 12.8% to 33.8% and 7.2% to 18.7%, respectively). More complex statistical techniques that models of simple regression (threshold reference) were used in 38.3% of the originals (31.2% in 1991 and 44.6% in 1992). CONCLUSIONS: The use of inferential statistics and the complexity of statistical analysis has increased suggesting a lower statistical accessibility in the originals of Medicina Clinica. The categories of variance analysis and survival analysis were those in which the greatest increase was observed in 1992 and were responsible for the increase in the complexity of 20% of the originals.

Analysis of Variance↗

PubMed2006

Flavor- and CP-violating physics from new supersymmetric thresholds.

Treating the minimal supersymmetric standard model as an effective theory, we study the implications of having dimension-five operators in the superpotential for flavor- and CP-violating processes, exploiting the linear decoupling of observable effects with respect to the new threshold scale c. We show that the assumption of weak-scale supersymmetry, when combined with the stringent limits on electric dipole moments and lepton-flavor-violating processes, provides sensitivity to Lambda as high as 10(7)-10(9) GeV (and up to 10(17) GeV through the theta term), while the next generation of experiments could directly probe the high-energy scales suggested by neutrino physics.

Journal Article↗

PubMed2000

[The establishment of the model for differential diagnosis of borderline cases with anterior crossbite using fuzzy set theory].

OBJECTIVE: To introduce the fuzzy set theory to orthodontics by using the diagnostic information drawn out from the diagnosed cases to solve the problem of borderline- case diagnosis. METHOD: Lateral cephalometric radiographs of 107 anterior crossbite patients in early permanent dentition were traced, measured, and 31 variables calculated. Diagnosis was made by experienced specialists and the cases were divided into three groups: dental anterior crossbite (52 cases), borderline cases (22 cases) and skeletal anterior crossbite (33 cases). Among 85 cases with accurate diagnosis we selected 70 cases to establish 6-factor model using stepwise discriminant analysis. This afforded 100 percent correct respective check and the predictive diagnosis of the other 15 cases showed that its correction rate was 93.3 percent which proved that most useful information was included. Then the contributions of the six variables were calculated and we established two sets: skeletal anterior crossbite set and dental anterior crossbite set with skeletal and dental means to be their thresholds. For each case the individual measurements of the six variables were standardized and afterwards transferred into constituent ratio and at the same time their degrees of membership of these two sets were calculated according to the distance between its location and the two thresholds. Using this fuzzy model we got the individual scores of the two sets. The diagnosis of the patient was coincident with the set of higher scores. This model was testified by 85 cases with accurate diagnosis and its correction was absolute. RESULT: 22 borderline cases were diagnosed by this model. CONCLUSION: The two-set difference were far less than that of the cases with accurate diagnosis which prove the model was reasonable.

Dentition, Permanent↗

PubMed1998

[Identification and prediction of responders to a therapy. A model and its preliminary application to hypertension].

The effect of a given treatment for a given disease may be estimated from randomized controlled clinical trials, expressed as a single treatment effect averaged over the trial population. However, in recent years there has been an increasing willingness to individualize therapeutic decisions. The method we report here identifies responders by assessing the individual probability of an event, according to the treatment group. We used a treatment-stratified Cox regression model including interaction between treatment and patient's covariates, with common regression coefficients for treated and untreated, except for the special case of a prognostic variable which has an interaction with treatment. Further, we used a discriminate function based on the final model, representing the absolute individual therapeutic effect, to identify the patients to be treated according to a given threshold of clinical efficacy. The model was explored on the INDANA database (which pools individual patient data from clinical trials of anti-hypertensive drug intervention). Data on 36,444 patients, from five randomized controlled trials were included. The results show the relationship between the proportion of avoided events among the avoidable ones, and the proportion of patients treated who were responders, as a function of the threshold of absolute benefit defining responders. The confidence intervals of the absolute therapeutic benefit for each individual were calculated, by using the Monte Carlo simulation method. A comparison of the survival of treated and controlled individuals, in both subgroups of responders and non responders, illustrated the relevance of the model. We conclude that the tools for predicting individual therapeutic benefit do exist. It will be important to assess the reproducibility of these results in other models or in other populations before widespread application. It will be necessary to have a properly computerized environment and to train doctors to use these tools.

