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PubMed1994

Radiation paradigm and its shift.

By adopting the concept of scientific paradigm after L. Sagan, the history of paradigm shift in 1950 in radiation protection standard by ICRP from a threshold to a non-threshold model was critically reviewed. The motives for the shift were found later to be scientifically inappropriate. But the present paradigm of a linear, non-threshold model introduced at the 1950s' shift has been accepted in general for main radiation risk, i.e., for carcinogenesis, though there have been many controversies on risk at low dose effects. We can find some motives for another shift among these controversies now. It is the purpose of the present review to stimulate the discussion on a possible new paradigm.

Humans↗

PubMed2005

Anticonvulsant properties of the novel nootropic agent nefiracetam in seizure models of mice and rats.

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy. METHODS: The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test. RESULTS: NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models. CONCLUSIONS: These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy.

Animals↗

PubMed1978

Re-examination of some of the Framingham blood-pressure data.

Mathematical smoothing of data for the Framingham study leads to the conclusion that there is no threshold of normality for blood-pressure. A reasonable therapeutic goal might be "the lower the better". However, examination of the unsmoothed Framingham data indicates that while systolic pressures fit this no-threshold model reasonably well, changes in diastolic pressure below about 90 mm Hg have little or no prognostic significance. The poor fit of the diastolic points to the no-threshold model may also help to explain why at Framingham raised systolic pressure seemed to have a greater impact than raised diastolic pressure.

Blood Pressure↗

PubMed1994

Genetic study of indirect inguinal hernia.

We performed a genetic analysis of 280 families with congenital indirect inguinal hernia ascertained in Shandong province. The multifactorial threshold model and segregation analysis were applied to these families to investigate the mode of inheritance of congenital indirect inguinal hernia. Our results indicate that congenital indirect inguinal hernia is not compatible with a multifactorial threshold model, and the frequent vertical transmission and high segregation ratio suggest autosomal dominant inheritance with incomplete penetrance and sex influence. Through further pedigree analysis of the multiple case families with at least two closely related affected members, we noted preferential paternal transmission of the disease gene, which might suggest the role of genomic imprinting in the aetiology of this condition.

Chi-Square Distribution↗

PubMedDate not supplied

Simple models of threshold curves in the expression of inborn errors of metabolism: application to some experimental observations.

The expression of an enzymatic deficiency in a metabolic network can present a biochemical threshold. This threshold can be characterised thus: (1) a low activity of the enzyme can sustain a normal flux, but (2) a minute further decrease of its activity makes the flux collapse. We give simple mathematical models displaying such a behaviour, and we apply the models to some examples of oxidative phosphorylation dependency on respiratory chain complex deficiency.

Computer Simulation↗

PubMed1993

Dobutamine pharmacokinetics and pharmacodynamics in normal children and adolescents.

Pharmacokinetic and pharmacodynamic data on adrenergic agents in children have revealed wide ranges of plasma clearance rates and hemodynamic responses in patients with critical illnesses or myocardial dysfunction. In order to more clearly elucidate the underlying pharmacologic processes, graded i.v. dobutamine infusions of 0.5, 2.5 and 5.0 micrograms/kg/min were sequentially administered to healthy children and adolescents. Plasma dobutamine concentrations and hemodynamic responses, including echocardiographic measures of systolic and diastolic function, were determined at each infusion rate. Pharmacodynamic data were evaluated by both threshold modeling and mean hemodynamic responses to each infusion rate. Mean plasma dobutamine clearance was 115 +/- 63 ml/kg/min, with an intersubject variability greater than 5-fold. These data establish that the previously published wide variability in dobutamine clearance is not due simply to underlying disease states. Dobutamine clearance was linear over the dosage range evaluated. Dobutamine improved systolic function even at plasma concentrations attained with infusion rates as low as 1 to 2 micrograms/kg/min. The improved systolic function was at least partially due to inotropic effects. In addition, dobutamine improved diastolic function and reduced afterload. Chronotropic effects were observed in only two subjects and only at higher plasma concentrations than the other hemodynamic effects. Individualized threshold modeling effectively described the log-linear relationship between plasma dobutamine concentration and hemodynamic response beyond the threshold concentration.

