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PubMed1984

Cortisone cure of the lidgap defect in fetal mice: a dose-response and time-response study.

Cortisone administered during pregnancy prevents the phenotypic expression of lidgap-Miller (lgM1), a genetically determined congenital defect in mice. The dose-response, on a probit log dose scale, is linear to a dose of 60 mg/kg maternal body weight, giving an observed maximum cure of 94% and an ED50(1) of 27 mg/kg. At higher doses the rate of prevention diminishes, to 56% at 320 mg/kg. Fetal (18-day) weight remains unaffected for doses of up to 60 mg/kg and then drops sharply at higher doses, suggesting that cortisone is toxic in this higher range. The severity of lidgap, measured in two ways (as one or both eyes open and as width of gap), decreases as its frequency falls. This finding is in keeping with the threshold model for birth defects. The threshold appears to be in the embryos rather than in their mothers. There is a broad optimum time of treatment: days 13-14 for the 80 mg/kg dose, and days 14-15 for the 30 mg/kg dose. Treatment on day 16 has little or no effect. It is not known how cortisone cures the lidgap trait. The action may be specific--to stimulate transcription of a specific gene, possibly of the lidgap locus itself--or more general, e.g., to alter cell division rate or extracellular matrix constituents.

Animals↗

PubMed1983

Dose-response models for the radiation-induction of skin tumours in mice.

Extensive data on radiation-induced skin tumours in mice were examined using 8 models, all based on the concept that incidences of radiation-induced tumours depend on a combination of two radiation effects: a tumour induction process and the loss of reproductive integrity by the potential tumour cells. Models with and without a threshold were used, in spite of theoretical objections to threshold models. No model fitted well both the epidermal and the dermal tumour data and models which proved to be statistically satisfactory for some of the data were rejected for biological reasons. It is concluded that, for skin tumours, dose-response curves depending on a combination of cancer induction and loss of cellular reproductive integrity are distorted by some special, relatively radio-resistant, factor which we have previously postulated as being involved in radiation skin carcinogenesis.

Animals↗

PubMed2006

Geobacter lovleyi sp. nov. strain SZ, a novel metal-reducing and tetrachloroethene-dechlorinating bacterium.

A bacterial isolate, designated strain SZ, was obtained from noncontaminated creek sediment microcosms based on its ability to derive energy from acetate oxidation coupled to tetrachloroethene (PCE)-to-cis-1,2-dichloroethene (cis-DCE) dechlorination (i.e., chlororespiration). Hydrogen and pyruvate served as alternate electron donors for strain SZ, and the range of electron acceptors included (reduced products are given in brackets) PCE and trichloroethene [cis-DCE], nitrate [ammonium], fumarate [succinate], Fe(III) [Fe(II)], malate [succinate], Mn(IV) [Mn(II)], U(VI) [U(IV)], and elemental sulfur [sulfide]. PCE and soluble Fe(III) (as ferric citrate) were reduced at rates of 56.5 and 164 nmol min(-1) mg of protein(-1), respectively, with acetate as the electron donor. Alternate electron acceptors, such as U(VI) and nitrate, did not inhibit PCE dechlorination and were consumed concomitantly. With PCE, Fe(III) (as ferric citrate), and nitrate as electron acceptors, H(2) was consumed to threshold concentrations of 0.08 +/- 0.03 nM, 0.16 +/- 0.07 nM, and 0.5 +/- 0.06 nM, respectively, and acetate was consumed to 3.0 +/- 2.1 nM, 1.2 +/- 0.5 nM, and 3.6 +/- 0.25 nM, respectively. Apparently, electron acceptor-specific acetate consumption threshold concentrations exist, suggesting that similar to the hydrogen threshold model, the measurement of acetate threshold concentrations offers an additional diagnostic tool to delineate terminal electron-accepting processes in anaerobic subsurface environments. Genetic and phenotypic analyses classify strain SZ as the type strain of the new species, Geobacter lovleyi sp. nov., with Geobacter (formerly Trichlorobacter) thiogenes as the closest relative. Furthermore, the analysis of 16S rRNA gene sequences recovered from PCE-dechlorinating consortia and chloroethene-contaminated subsurface environments suggests that Geobacter lovleyi belongs to a distinct, dechlorinating clade within the metal-reducing Geobacter group. Substrate versatility, consumption of electron donors to low threshold concentrations, and simultaneous reduction of electron acceptors suggest that strain SZ-type organisms have desirable characteristics for bioremediation applications.

