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PubMed2002

Applications of hormesis in toxicology, risk assessment and chemotherapeutics.

There is much debate over the fundamental shape of the dose-response curve in the low-dose zone, particularly in the fields of toxicology and risk assessment. The defaults, principally accepted dose-response models in the major texts in these areas and in government regulatory activities, are a threshold model for non-carcinogens and a linear model for most carcinogens. We have argued that in properly designed studies the U-shaped hormetic response predominates and is more fundamental. In this article, a broad range of basic issues associated with the acceptance of U-shaped dose responses as central to toxicology, pharmacology and their applications to risk assessment and medicine will be discussed.

Animals↗

PubMed2003

Reconciling HIV incidence results from two assays employed in the serological testing algorithm for recent HIV seroconversion (STARHS).

The Abbott HIVAB and Vironostika HIV-1 Microelisa assays have both been validated for use in the serological testing algorithm for recent HIV seroconversion (STARHS). This ability to identify recently-acquired infection provides valuable insight into the epidemic. The availability of each assay during different periods led to longitudinal studies of annual HIV incidence being based on a mixture of results from each. We investigated whether results from both assays could be reconciled. Using statistical methods, the correlation of the two assays' results and other performance characteristics were examined. Of 378 anti-HIV-1 positive specimens examined by both assays, the Abbott assay flagged 40 as from recent infections, whereas Vironostika flagged 50. The correlation coefficient between screening reactivities in each assay was 0.84, and 0.77 in confirmatory mode. Abbott screening results were significantly higher than its confirmatory results, and some specimens from recent infections may consequently have gone undetected by that assay. This problem was not found with the Vironostika assay. Observational data indicated that the estimated HIV incidence derived from HIVAB results increased as the assay threshold, with its pre-defined seroconversion window, was increased. For Vironostika, the estimated HIV incidence remained stable over a wide range of thresholds. Modelling of the observed relationship between the two assays allowed an estimate of the equivalent threshold in the alternative assay, thus providing a means of reconciling results. Our findings suggest that the Vironostika assay is more reliable than the HIVAB, is easier to use, and is able to allow processing of more specimens per run.

Algorithms↗

PubMed1982

Osmotic control of plasma vasopressin in the dog.

Seven dogs prepared with carotid loops were used to evaluate the responsiveness of the cerebral osmoreceptors regulating plasma vasopressin concentration (pAVP). Intracarotid and intravenous infusions of hypo- and hypertonic solutions were used to alter cerebral plasma osmolality. Bilateral intracarotid infusion of hypertonic saline (0.90 mmol NaCl kg-1 . min-1 . artery-1) significantly elevated jugular vein plasma osmolality (pOsm) in the first minute (P less than 0.05). Systemic values, determined from saphenous vein samples, were increased after 6 min. After 4 min of infusion, systemic pAVP was significantly increased, attaining a constant level at 6 min. Subsequent experiments with infusions 6 min in duration demonstrated that hypertonic saline infused intracarotidly significantly increased pAVP in a dose-related fashion, whereas similar solutions administered intravenously did not alter pAVP. Hypotonic infusions (intravenous or intracarotid) did not change pAVP consistently. The lack of a depression in pAVP during hypotonic infusions is consistent with the argument that jugular pOsm must be elevated above a threshold to stimulate the release of vasopressin. Linear relationships were demonstrated for jugular pNa+ and pOsm to pAVP employing the threshold model. Cerebral osmoreceptors that regulate plasma vasopressin concentration respond linearly to increasing tonicity above a threshold stimulating the release of vasopressin.

Animals↗

PubMed1992

Palatine and mandibular tori. A morphologic study in the current Norwegian population.

