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PubMed2000

Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer.

BACKGROUND AND PURPOSE: This paper investigates the outcome using different dose/fractionation schedules in high dose rate (HDR) post-operative vaginal vault radiotherapy in patients with low to intermediate risk endometrial cancer. MATERIALS AND METHODS: The world literature was reviewed and thirteen series were analyzed representing 1800 cases. RESULTS: A total of 12 vaginal vault recurrences were identified representing an overall vaginal control rate of 99.3%. A wide range of dose fractionation schedules and techniques have been reported. In order to analyze a dose response relationship for tumor control and complications, the biologically effective doses to the tumor and late responding tissues were calculated using the linear quadratic model. A threshold was identified for complications, but not vaginal control. While dose fractionation schedules that delivered a biologically effective dose to the late responding tissues in excess of 100 Gy(3) (LQED=60 Gy) predicted for late complications, dose fractionation schedules that delivered a modest dose to the vaginal surface (50 Gy(10) or LQED=30 Gy) appeared tumoricidal with vaginal control rates of at least 98%. CONCLUSIONS: By using convenient, modest dose fractionation schedules, HDR vaginal vault - brachytherapy yields very high local control and extremely low morbidity rates.

Brachytherapy↗

PubMed2006

Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised, and correlate with the number of CGG repeats.

BACKGROUND: Grey zone or intermediate alleles are one of the three recognised classes of the X-linked fragile X mental retardation 1 (FMR1) gene showing intergenerational instability. These classes are defined according to the number of CGG repeats in the FMR1 5'-untranslated region. Although large CGG expansions (>200 repeats) cause a neurodevelopmental anomaly through silencing of the gene, resulting in a deficit of FMR1 specific protein, smaller expansions (approximately 55-200 repeats) are associated with an increased transcription and late-onset specific phenotypes. Those alleles with a CGG repeat number ranging between approximately 41 and 55 are relatively poorly defined with regard to both transcriptional and translational activity, and also potential phenotypic effects. METHODS AND RESULTS: Based on a sample of 33 males carrying FMR1 alleles within the grey zone range, defined here as 41-60 CGGs, we show an increased transcriptional activity relative to that seen in common alleles (5-40 CGGS). This is the first study to report a significant relationship between FMR1 mRNA levels and CGG repeat number within the grey zone range (p<0.001). From a piecewise linear regression model, the threshold for onset of the increase in mRNA levels as a function of CGG repeat size has been determined at approximately 39 repeats (standard error (SE) 3.24), and that for the reduction in the rate of this increase at approximately 54 repeats (SE 4.27). CONCLUSIONS: The ambiguities associated with the definition and transcription dynamics of the FMR1 gene within the grey zone range are dealt with. There may be specific phenotypes associated with the toxic "gain-of-function" effect of raised mRNA.

5' Untranslated Regions↗

PubMed1992

The effect of hyperfractionation on spinal cord response to radiation.

The T10-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily or a hyperfractionated regimen of 1.2 Gy twice daily separated by 8 hr. After a fractionated dose of 24-60 Gy given by either regimen, a top-up dose of 15 Gy was given. Hind limb strength was then measured weekly for 15 months. The time to onset of paralysis was inversely associated with the total dose. Overall, the spinal cord was not spared by hyperfractionation to the extent predicted by the modified Ellis power law or the linear-quadratic model. The threshold dose for the development of paralysis was higher in the hyperfractionated than in the conventionally fractionated group. However, the latent period for paralysis and the dose producing hind limb paralysis in 50% of the mice (ED50) were not significantly different between the two regimens. The continuation of the process of sublethal damage (SLD) repair in the spinal cord beyond 8 hr after irradiation may have influenced these results. The slow component of SLD repair should be considered in the design of hyperfractionated or accelerated radiation therapy schedules for clinical use.

Animals↗

PubMed2004

Frequency bandwidth limitation of external pulse electric field in microchannels. Applications to analyte velocity modulation detections.