Adolescent↗

PubMed2006

Interval mapping for loci affecting unordered categorical traits.

Many traits including shapes and colors of flowers, fruits and seeds in plants, as well as coat colors and some behavioral properties in animals, are recorded in discrete categories. If categories are ordered, genetic analyses of the categorical traits are often performed using the threshold model, which considers a latent continuous variable, called the liability, underlying a trait and assumes the monotonic relationship between the phenotype and the liability. In some categorical traits, however, descriptions of phenotypes are purely nominal and the phenotypic scores cannot be ordered. The threshold model is unreasonable for the analyses of such unordered categorical traits. In this study, we developed a method for interval mapping of loci affecting unordered categorical traits with more than two categories. The probability of the phenotype of an individual falling in each of the categories was expressed by a polychotomous logistic model, in which the log-odds for each category relative to the reference category were assumed to follow a linear model including genotype at a locus affecting a trait as covariate. Based on the model, the interval mapping using a maximum likelihood method was devised for the analysis of complex categorical traits described with unordered categories. We confined ourselves to the case of F2 populations derived from a cross between two inbred lines, although this approach can easily be extended to the analyses for other populations of general structures. As results of analyses of simulated data show, the method showed high efficiency in detecting the loci affecting unordered categorical traits.

Animals↗

PubMed2005

[Methodology of mapping quantitative trait loci for discrete traits using maximum likelihood].

The maximum likelihood method was used to compare the efficiency of interval mapping with either the threshold model or the linear model. The irfluencing factors of quantitative trait loci (QTL) detection efficiency (e.g. QTL effect, heritability and incidence of categories) were simulated in our study. Daughter design with multiple families was applied, and the number of segregating population was 500. The results showed that the threshold model was superior in terms of parameter estimation. It was a more efficient and accurate model of QTL mapping for discrete traits. In addition, the accuracy of QTL mapping depended on the effect of the putative QTL, the value of heritability and incidence directly. With an increase of QTL effect, heritability and incidence of categories, the accuracy of QTL mapping improved correspondingly.

Algorithms↗

PubMed2003

Genetic analysis of longitudinal trajectory of clinical mastitis in first-lactation Norwegian cattle.

Clinical mastitis records for 36,178 first-lactation daughters of 245 Norwegian Cattle (NRF) sires were analyzed with a Bayesian longitudinal threshold model. For each cow, the period going from 30 d before calving to 300 d after calving was divided into 11 intervals of 30 d length each. Absence or presence of clinical mastitis within each interval was scored as "0" or "1", respectively. A Bayesian threshold model consisting of a set of explanatory variables plus Legendre polynomials on time of order four was used to describe the trajectory of liability to clinical mastitis. Heritability ranged between 0.07 and 0.13 before calving, from 0.04 to 0.15 during the first 270 d after calving, and increased sharply thereafter, as a consequence of the form of the polynomial. Genetic correlations between adjacent days were close to 1, and decreased when days were further apart. Most genetic correlations were moderate to high. A measure of probability of future daughters contracting clinical mastitis during lactation was computed for each sire. A typical curve had a peak near calving followed by a decrease thereafter. The best sires had a low peak around calving and a low expected probability of mastitis among daughters throughout lactation. Expected fraction of days without mastitis was derived from the probability curves and used for ranking of sires. Rank correlations with genetic evaluations of sires obtained from cross-sectional models were high. However, sire selection was affected markedly, especially at high selection intensity. An advantage of the longitudinal model for clinical mastitis is its ability to take multiple treatments and time aspects into account.

Animals↗

PubMedDate not supplied

Likelihood and Bayesian analyses reveal major genes affecting body composition, carcass, meat quality and the number of false teats in a Chinese European pig line.