Five thousand Norwegians, 2783 females and 2217 males, ranging in age from 16 to 89 years, have been screened for the presence of torus palatinus and/or torus mandibularis and analyzed with regard to size and shape of tori, sex, and age. The tori have been classified according to size as small, medium, and large. No measurements have been made, consistent with the view that these characteristics are non-metrical and should be assessed by means of a standard procedure. The prevalence figures of both tori were fairly low, in accordance with former reports. In torus palatinus there was female predominance, with a sex ratio of 5:3. In torus mandibularis the males were in majority, and the sex proportion was 4:3. In both sexes prevalence of the two tori was highest in the 35- to 65-year age group. Further analysis indicated in both tori a real correlation between prevalence and size and some correlation also between size and shape of torus palatinus but not of torus mandibularis. The figures of concurrence of the two tori were low, denoting a non-significant correlation. Still, the analysis showed that each torus occurred more than twice as frequently in an individual bearing the other torus. Torus morphoanalysis, explaining diverging patterns of clinical conduct in the two tori, and the relative weight of hereditary versus environmental factors as morphogenetic determinants of the condition, including a quasi-continuous genetic or threshold model, have contributed to shed new light on the torus phenomenon. The occurrence and propagation of torus mandibularis complies reasonably well with this model, and the present analysis indicates that even torus palatinus should appropriately be considered a threshold character.

Adolescent↗

PubMed1995

Migraine and concomitant symptoms among 8167 adult twin pairs.

We studied the inheritance of migraine and concomitant symptoms among 2690 monozygotic (1524 female and 1166 male) pairs and 5497 dizygotic (2951 female and 2546 male) twin pairs. Our material consists of a population-based questionnaire study among Finnish twins in 1981. The definition of migraine is based on a questionnaire method. Concordance was assessed using probandwise concordance rates and tetrachoric correlations for monozygotic (MZ) and dizygotic (DZ) twin pairs. For estimating the contribution of genetic factors to the susceptibility of migraine, a polygenic multifactorial model was used. Structural equation models were applied for estimating variance components and to compare different genetic models. Nearly one-half (40% to 50%) of the liability to migraine is attributable to genetic factors. In all structural analyses, the model with both additive genetic and unshared environmental component had the best goodness-of-fit value. The genetic component varied between 34% to 51% in different migraine types. There were no remarkable differences between sexes except in the effects due to dominance, where the proportion was 26% for men and 14% for women. Concomitant symptoms among subjects within pairs concordant for headache had genetic effects varying from 56% (subjects with unilaterality) and 56% (subjects with visual symptoms) to 45% (persons with nausea and vomiting). The two threshold model of headache points to the continuum model of headache, and the thresholds represent different levels of severity of the pain. Our results emphasize a multifactorial and higher than previously reported genetic pattern in the etiology of migraine. Also unshared environmental factors play an important role.

Diseases in Twins↗

PubMed2005

The relationship between the Rating Scale and Partial Credit Models and the implication of disordered thresholds of the Rasch models for polytomous responses.

There is a perception in the literature that the Rating Scale Model (RSM) and Partial Credit Model (PCM) are two different types of Rasch models. This paper clarifies the relationship between the RSM and PCM from the perspectives of literature history and mathematical logic. It is shown that not only are the RSM and the PCM identical, but the two approaches used to introduce them are statistically equivalent. Then the implication of disordered thresholds is discussed. In addition, the difference between the structural thresholds and the Thurstone thresholds are clarified.

Data Interpretation, Statistical↗

PubMed2006

Analysis of litter size and days to lambing in the Ripollesa ewe. I. Comparison of models with linear and threshold approaches.