Pulse field driven electro-separations have been used for different analytical advantages, such as signal quality improvement and separation performance improvement. We have studied the temporal electro-osmosis in microchannels due to viscous diffusivity under the external pulse electric fields. Theoretical studies derived from Navier-Stokes equations conclude the dependence of the time to steady state electro-osmosis on the channel sizes. Pulse field frequency should be limited by the electro-osmosis setting-in time. We also observed the unstable electro-osmosis as the external field frequency increases. As channel geometry characterization results are employed in the mathematical models, the threshold frequencies obtained in experimental data are consistent with the computational predictions. In previous studies, effective signal quality improvement of electro-separations has been demonstrated, when external pulse fields modulate analyte velocities with synchronous lock-in detection. The results indicate signal-to-noise ratio improvement would be more significant at the high frequency regime where flicker noise is not dominant. Since bandwidth limitation due to fluid viscosity constrains the pulse frequency, optimum analyte velocity modulation is in need of further investigation. Under the bandwidth constrains, we have investigated the theoretical optimum modulation frequencies.

Computer Simulation↗

PubMed1998

Improved internal defibrillation success with shocks timed to the morphology electrogram.

BACKGROUND: A previous retrospective study by our group suggested that shocks timed to the upslope of the shocking lead electrogram improved defibrillation efficacy. The goal of this study was to prospectively determine whether defibrillation threshold could be reduced by use of an algorithm that timed shocks to the upslope of coarse ventricular fibrillation (test treatment) compared with shocks delivered asynchronously after 10 seconds of fibrillation (control treatment). METHODS AND RESULTS: Ten pigs were instrumented with a 3-lead system for internal defibrillation. Initial estimates of the energy required to achieve defibrillation E50 for both treatments were made by an up/down method. Subsequently, additional shocks at V50+/-10% and V50-20% were given for each treatment to obtain data points at higher and lower intensities. Probability-of-success curves were estimated for both treatments by the best-fit method. Energies required were significantly lower for the timed shocks than for the asynchronous shocks (P<0.00 1). E80 was reduced 15.5%, from 27.1+/-2.5 to 22.9+/-1.8 J (P<0.002). The width of the probability-of-success curve (E80-E20) for the test treatment was also significantly narrower than that for the control treatment (7.1+/-0.9 versus 10.8+/-1.7, P<0.01). Normalized curve width (E80-E20)/E50 was decreased from 51+/-5% of E50 for control shocks to 37+/-4% of E50 for synchronous shocks (P<0.02). CONCLUSIONS: In this model, defibrillation threshold is lower and more deterministic when shocks are timed to the upslope of the shocking lead electrogram. If a similar reduction is observed in humans, shock timing may lower defibrillation threshold and simplify programming of shock intensity.

Algorithms↗

PubMed1999

A mathematical model of the ecology of Lyme disease.

A mathematical model of enzootic Lyme-disease transmission in a natural focus is presented. This model is based on the life history of the vector tick Ixodes scapularis Say and the primary reservoir host Peromyscus leucopus. Using this model, the threshold condition for the disease to be able to invade a nonenzootic region is determined as a function of the various possible transmission chains operating throughout the year. These expressions show that the transmission chain in which ticks acquire the disease from mice in the fall and transmit it back to mice as nymphs in the spring is the most important chain (contributing approximately 87% of the elasticity of the threshold for the parameter choices examined). Equilibrium disease levels were examined under the assumption of a constant tick population; these levels were determined as a function of tick and mouse density, the vertical transmission rate, the infectivity of mice, and the survivorship parameters of the ticks and of the tick-host contact rates. Vertical transmission has a disproportionately large effect, since unfed infected larval ticks have two opportunities to feed on mice, rather than only one opportunity (as for a newly infected unfed nymph). Finally, a global sensitivity analysis based on Latin hypercube sampling is performed, in which is shown the importance of quantifying the natural history of infection in mice, and of elucidating the contribution of other hosts for I. scapularis than mice.