Acetates↗

PubMed1982

Simultaneous visual detection and identification: theory and data.

A signal-detection model is presented for the two-alternative forced-choice procedure that gathers simultaneous detection and identification judgments. By using vector representation, a measure of independent processing within the visual system is derived. The independence measure is applied to data on the detection and identification of stimuli that differ along the dimensions of orientation, spatial frequency, and size. Data are presented that favor the signal-detection model over a high-threshold model.

Humans↗

PubMed1985

Visual processing of moving stimuli.

This review covers a period bracketed by two OSA Symposia--"Vision under Stabilized Image Conditions," held in San Francisco in 1978, and "Motion and Vision in Man and Machine," held in New Orleans in 1983--during which image stabilization came of age as a standard technique of visual psychophysics. It seems clear that the first spatiotemporal signal-processing step in the visual system depends on image motion; e.g., a constant velocity effectively provides the mathematical convolution of stimulus patterns with retinal receptive fields. Thus the motion of the stimulus pattern at the retina is an important experimental variable over which we have only recently gained full control. We can now replace the haphazard behavior of the subject's natural eye movements by simpler forms of motion that are known and controlled by the experimenter. Results obtained in our laboratory with such stabilized fixation control include threshold measurements for moving lines and gratings, comparison of contrast sensitivities with natural and artificial eye movements, effects of orientation on moving-grating thresholds, models of the stabilized spatiotemporal threshold surface, and effects of retinal inhomogeneity on selectivity for spatial frequency and velocity. Other experiments, too numerous to include here, have also used these techniques.

Eye Movements↗

PubMed1998

[Carcinogenesis: from epidemiology to molecular biology].

Carcinogenesis is a multi-step process and at least three stages can be distinguished: initiation, promotion and progression. Initiation is made up of events whereby an exogenous or endogenous carcinogen induces alterations in the genome of the cell; this results in a lesion that can be inherited and which confers upon that cell the potential for neoplastic growth. This is the result of activation of cellular proto-oncogenes into transforming oncogenes and/or the inactivation of the two alleles of tumor suppressor genes (anti-oncogenes). Although it is conceivable that a single event or a single lesion can initiate a cell it is probable that in most cases initiation is the consequence of a series of events since the different types of proto-oncogenes do not function independently of each other. The coordinated activation of more than one oncogene is generally required to confer the full potential for neoplastic growth. DNA repair and apoptosis play a critical role in carcinogenesis and the effectiveness of these mechanisms might be influenced by the dose and the time interval between individual events (dose rate). Epidemiological and experimental data show also the main role of cell proliferation after initiation. Proliferation influences the probability of DNA repair and contributes to further genomic alteration. Cell to cell interaction within a tissue participates in the control of cell proliferation and cell repair. The evolution of one initiated cell is not independent of the surrounding cells and disorganization of a tissue is a factor in carcinogenesis. Presently carcinogenesis appears to be a complex phenomenon which cannot be a adequately modelled. The linear no-threshold model has been used for the purpose of cancer prevention and legal norms, however it should be realized that its experimental and theoretical bases are debatable and that much recent data do not support them. Its predictions should therefore be considered with great caution. All efforts should be made in the future to build new models incorporating available epidemiological and fundamental data.

Carcinogens↗

PubMed1998

Ionizing radiation and genetic risks. VIII. The concept of mutation component and its use in risk estimation for multifactorial diseases.