The analysis focused on model fitting of 2 ewe reproductive traits, litter size, and days to lambing (interval between the introduction of the ram into the flock and the subsequent parturition of the ewes). The experimental data set of the Universitat Autònoma of Barcelona flock was used, including 1,598 records of litter size and 1,699 records of days to lambing from 376 Ripollesa ewes between 1986 and 2005. Univariate and bivariate models were considered as beginning points with linear or threshold approximation for litter size. Model fitting was evaluated in terms of goodness-of-fit and predictive ability, using the mean square error and the correlation between phenotypic and predicted records (rho(y,ŷ)) as reference parameters. The bivariate model was preferable for both variables, minimizing mean square error and maximizing rho(y,ŷ). A threshold approximation for litter size was preferable over a linear approximation. Models were also compared with a simulation study, comparing the correlation coefficient between simulated and predicted breeding values (rho(a,â)). The bivariate threshold model was favored, with a rho(y,ŷ) of 0.677 and 0.834 for litter size and days to lambing, respectively. Correlation coefficients between simulated and predicted breeding values in the bivariate linear model were reduced slightly to 0.651 and 0.831, respectively, and they were lowest with linear univariate models (0.642 and 0.802). Although the bivariate models for ewe litter size and days to lambing were more accurate than the univariate models, the threshold approaches showed a greater advantage under the bivariate model. For the purpose of genetic evaluation of litter size in sheep, use of the threshold-linear model seems justified. In the Ripollesa breed, the evaluation of litter size can benefit from recording birth weight.

Animals↗

PubMed1997

Analysis of two-locus traits under heterogeneity for recessive versus dominant inheritance.

Complex traits have been modeled under various modes of two-locus inheritance. One example of a two-locus threshold model is the situation where an individual is susceptible to a disease trait if he or she carries three or more disease alleles. Under this model, if each locus is examined individually the inheritance appears recessive for some mating types and dominant for others. We developed a heterogeneity test, the Model-heterogeneity test, where an admixture of dominant and recessive sibships can be present. The properties of the Model-heterogeneity test were examined and compared to the Admixture test. The power of the Model-heterogeneity test to detect linkage is comparable to that of the Admixture test.

Chromosome Mapping↗

PubMedDate not supplied

Receptors, sparks and waves in a fire-diffuse-fire framework for calcium release.

Calcium ions are an important second messenger in living cells. Indeed calcium signals in the form of waves have been the subject of much recent experimental interest. It is now well established that these waves are composed of elementary stochastic release events (calcium puffs or sparks) from spatially localised calcium stores. The aim of this paper is to analyse how the stochastic nature of individual receptors within these stores combines to create stochastic behaviour on long time-scales that may ultimately lead to waves of activity in a spatially extended cell model. Techniques from asymptotic analysis and stochastic phase-plane analysis are used to show that a large cluster of receptor channels leads to a release probability with a sigmoidal dependence on calcium density. This release probability is incorporated into a computationally inexpensive model of calcium release based upon a stochastic generalisation of the fire-diffuse-fire (FDF) threshold model. Numerical simulations of the model in one and two dimensions (with stores arranged on both regular and disordered lattices) illustrate that stochastic calcium release leads to the spontaneous production of calcium sparks that may merge to form saltatory waves. Illustrations of spreading circular waves, spirals and more irregular waves are presented. Furthermore, receptor noise is shown to generate a form of array enhanced coherence resonance whereby all calcium stores release periodically and simultaneously.

Animals↗

PubMed1989

Syndromology: an updated conceptual overview. VI. Molecular and biochemical aspects of dysmorphology.

The role of chance using a stochastic single gene model has been shown to generate a continuous liability curve resembling that obtained from a multifactorial threshold model. Segregation of some malformations may be explained by a single defective gene that predisposes to, but does not necessarily result in, the malformation. Low penetrance and remarkably variable expressivity that characterize a number of presumed autosomal dominant malformation syndromes are possibly reflections of specific stochastic influences that are intrinsic to the embryonic process itself. Gene analysis is discussed and illustrated. Using polymorphic DNA probes to study cleft palate and ankyloglossia in males and ankyloglossia only in females in a large Icelandic family, the responsible gene was found to be located on the long arm of the X chromosome in the Xq21.1 region. In addition to gene analysis, some of the implications of transgenic analysis using mice are discussed. Among disorders of collagen metabolism, both the osteogenesis imperfectas and the Ehlers-Danlos syndromes are shown to represent genetically heterogeneous groups of connective tissue disorders. The days of thinking about osteogenesis imperfecta as one disorder and the Ehlers-Danlos syndrome as another are a thing of the past; persistence of such thinking is erroneous and misleading. Of the many disorders affecting bone mineral, the complexities of hypophosphatasia and pseudohypoparathyroidism are singled out for discussion. For lysosomal storage disorders, an overview of the mucopolysaccharidoses is provided. Finally, the recently delineated peroxisomal disorders--hyperpipecolic acidemia, rhizomelic chondrodysplasia, neonatal adrenoleukodystrophy, Zellweger syndrome, and infantile Refsum disease--are known to share a distinctive biochemical phenotype, although fibroblast complementation analysis suggests that some of these disorders are etiologically distinct.