Animals↗

PubMed2006

Error thresholds in a mutation-selection model with Hopfield-type fitness.

The deterministic limit of a Hopfield-type mutation-selection model in the sequence space approach is investigated. Genotypes are identified with two-letter sequences. Mutation is modelled as a Markov process, fitness functions are of Hopfield type, where the fitness of a sequence is determined by the Hamming distances to a number of predefined patterns. Using a maximum principle for the population mean fitness in equilibrium, the error threshold phenomenon is studied for quadratic Hopfield-type fitness functions with small numbers of patterns. Different from previous investigations of the Hopfield model, the system shows error threshold behaviour not for all fitness functions, but only for certain parameter values.

Algorithms↗

PubMed2004

Unconscious perception: the need for a paradigm shift.

According to Snodgrass, Bernat, and Shevrin (2004), unconscious perception can be demonstrated convincingly only at the objective detection threshold, provided that the conditions of their objective detection/strategic model are met, whereas both the subjective threshold model of Cheesman and Merikle (1984, 1986) and the objective threshold/rapid decay model of Greenwald, Draine, and Abrams (1996) are inconclusive. We argue on theoretical, metatheoretical, and empirical grounds that all three dual-process models, which are based on both conscious and unconscious perception, should be rejected in favor of the single-process conscious perception model.

Humans↗

PubMed1993

Point-neuron model for binaural interaction in MSO.

A point-neuron model for the activity of individual cells in the medial superior olive (MSO) is described and shown to generate discharge patterns consistent with the activity of real neurons as reported in response to low-frequency sinusoidal stimulation. Inputs to the model cell are specified as primarylike firing patterns, and the cell membrane characteristics are specified in terms of constant-potential sources and time-varying conductances. Some conductances are determined in response to the input firings and some in response to output firing times, which are generated when the membrane potential of the model cell crosses threshold. Output firing patterns generated by the model cells are consistent with those reported from neurons in dog and cat MSO. These patterns are also compatible with those of the functionally specified coincidence model described in Colburn et al. (1990). Given these observations, the following questions are addressed: What parameter values in the point-neuron model are required to generate output patterns like those observed? How do these values compare to those expected or estimated from intracellular measurements in brainstem neurons? How might one reconcile the fact that inhibitory inputs are not necessary in the model for the generation of the observed firing patterns with the fact that MSO cells receive numerous inhibitory inputs?

Acoustic Stimulation↗

PubMed1997

Limitations to the robustness of binormal ROC curves: effects of model misspecification and location of decision thresholds on bias, precision, size and power.

This paper concerns robustness of the binormal assumption for inferences that pertain to the area under an ROC curve. I applied the binormal model to rating method data sets sampled from bilogistic curves and observed small biases in area estimates. Bias increased as the range of decision thresholds decreased. The variance of area estimates also increased as the range of decision thresholds decreased. Together, minor bias and inflated variance substantially altered the size and power of statistical tests that compared areas under bilogistic ROC curves. I repeated the simulations by applying the binormal assumption to data sampled from binormal curves. Biases in area estimates were minimal for the binormal data, but the variance of area estimates was again higher when the range of decision thresholds was narrow. The size of tests that compared areas did not vary from the chosen significance level. Power fell, however, when the variance of area estimates was inflated. I conclude that inferences derived from the binormal assumption are sensitive to model misspecification and to the location of decision thresholds. A narrow span of decision thresholds increases the variability of area estimates and reduces the power of area comparisons. Model misspecification produces bias that alters test size and can exaggerate the loss of power that accompanies increased variability.

Bias↗

PubMed1991

Contrast overconstancy.