Multifactorial diseases, which include the common congenital abnormalities (incidence: 6%) and chronic diseases with onset predominantly in adults (population prevalence: 65%), contribute substantially to human morbidity and mortality. Their transmission patterns do not conform to Mendelian expectations. The model most frequently used to explain their inheritance and to estimate risks to relatives is a Multifactorial Threshold Model (MTM) of disease liability. The MTM assumes that: (i) the disease is due to the joint action of a large number of genetic and environmental factors, each of which contributing a small amount of liability, (ii) the distribution of liability in the population is Gaussian and (iii) individuals whose liability exceeds a certain threshold value are affected by the disease. For most of these diseases, the number of genes involved or the environmental factors are not fully known. In the context of radiation exposures of the population, the question of the extent to which induced mutations will cause an increase in the frequencies of these diseases has remained unanswered. In this paper, we address this problem by using a modified version of MTM which incorporates mutation and selection as two additional parameters. The model assumes a finite number of gene loci and threshold of liability (hence, the designation, Finite-Locus Threshold Model or FLTM). The FLTM permits one to examine the relationship between broad-sense heritability of disease liability and mutation component (MC), the responsiveness of the disease to a change in mutation rate. Through the use of a computer program (in which mutation rate, selection, threshold, recombination rate and environmental variance are input parameters and MC and heritability of liability are output estimates), we studied the MC-heritability relationship for (i) a permanent increase in mutation rate (e.g., when the population sustains radiation exposure in every generation) and (ii) a one-time increase in mutation rate. Our investigation shows that, for a permanent increase in mutation rate of 15%, MC in the first few generations is of the order of 1-2%. This conclusion holds over a broad range of heritability values above about 30%. At equilibrium, however, MC reaches 100%. For a one-time increase in mutation rate, MC reaches its maximum value (of 1-2%) in the first generation, followed by a decline to zero in subsequent generations. These conclusions hold for so many combinations of parameter values (i.e., threshold, selection coefficient, number of loci, environmental variance, spontaneous mutation rate, increases in mutation rate, levels of 'interaction' between genes and recombination rates) that it can be considered to be relatively robust. We also investigated the biological validity of the FLTM in terms of the minimum number of loci, their mutation rates and selection coefficients needed to explain the incidence of multifactorial diseases using the theory of genetic loads. We argue that for common multifactorial diseases, selection coefficients are small in present-day human populations. Consequently, with mutation rates of the order known for Mendelian genes, the FLTM with a few loci and weak selection provides a good approximation for studying the responsiveness of multifactorial diseases to radiation exposures.

Adult↗

PubMed2003

Estimation of the general threshold limit values for dust.

In 1997 the German MAK Commission set new general threshold limit values for dust. The procedure has recently been assessed (McLaughlin et al. 2001). One of the points raised was the use of inappropriate statistical methods. We want to address this point to a greater extent by discussing several alternatives implied by the already established threshold models, and we present results from a new approach that has been refined in the meantime: the use of the additive isotonic model. The underlined assumption of monotonicity regarding the dose-response relationship has been extensively investigated. One very flexible model, based on smoothing splines, shows in some of the samples a decline in the risk over a certain range of the exposure compared to the risk at baseline. Another approach with fractional polynomials and segmented regression lines shows that this result can be explained by chance. These methods show an increasing risk with increasing exposure. Additionally, permutation tests are used to prove the trend within the isotonic framework. The results from the additive isotonic model confirm previous assessments of the general threshold limit value.

Dose-Response Relationship, Drug↗

PubMed1982

Fetal mortality associated with cleft lip and cleft palate.

Analysis of 1,516 pregnancies in sibships of probands with cleft lip with or without cleft palate [CL(P)], and 774 pregnancies in those of probands with isolated cleft palate (CP) indicated that fetal mortality significantly increases with liability to clefting. These data are compatible with the multifactorial two-threshold model, according to which a lower threshold level of liability results in a cleft formation whereas a higher level of liability causes a fetal death.

Cleft Lip↗

PubMed2005

Genetic parameters for stayability, stayability at calving, and stayability at weaning to specified ages for Hereford cows.