Adolescent↗

PubMed2000

Forest-fire models as a bridge between different paradigms in self-organized criticality

We turn the stochastic critical forest-fire model introduced by Drossel and Schwabl [Phys. Rev. Lett. 69, 1629 (1992)] into a completely deterministic threshold model. This model has many features in common with sandpile and earthquake models of self-organized criticality. Our deterministic forest-fire model exhibits in detail the same macroscopic statistical properties as the original Drossel-Schwabl model. We use the deterministic model to elaborate on the relation between forest-fire, sandpile, and earthquake models.

Journal Article↗

PubMed1981

Age-of-onset and genetic transmission in affective disorders.

Age-of-onset data were gathered on first-degree relatives of 252 probands with bipolar and unipolar affective disorders. Early onset probands (younger than 40 at onset) had more early onset relatives and a greater risk for affective disorder among their relatives than late onset probands (40 or older). This indicates that age-of-onset is a familial factor correlated with the liability to affective illness. Multiple threshold models of inheritance were applied to the data using age-of-onset as a liability-threshold determinant. The hypothesis of autosomal single-major locus was ruled out. Multifactorial-polygenic inheritance provided a better fit to the data. The data suggest that early and late onset affective disorders can be placed at different thresholds on a genetic environmental continuum and that the early onset form is more deviant genetically than the late onset type. The implications for genetic research in affective disorder are discussed.

Affective Disorders, Psychotic↗

PubMed2001

Satiety threshold during maintained cocaine self-administration in outbred mice.

Male Swiss Webster mice maintained cocaine self-administration in a regular and dose-dependent manner. These characteristics made it possible to apply the satiety threshold model of drug self-administration developed recently for cocaine self-administration in rats. Non-linear regression analysis revealed that cocaine satiety threshold was 1.3 +/- 0.6 mg/kg and the functional half-life of the cocaine was 8.1 +/- 2.2 min. Whether the self-administration of cocaine was maintained by lever presses or nose pokes did not influence the inter-injection intervals. The results are consistent with the pharmacological model of maintained cocaine self-administration. The ability to determine addiction-relevant phenotypes (the satiety threshold and functional half-life of cocaine) in inbred strains of mice may help to identify the genetic determinants of cocaine self-administration behavior.

Animals↗

PubMed1998

Interpretation of distortion product otoacoustic emission measurements. II. Estimating tuning characteristics using three stimulus tones.

The simple model introduced in Part I [J. Acoust. Soc. Am. 102, 413-429 (1997)] is used to simulate the response of the cochlea to three stimulus tones. The focus is on "emission suppression tuning curves" constructed using a third tone to suppress the cubic distortion tone emission (CDT, 2f1-f2) generated by two primary tones at frequencies f1 and f2 (intensities L1 and L2). A criterion decrease (here, 5 dB) of the CDT emission amplitude defines the 2f1-f2 emission suppression tuning curve. Applying traditional tuning curve measures to emission suppression tuning curves appears ineffective in determining the underlying cochlear amplifier characteristics. However, it is shown that there are three characteristics of emission suppression tuning curves which are particularly useful: (1) the "f2 threshold" which is the level of the third tone, L3, required for the criterion CDT amplitude decrease, under the condition that the third tone frequency, f3, is approximately equal to f2; (2) the "shoulder threshold" similarly defined for f3 << f2; and (3) the "tuning width," w40. The tuning width is defined to be the distance (in octaves) from the frequency f2 to the upper f3 frequency for which there is a criterion CDT decrease, in this case using the L3 level which is 40 dB above the f2 threshold. Model calculations appropriate to gerbils show that these measures are most accurately related to the underlying cochlear amplifier characteristics for parameters where the primary stimulus amplitudes satisfy L1/L2 > 20 dB and for which L1 is 25 dB or more below the sharp "notch" seen in the two tone input-output function. In this parameter region, the cochlear amplifier characteristics are related to measured quantities by the relationships wr approximately equal to w40 and Ga approximately equal to TE + w40gp. Here, Ga is the gain (dB) of the cochlear amplifier, defined as the total increase in cochlear response over the passive response, wr is the distance (octaves) over which the active cochlear response rises to a maximum, and gp is the passive increase (dB/octave) of the traveling wave along the basilar membrane. The measured quantities are TE, the difference (dB) between the shoulder threshold and the f2 threshold, and the tuning width, w40 (octaves), defined above. Model predictions are confirmed by measurements in adult gerbils.