In foveal vision there is a tendency toward contrast constancy above threshold. Contrast sensitivity varies greatly across different spatial and temporal frequencies and at different luminances, but perception of contrast above threshold varies much less (in logarithmic terms). In parafoveal vision (1-2 degrees eccentricity) the contrast of high-spatial-frequency gratings appeared higher than a 3-cycle per degree (c/deg) comparison grating, even though their threshold sensitivity was lower. I call this overconstancy. For two experienced observers, the effect was greatest at high spatial frequencies (12-18 c/deg) and at contrasts close to threshold. A simple model of contrast coding was able to fit all the data accurately: R' = [(C-T)/(Cnorm-T)]m, where R' is the final response, C is contrast, T is threshold contrast, and Cnorm and m are parameters. Cnorm represents the contrast at which different response functions converge to a common value (R' = 1), while m is the slope of the upper branch of a given function on logarithmic axes. This model, incorporating threshold subtraction, nonlinear compression, and response normalization, was derived from research on contrast matching, magnitude estimation, and discrimination. On this model overconstancy results when C less than Cnorm, and the contrast response for the test condition is more compressive (lower m) than in the comparison condition. In the parafovea m decreased linearly with increasing spatial frequency for both subjects, but Cnorm was approximately constant at 40-50%.

Contrast Sensitivity↗

PubMed2000

Stochastic resonance in a statistical model of a time-integrating detector.

We study an optimal nonparametric regression model for a threshold detector exposed to a noisy, subthreshold signal. The problem of recovering the signal is similar to that faced by neurons in nervous systems, although our model is intended to be normative rather than realistic. In our approach, the time-integrating activity of the neuron is modeled by kernel regression. Several aspects of the performance of the model are studied, including the existence of an optimal amount of noise (stochastic resonance). We construct a sequential, data-driven procedure for estimating the subthreshold signal. The performance of our model for threshold data is compared with kernel estimation for fully observed data. Finally, we discuss differences between our estimator and the best estimator for a constant signal.

Animals↗

PubMedDate not supplied

Risk assessment and risk management implications of hormesis.

International and US radiation protection standards are based upon risk assessment and risk management processes. The assessment of radiation risk is derived from the linear no-threshold (LNT) model. Risk management is based on more subjective value judgements. If the radiation dose-response was found to be hormetic, considerable quantitative data would be needed before current radiation protection standards would change. There would be added complexity, and consideration might have to be given to the additive effects of an individual's exposures to medical radiation and other potential carcinogens.

Adaptation, Physiological↗

PubMed1984

Genetic analysis of cleft lip with or without cleft palate in Danish kindreds.

The present study population consists of 2,532 families ascertained through non-syndromic cleft lip with or without cleft palate (CL +/- P) surgical probands born in Denmark between 1941 and 1971. Three samples were derived for analyses of the trait "clefted (CL +/- P) or not." Sample 1 consists of the 26 largest multigenerational families with four or more affected members. Both samples 2-MG and 2-N consist of nuclear families with at least two children and at least one proband among the children. Sample 2-MG contains 846 nuclear families derived from the kindreds with three or more generations. Sample 2-N contains a further 1,181 kindreds with only two generations, nuclear family information available. Four methods of analysis were used: 1) Pedigree analysis was performed on each of the multigenerational kindreds of Sample 1. Results were consistent with autosomal recessive inheritance in eight families and codominant inheritance in three families. These simple genetic hypotheses could not be distinguished in the remaining 15 families. 2) The goodness-of-fit of the multifactorial threshold (MF/T) model was tested in Samples 2-MG and 2-N. The MF/T model was rejected in both samples. 3) Classical segregation analysis was performed on Samples 2-MG and 2-N. Results were consistent with a possible recessive major gene for CL +/- P in Sample 2-MG, but not in Sample 2-N, and with significant admixture of sporadic cases in both samples. 4) Complex segregation analysis under the mixed model was performed on Samples 2-MG and 2-N. In Sample 2-MG, results were consistent with either the general mixed model or with an hypothesis of no major gene. In Sample 2-N, four hypotheses were equally likely: the mixed model with no polygenic component, the mixed model with the major gene component, the mixed model with no sib environmental correlation, and major gene alone. Three conclusions may be drawn: 1) The data provide no support for the MF/T model. 2) The data are consistent with the possibility of a major gene in a portion of the kindreds. 3) The data provide evidence for genetic heterogeneity for CL +/- P.