Genetic parameters for stayability to six ages (ST1, . . ., ST6), for five measures of stayability to calving (SC2, . . ., SC6), and for five measures of stayability to weaning (SW2, . . ., SW6), were estimated using records of 2,019 Hereford cows collected from 1964 to 1979 from a selection experiment with a control line and three lines selected for weaning weight, yearling weight, and an index of yearling weight and muscle score. The model included birth year of the cow as a fixed effect and the cow's sire as a random effect. Analyses were performed with 1) a generalized linear mixed model for binary data using a probit link with a penalized quasi-likelihood function, and 2) with a linear mixed model using REML. Genetic trends were estimated by regressing weighted means of estimated transmitting abilities (ETA) of sires by birth year of their daughters on birth year. Environmental trends were estimated by regressing solutions for year of birth on birth year. Estimates of heritability (SE) for ST were between 0.09 (0.08) and 0.30 (0.14) for threshold model and between 0.05 (0.04) and 0.19 (0.09) for linear model. Estimates of heritability from linear model analyses transformed to an underlying normal scale were between 0.09 and 0.35. Estimates of heritability (SE) for SC were between 0.29 (0.10) and 0.39 (0.11) and between 0.18 (0.09) and 0.25 (0.08) with threshold and linear models. Estimates of heritability transformed to an underlying normal scale were between 0.30 and 0.40. Estimates of heritability (SE) for SW were between 0.21 (0.14) and 0.47 (0.19) and between 0.12 (0.08) and 0.26 (0.12) with threshold and linear models, respectively. Estimates of heritability transformed to an underlying normal scale were between 0.21 and 0.50. Estimates of genetic and environmental trends for all lines were nearly zero for all traits. Correlations between ETA of sires for stayability to specific ages, for stayability to calving, and for stayability to weaning with threshold and linear models ranged from 0.09 to 0.82, from 0.68 to 0.90, and from 0.67 to 0.87, respectively. Selection for stayability would be possible in a breeding program and could be relatively effective as a result of the moderate estimates of heritability, which would allow selection of sires whose daughters are more likely to remain longer in the herd. Selection for weaning and yearling weights resulted in little correlated response for any of the measures of stayability.

Age Factors↗

PubMed2004

Orthographic learning at a glance: on the time course and developmental onset of self-teaching.

Experiment 1 examined the time course of orthographic learning among Grade 3 children. A single encounter with a novel orthographic string was sufficient to produce reliable recall of orthographic detail. Moreover, newly acquired orthographic information was retained 1 month later. These data support the logistic learning functions featured in contemporary connectionist models of reading rather than a "threshold" model of orthographic learning. Experiments 2 and 3 examined self-teaching among novice readers. In contrast to the findings from less regular orthographies such as English and Dutch, beginning readers of a highly regular orthography (Hebrew) appear to be relatively insensitive to word-specific orthographic detail, reading in a nonlexical "surface" fashion. These results suggest fundamental differences between shallow and deep orthographies in the development of orthographic sensitivity.

Child↗

PubMed1990

Familial phonological disorders: four pedigrees.

The pedigrees of 4 children with a severe phonological disorder demonstrating three generations of members with speech/language problems are presented. All 4 probands were female with two mothers, two fathers, and five out of six siblings affected. All pedigrees contained family members with dyslexia and learning disabilities as well as speech disorders. Family members varied in the type of speech problems that they demonstrated and the severity of their disorder, thus suggesting variable expressivity and incomplete penetrance. An autosomal dominant mode, a multifactorial-polygenic model, and a sex-specific threshold model for expression are discussed.

Child↗

PubMed2005

Neoplastic transformation in vitro induced by low doses of 232 MeV protons.