Decision Support Techniques↗

PubMed1988

The epidemiology of canine visceral leishmaniasis in southern France: classical theory offers another explanation of the data.

This paper describes a compartmental model incorporating biological details of the transmission of canine visceral leishmaniasis in southern France. In contrast to earlier, empirical models (Jolivet, 1977; Rioux, Croset & Lanotte, 1977) the new model (1) predicts a threshold density of sandflies below which transmission cannot be sustained, (2) suggests that, until better data become available, the maximum prevalence of infection obtained at high sandfly density should be considered an unknown quantity.

Animals↗

PubMed1988

Prediction of children's blood lead levels on the basis of household-specific soil lead levels.

To help guide policy decisions about removing lead-contaminated soils, the authors estimated a regression model for predicting a child's blood lead level on the basis of his or her household-specific soil lead level. The data analyzed were blood lead levels (1-45 micrograms/dl) and household-specific soil lead levels (53-20,700 ppm) of 596 children aged 1-5 years who lived in the Helena Valley of Montana and the Silver Valley of Idaho during August 1983. A non-threshold, multiple linear regression model indicated that the estimated mean natural log transformed blood lead level increased by 0.231 micrograms/dl for each unit increase in natural log transformed soil lead level (ppm), after adjusting for the average number of daily outdoor play hours and whether someone in the household smoked. The model predicted that, at a soil lead level of 1,000 ppm, a child who does not play outside and who does not live in a household where someone smokes would be at low risk of lead toxicity (blood lead level between 4 and 24 micrograms/dl).

Child, Preschool↗

PubMed2003

A qualitative analysis of a model for the transmission of varicella-zoster virus.

Varicella-zoster virus (VZV) is a herpesvirus which is the known agent for causing varicella (chickenpox) in its initial manifestation and zoster (shingles) in a reactivated state. The standard SEIR compartmental model is modified to include the cycle of shingles acquisition, recovery, and possible reacquisition. The basic reproduction number R(0) shows the influence of the zoster cycle and how shingles can be important in maintaining VZV in populations. The model has the typical threshold behavior in the sense that when R(0)</=1, the VZV disappears from the population, and when R(0)>1, the virus persists over time and so chickenpox and shingles remain endemic.

Chickenpox↗

PubMed1998

A model of cortically induced synchronization in the lateral geniculate nucleus of the cat: a role for low-threshold calcium channels.

Recently Sillito et al. (Nature 1994;369:479-82) discovered correlations in the spike trains of a relatively distant pair of cat lateral geniculate nucleus cells when simultaneously stimulated by a drifting grating; no such correlation occurs when the visual cortex is removed. In a further analysis of the data, we have found that short, high-frequency bursts contribute substantially to the synchronization and we hypothesize that the origin of the bursts is the low-threshold calcium spike. Guided by this hypothesis, our model of the corticogeniculate pathway and early visual system reproduces the experimental data in nearly every detail, as well as making predictions about cortical activity during the synchronizing process. We also discuss the possible behavioral relevance of correlations in the geniculo-cortical loop as well as other neural systems.

Action Potentials↗

PubMed1985

Retinal inhomogeneity. III. Circular-retina theory.

By introducing a local contrast-sensitivity function, defined as the Fourier transform of the local point-spread function, we have constructed a model of retinal inhomogeneity that predicts the contrast sensitivity for circular homogeneous or inhomogeneous sinusoidal targets up to 16 degrees in diameter. This model assumes that (1) contrast sensitivity is mediated by a standard, receptive-field-type filter function (one that fits our data somewhat better than available receptive-field models); (2) retinal inhomogeneity is circularly symmetric; i.e., receptive-field size varies only with eccentricity; (3) this size variation is governed by a linear scaling factor out to at least 8 degrees eccentricity; and (4) the local contrast sensitivities at different parts of the retina combine in accord with a fourth-power probability-summation rule. The parameters of the model were determined by fitting contrast-sensitivity data for a new class of stimulus patterns: locally sinusoidal, circularly symmetric targets with radially varying spatial frequency (but constant amplitude). The model also fits contrast thresholds for circular cosine disks and annuli of various sizes and eccentricities. (Predictions for noncircular patterns require a minor extension.) The results suggest that the uniform, homogeneous sinusoidal patterns used throughout the literature provide surprisingly little information about the form of receptive fields.