Child↗

PubMed1992

Genetic analysis of cleft lip with or without cleft palate in Madras, India.

We performed a genetic analysis of 331 non-syndromic cleft lip with or without cleft palate (CL +/- P) proband families ascertained in Madras, India. Predictions of the multifactorial threshold (MF/T) model are tested; goodness-of-fit tests of the MF/T model and complex segregation analysis are also utilized to clarify the genetic etiology of CL +/- P in this study population. There was little evidence for the MF/T model. The most reasonable conclusion from mixed model analysis is that of a major locus with reduced transmission probability. This is not altogether surprising if manifestation of CL +/- P also depends on in utero exposure to harmful environmental agents during the critical period of facial development, as suggested by Melnick et al. [1980] and demonstrated in an animal model of CL +/- P [Melnick et al., 1981]. Further the results in the Madras population are quite similar to those in other populations of Europe and Asia.

Cleft Lip↗

PubMed2006

Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure.

Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect.

Algorithms↗

PubMed1985

Characterization of tumor progression from threshold tumor inocula: evidence for natural resistance.

An examination of the variant generation and selection hypothesis of tumor progression was undertaken using the NK-sensitive, NAb-sensitive SL2-5 lymphoma in the threshold inoculum model of tumor progression. Tumor cells obtained from the i.p. injection site expressed increased heterogeneity for sensitivity to syngeneic NAb and to NR measured in the 131IUdR-labelled tumor elimination assay. Cells retrieved from the s.c. injection site exhibited reductions in sensitivity to NR which correlated with decreases in sensitivity to syngeneic NAb and NK cells in vitro. These data confirm and extend our previous observations with the NK-resistant L5178Y-F9 lymphoma and further substantiate the evidence for the participation of NAb and NK cells in host-mediated anti-tumor resistance. Characterization of the model revealed that the selection for reduced sensitivity to NR in thymus-depleted AT x BM mice and normal animals could not be distinguished, suggesting that thymus-independent mechanisms may be major contributors to the surveillance of nascent tumors. The decreases in susceptibility to NR occurred in a stepwise and time-dependent manner in accord with the sequential multistage concept of progression. Furthermore, the selection for tumor cells which exhibited reductions in sensitivity to NR correlated with selection for increased tumorigenicity, in keeping with the idea that progression is associated with development towards an increasingly autonomous tumor.

Animals↗

PubMed1998

Predicting temporal fluctuations in an intracellular signalling pathway.

We used a newly developed stochastic-based program to predict the fluctuations in numbers of molecules in a chemotactic signalling pathway of coliform bacteria. Specifically, we examined temporal changes in molecules of CheYp, a cytoplasmic protein known to influence the direction of rotation of the flagellar motor. Signalling molecules in the vicinity of a flagellar motor were represented as individual software objects interacting according to probabilities derived from experimentally-observed concentrations rate constants. The simulated CheYp molecules were found to undergo random fluctuations in number about an average corresponding to the deterministically calculated concentration. Both the relative amplitude of the fluctuations, as a proportion of the total number of molecules, and their average duration, increased as the simulated volume was reduced. In a simulation corresponding to 10% of the volume of a bacterium, the average duration of fluctuations was found to be 80.7 ms, which is much shorter than the observed alternations between clockwise and counter clockwise rotations of tethered bacteria (typically 2.6 s). Our results are therefore not in agreement with a simple threshold-crossing model for motor switching. However, it is possible to filter the CheYp fluctuations to produce temporal distributions closer to the observed swimming behaviour and we discuss the possible implications for the control of motor rotation.

Escherichia coli↗