The aim was to define the dose--response curve for high-energy proton-induced neoplastic transformation in vitro. The HeLa x skin fibroblast human hybrid cell assay was used to determine the frequency of neoplastic transformation following doses of 232 MeV protons (mean linear energy transfer, LET=0.44 keV microm(-1)) in the range 5-600 mGy. Proton irradiations were carried out at the Loma Linda University Proton Treatment Facility, CA, USA. The data indicate no evidence for induction of transformation below a dose of 100 mGy. At doses of 5 and 50 mGy, there is evidence for a possible suppression of transformation frequencies below that for spontaneous transformation. The shape of the dose--response curve for high-energy proton-induced transformation of the human hybrid cell line CGL1 does not follow a linear no-threshold model and shows evidence for a threshold as well as for possible suppression of transformation at doses <100 mGy, similar to that seen for other low-LET radiations.

Cell Transformation, Neoplastic↗

PubMed2004

Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study.

Type 2 diabetes susceptibility is determined by multiple genetic and environmental factors. Genome-wide linkage scans have localized common regions, possibly harboring susceptibility genes on chromosomes 1, 2, 12, and 20. Variability in linkage findings underscores the probable genetic heterogeneity of type 2 diabetes. Thus, we conducted a genome scan of diabetes status using maximum likelihood methods that model affection status by a liability threshold model. Hypertensive sibships and their offspring and/or parents in the Hypertension Genetic Epidemiology Network study were recruited from five field centers. The diabetes phenotype was derived using the World Health Organization criteria and adjusted for race/study center, age, age2, sex, and with and without percent body fat. In total, 567 diabetic participants were identified in 437 families. Variance component linkage analysis was performed among 1,545 Caucasians and 1,608 African Americans using race-specific marker allele frequencies. We detected a quantitative trait loci (QTLs) influencing diabetes variance (logarithm of odds = 3.4) on chromosome 22, which overlaps a positive type 2 diabetes finding among Canadian Oji-Cree Indians. We also observed suggestive evidence for linkage on chromosomes 1, 2, 5, 8, 14, 17, and 19. The identification and replication of type 2 diabetes QTLs will bring us closer to the detection of functional genes that influence diabetes susceptibility.

Chromosome Mapping↗

PubMed1979

Initiation of each avian inspiration by a CO2 threshold mechanism.

The avian respiratory oscillator has been investigated in a unidirectionally ventilated chicken by changing the dynamic pattern of inflow CO2 concentration (FCO2). Stimulation with periodic FCO2 results in a one-to-one synchronization of the respiratory movements that we have called pacing (Respir. Physiol. 22: 167--177, 1974). A two-parameter CO2 threshold model is proposed to explain this behavior. The model states that when FCO2 reaches a threshold level (L), it initiates the beginning of inspiration a constant time interval (LB) later. According to this model, when a triangular FCO2 concentration is used to synchronize the breathing pattern, the time from the minimum of the wave form to the beginning of inspiration (C-B interval) is dependent on the mean value and the rate of rise of FCO2 as determined by period and amplitude of the triangle. Particularly interesting is the prediction that the direction of the relationship (increasing or decreasing) between FCO2 amplitude and the C-B interval is dependent on whether the mean value of FCO2 is above or below the threshold level. Experimental data obtained during amplitude changes support the above prediction.

Animals↗

PubMed1984

Acupuncture on experimental epilepsies.

The therapeutic effect of acupuncture on epilepsies was evaluated in 4 experimental models. 24 acupuncture points were tried. In electroconvulsive threshold model, square wave electrical stimulus of 0.2 msec and 6 Hz was applied through a pair of cotton electrodes at the cornea of mice for 3 sec. The stimulus intensity to induce stun reaction of the mouse was compared. In 86 control animals, the stimulus threshold was 0.70 +/- 0.22 mA. In the acupuncture treated group (N = 80), the threshold was 0.75 +/- 0.14 mA. In maximal electroshock model, the stimulus parameters were 60 Hz, 0.4 sec and 75 mA. The tonic extensor response of the hindlimbs of the mice was observed. 75.7% of the 115 control mice and 77.5% of the 80 acupuncture treated mice were observed to have tonic extensor response. In the focal cortical penicillin model, penicillin was applied at the subpial space over the exposed cortex of 24 cats. After the appearance of repeated spikes in ECoG, acupuncture was performed. In 175 trials the interictal spikes were decreased in 16 times, increased in 82 times. In 99 trials during seizures, the ictal activity was decreased in 4 times, increased in 79 times. In the intravenous penicillin model, high dose penicillin (1,000,000-1,500,000 U/kg) was given to 20 cats. It induced repetitive spikes and frequently even seizure discharges in EEG. Acupuncture was then tried. In 192 instances, acupuncture reduced the spikes in 13, increased the spikes in 103 times. In 74 trials during seizures, the ictal activity was suppressed in 4 times and aggravated in 66 times.(ABSTRACT TRUNCATED AT 250 WORDS)