Humans↗

PubMed2006

Threshold control of motor actions prevents destabilizing effects of proprioceptive delays.

It is usually assumed that proprioceptive feedback comes to motoneurons too late to contribute to the initial activity of agonist muscles during fast arm movements, leading to the suggestion that this feedback is only efficient in slow movements and postural control. The argument does not take into account that the changes in the motoneuronal membrane potentials and the associated changes in the state of spinal neurons preceding the initial activity of muscles deeply affect, in a forward way, the state of reflex systems by shifting their thresholds, as suggested in the lambda model for motor control. As a result, the initial muscle activity emerges with full contribution of these systems so that the effects of reflex delays become negligible. We tested the hypothesis that threshold control of muscle activation may be instrumental in preventing destabilizing effects of proprioceptive delays in spinal and trans-cortical pathways to motoneurons. The analysis was made by recording fast elbow movements (peak velocity approximately 300-500 degrees/s) and simulating them in a dynamic model that incorporates the notion of threshold control of intrinsic and reflex muscle properties. The model was robust in reproducing experimental movement patterns (R (2)>0.95). It generated stable output despite substantial proprioceptive (up to 100 ms) and electromechanical (40 ms) delays. Stability was thus ensured for delays not only in segmental (about 25-50 ms) but also in trans-cortical loops (50-70 ms). Our study illustrates that a natural physiological process--threshold control--may manifest feed-forward properties hitherto attributed to hypothetical internal neural models.

Adult↗

PubMed2006

Improved protein recovery in reversed-phase liquid chromatography by the use of ultrahigh pressures.

The effect that elevated pressure used in ultrahigh-pressure liquid chromatography (UHPLC) has on protein recovery was investigated. Specifically, protein carryover ("ghosting") and recovery were examined. Four model proteins (ribonuclease A, ovalbumin, myoglobin, BSA) were separated by gradient RPLC at both conventional (160 bar) and ultrahigh pressures (>1500 bar). A custom gradient UHPLC system was used to generate conventional pressures on 5-microm diameter reversed-phase supports and ultrahigh pressures on identical 1.4-microm supports. The results indicate that, by increasing the pressure, protein carryover from run to run is reduced and in some cases eliminated above a certain threshold pressure for the model proteins studied. Further work indicates that recovery was enhanced for each of the proteins studied, even approaching 100% for certain proteins.

Chromatography, High Pressure Liquid↗

PubMed2004

Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy.

Retinal capillary quiescence is regulated by a delicate balance between proangiogenic and anti-angiogenic factors. Pathological angiogenesis is the result of a shift in this balance towards proangiogenic influences. Pathological angiogenesis is produced in a rat model of oxygen-induced retinopathy (OIR) by exposing newborn rat pups to alternating periods of hyperoxia and hypoxia. Based upon previous work, two similar exposure paradigms were investigated and compared, exposure of rat pups to alternating periods of 45 and 12.5% oxygen, and to alternating periods of 40 and 15% oxygen. The resulting retinal pathology was assessed by measurement of retinal clock hours with pathological blood vessel growth and the percentage of the retina that is avascular. The 45 and 12.5% exposure produced significantly greater incidence and severity of pathology than the 40 and 15% protocol. To explain the difference in pathology between these two very similar exposure protocols, retinal levels of proangiogenic vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) and anti-angiogenic pigment epithelium-derived factor (PEDF) were measured by ELISA and western blot analysis at 0, 2, and 6 days post-exposure. In whole retinal lysates, there were no significant differences in VEGFR2 and PEDF levels. However, VEGF levels were approximately 48 and 78% higher on post-oxygen exposure day 0 and 2, respectively, in the group treated with alternating periods of 45 and 12.5% oxygen compared to the group treated with alternating periods of 40 and 15% oxygen. There was no significant difference in VEGF levels between these two groups on day 6 post-exposure. Therefore, the difference in pathology observed between these two experimental paradigms is associated with differences in whole retinal VEGF levels, but not changes in whole retinal VEGFR2 or PEDF levels. The results of this study suggest the existence of a threshold in the rat model of OIR, such that a small change in blood oxygen profile triggers a disproportionate increase in subsequent neovascularization, which is accompanied by more dramatic changes of retinal VEGF level than VEGFR2 or PEDF level. If a similar threshold exists for humans, it could explain why some oxygen-treated premature infants develop retinopathy and others do not, despite similar gestational ages, birth weights and clinical courses.