Acoustic Stimulation↗

PubMed1987

Delusional depression: further evidence for genetic contribution.

To quantify the contribution of genetic factors in the pathogenesis of delusional depression, the incidence of major depression in the first degree relatives of 77 delusional, 76 nondelusional depressive patients, and 153 age- and sex-matched controls was calculated in a case-control study. The morbid risk for psychiatric disorders, including major depression and bipolar I disorder, did not distinguish the two proband groups. The segregation analysis showed that the model of multifactorial inheritance fits best to our results. Heritability was estimated on the basis of a threshold model for multifactorial inheritance, and a high contribution of genetic factors for both subgroups was found.

Adult↗

PubMed1987

Mixed-model analysis of a censored normal distribution with reference to animal breeding.

A mixed-model procedure for analysis of censored data assuming a multivariate normal distribution is described. A Bayesian framework is adopted which allows for estimation of fixed effects and variance components and prediction of random effects when records are left-censored. The procedure can be extended to right- and two-tailed censoring. The model employed is a generalized linear model, and the estimation equations resemble those arising in analysis of multivariate normal or categorical data with threshold models. Estimates of variance components are obtained using expressions similar to those employed in the EM algorithm for restricted maximum likelihood (REML) estimation under normality.

Analysis of Variance↗

PubMed1998

[Comparison of the multifactorial model as a hereditary mechanism of non-myoclonic generalized idiopathic epilepsy and partial idiopathic epilepsy].

OBJECTIVE AND METHODS: An experimental study about the predictions from the multifactorial threshold model created by Falconer is presented, assuming that this model may explain the genetic mechanisms underlying the family aggregation of idiopathic epilepsies. RESULTS: We failed to confirm the following predictions from the falconer model: decreased prevalence of disease in relatives, proportional to decreased family links, and the order of birth effect. An heredity greater than 100% was calculated which is concordant with the presence of at least a locus with a major gen affect. CONCLUSION: Our results reject the multifactorial threshold effect and suggest the presence of a major gen or Mendelian effect. An analysis of complex segregation is suggested for future studies.

Adolescent↗

PubMed2004

The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats.

Rats that self-administered cocaine at unit doses between 0.75 and 12 micromol/kg with mean inter-injection intervals between approximately 2 and 18 min also reliably self-administered the cocaine analogue WIN 35,428 (beta-CFT; (-)-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester) at unit doses between 0.1 and 1.6 micromol/kg with mean intervals between 10 and 116 min. The long inter-injection intervals of WIN 35,428 necessitated sessions of more than 12 h. The inter-injection intervals were regular and proportional to the unit dose, consistent with the satiety threshold model. Analysis of the mean intervals as a function of unit doses generated values for the mean satiety threshold of cocaine and WIN 35,428 of 6.10 and 0.87 micromol/kg, respectively. The mean t(1/2) for cocaine and WIN 35,428 were 11.1 and 69.4 min, respectively. The approximately 43-fold lower rate of consumption of WIN 35,428 relative to cocaine was a product of the seven-fold greater pharmacodynamic potency and the six-fold greater pharmacokinetic potency.

Animals↗