Acupuncture Therapy↗

PubMed1990

Nature of defibrillation: determinism versus probabilism.

The gradual transitions that are found between unsuccessful and successful shock strengths in percent success or dose-response curves suggest that defibrillation is a probabilistic phenomenon. This concept appears to be reinforced by the fact that a frequency distribution is observed in defibrillation threshold data and that a dose-response relationship is also obtained by integration of the frequency distribution. The purpose of this study was to investigate whether a deterministic threshold model (based on experimental results) could produce 1) gradual transitions in dose-response curves, and 2) a threshold frequency distribution for individual subjects. In the experimental phase of the study, a linear deterministic relationship was found between transthoracic threshold current and defibrillation episode number (other variables held constant) in pentobarbital-anesthetized dogs. The correlation coefficient for each dog was between 0.77 and 0.98 (P less than 0.01), and both positive and negative slopes were found. Based on these results, threshold current was modeled for computer simulation as a linear function of episode number. The model was thus purely deterministic with no random variability. For each simulated experiment, several parameters were varied: order of shocks (increment, decrement, random order), slope of threshold function, and percent error of the initial threshold. Several hundred computer simulations were performed to determine the effect of varying these parameters. In all cases, threshold-frequency distributions and sigmoidal dose-response curves with gradual transitions were produced. The results of this investigation demonstrate that the apparent probabilistic behavior of defibrillation can be produced by a deterministic relationship.

Animals↗

PubMed1985

Constraints, satisfaction and residential mobility: Speare's model reconsidered.

Our study has shown that the stress threshold model, as formulated by Speare, only works partially. Consistent with Speare's model, we have found that subjective satisfaction is a strong predictor of thoughts about moving. Thoughts about moving is a good predictor of actual mobility. There are, however, three major problems with the model: stress as measured by satisfaction is not a particularly good predictor of actual mobility, although it does have some indirect influence through thoughts about moving; the "structural" variables have a strong independent impact on the mobility process beyond satisfaction; the satisfaction variables have little influence in mediating the effects of structural variables on mobility thoughts and behavior. The question of why our results differ from Speare's cannot be definitively answered here. We believe that our research has certain virtues in its direct measurement of satisfaction with home and community and also its much larger sample of movers. Speare's sample may have the virtue of being more representative of a large urban population since it was drawn from all segments of Rhode Island. Yet, while our sample is selective of areas within Seattle, we believe it provides a good representation of a wide variety of residential environments. Overall, our results are more consistent with the other studies which have addressed these issues (Bach and Smith, 1977; Lee, 1978; Michelson, 1977; Newman and Duncan, 1979), although the methods and approaches are not identical. Some of these studies were reviewed in the first part of the paper. We believe that understanding of the attitudinal predictors of changing residence is roughly at the same stage as research in the early post-World War II period on the attitudinal correlates of fertility behavior among American women. Research such as the Princeton study (Westoff et al., 1961; 1963) demonstrated that a variety of social attitudes about home, family, work and childbearing correlated poorly with levels of fertility. In contrast, such variables as objective religious affiliation, educational attainment, and race were clear correlates of fertility behavior. We still do not fully understand why these structural variables are important but we know that they are key predictors of behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Attitude↗