Animals↗

PubMed1997

Compartmental model of vertebrate motoneurons for Ca2+-dependent spiking and plateau potentials under pharmacological treatment.

In contrast to the limited response properties observed under normal experimental conditions, spinal motoneurons generate complex firing patterns, such as Ca2+-dependent regenerative spiking and plateaus, in the presence of certain neurotransmitters and ion-channel blockers. We have developed a quantitative motoneuron model, based on turtle motoneuron data, toinvestigate the roles of specific ionic currents and the effects of their soma and dendritic distribution in generating these complex firing patterns. In addition, the model is used to explore the effects of multiple ion channel blockers and neurotransmitters that are known to modulate motoneuron firing patterns. To represent the distribution of ionic currents across the soma and dendrites, the model contains two compartments. The soma compartment, representing the soma and proximal dendrites, contains Hodgkin-Huxley-like sodium (INa) and delayed rectifier K+ (IK-dr) currents, an N-like Ca2+ current (ICa-N), and a calcium-dependent K+ current [IK(Ca)]. The dendritic compartment, representing the lumped distal dendrites, contains, in addition to ICa-N and IK(Ca) as in the soma, a persistent L-like calcium current (ICa-L). We determined kinetic parameters for INa, IK-dr, ICa-N, and IK(Ca) in order to reproduce normal action-potential firing observed in turtle spinal motoneurons, including fast and slow afterhyperpolarizations (AHPs) and a linear steady-state frequency-current relation. With this parameter set as default, a sequence of pharmacological manipulations were systematically simulated. A small reduction of IK-dr [mimicking the experimental effect of tetraethylammonium (TEA) in low concentration] enhanced the slow AHP and caused calcium spiking (mediated by ICa-N) when INa was blocked. Firing patterns observed experimentally in high TEA [and tetrodotoxin (TTX)], namely calcium spikes riding on a calcium plateau, were reproduced only when both IK-dr and IK(Ca) were reduced. Dendritic plateau potentials, mediated by ICa-L, were reliably unmasked when IK(Ca) was reduced, mimicking the experimental effect of the bee venom apamin. The effect of 5-HT, which experimentally induces the ability to generate calcium-dependent plateau potentials but not calcium spiking, was reproduced in the model by reducing IK(Ca) alone. The plateau threshold current level, however, was reduced substantially if a simultaneous increase in ICa-L was simulated, suggesting that serotonin (5-HT) induces plateau potentials by regulating more than one conductance. The onset of the plateau potential showed significant delays in response to near-threshold, depolarizing current steps. In addition, the delay times were sensitive to the current step amplitude. The delay and its sensitivity were explained by examining the model's behavior near the threshold for plateau onset. This modeling study thus accurately accounts for the basic firing behavior of vertebrate motoneurons as well as a range of complex firing patterns invoked by ion-channel blockers and 5-HT. In addition, our computational results support the hypothesis that the electroresponsiveness of motoneurons depends on a nonuniform distribution of ionic conductances, and they predict modulatory effects of 5-HT and properties of plateau activation that have yet to be tested experimentally.

Action Potentials↗