Segregation analyses were performed using both maximum likelihood--via a Quasi Newton algorithm--(ML-QN) and Bayesian--via Gibbs sampling--(Bayesian-GS) approaches in the Chinese European Tiameslan pig line. Major genes were searched for average ultrasonic backfat thickness (ABT), carcass fat (X2 and X4) and lean (X5) depths, days from 20 to 100 kg (D20100), Napole technological yield (NTY), number of false (FTN) and good (GTN) teats, as well as total teat number (TTN). The discrete nature of FTN was additionally considered using a threshold model under ML methodology. The results obtained with both methods consistently suggested the presence of major genes affecting ABT, X2, NTY, GTN and FTN. Major genes were also suggested for X4 and X5 using ML-QN, but not the Bayesian-GS, approach. The major gene affecting FTN was confirmed using the threshold model. Genetic correlations as well as gene effect and genotype frequency estimates suggested the presence of four different major genes. The first gene would affect fatness traits (ABT, X2 and X4), the second one a leanness trait (X5), the third one NTY and the last one GTN and FTN. Genotype frequencies of breeding animals and their evolution over time were consistent with the selection performed in the Tiameslan line.

Animals↗

PubMed1996

Murine and simian retrovirus models: the threshold hypothesis.

By considering the dynamic relationship between retroviruses and their hosts, we have developed a unifying hypothesis to explain such disparate clinical phenomena as differential pathogenicity of a given virus in adults and neonates, transient infection with clearance of provirus-containing cells, long-term non-progression and vaccine effects of fully pathogenic viruses. The threshold hypothesis predicts that an opportunity exists during acute retroviral infection to influence the ultimate clinical outcome: if virus replication is kept below threshold by any means, including drug therapy or passive immunoprophylaxis with neutralizing antibodies, the host will prevail and win the race.

Animals↗

PubMed1999

A note on issues in meta-analysis for behavioral genetic studies using categorical phenotypes.

Meta-analysis of behavioral genetic studies would provide (i) tighter confidence intervals around parameter estimates, (ii) clarification of apparently discrepant study findings, and (iii) a mechanism for analyzing systematic causes of between-study differences. We examined some key issues that arise in the meta-analysis of categorical phenotypes. Data were simulated under a multifactorial threshold model that assumed an underlying normal liability distribution, and summary statistics (probandwise concordance rate, recurrence risk ratio, odds ratio, kappa) compared for given values of the liability correlation between relatives and given population prevalence. Although the odds ratio and kappa statistic performed well at moderate to high values of the population prevalence (15-50%), at low values all of these statistics were sensitive to overall prevalence. In cases where the assumption of a multifactorial threshold model is reasonable, direct estimation of genetic and environmental parameters from the summary statistics from all studies appears to be a preferable strategy. For cases where data from non-randomly ascertained samples are used, the impact of misspecification of the model for ascertainment was examined. For some parameter values, such misspecifications led to quite serious biases to estimates of genetic and environmental parameters. These biases varied in complex ways as a function of research design and of the true causes of variation in the population, so that the same misspecification could lead to an overestimate of the importance of genetic influences in twin data but an underestimation in adoption data or to an overestimate of the importance of genetic effects from twin data if shared environmental as well as genetic influences were simulated but an underestimate of genetic effects if shared environmental effects were assumed unimportant. These complexities emphasize the importance of being sensitive to the effects of misspecifying ascertainment corrections in any meta-analysis of behavioral genetic data.

Confidence Intervals↗

PubMed2003

The role of active metabolites in dihydrocodeine effects.

OBJECTIVE: The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. METHODS: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. RESULTS: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. CONCLUSION: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.

Analgesics, Opioid↗

PubMed2005

When more is not better: the role of cumulative risk in child behavior outcomes.

BACKGROUND: Cumulative risk research has established the deleterious effects of co-occurring risk factors on child behavior outcomes. However, extant literature has not addressed potential differential effects of cumulative risk at different points in development and has left open questions about whether a threshold model or a linear risk model better describes the impact of cumulative risk on behavior outcomes. The current study examined the impact of cumulative risk factors (i.e., child maltreatment, inter-parental violence, family disruption, low socioeconomic status, and high parental stress) in early and middle childhood on child behavior outcomes in adolescence. METHODS: Using data from an ongoing longitudinal study of at-risk urban children (N=171), the cumulative effects of these five risk factors across early and middle childhood were investigated. RESULTS: The findings support the cumulative risk hypothesis that the number of risks in early childhood predicts behavior problems in adolescence. Evidence for a linear but not a threshold model of cumulative risk was found; the more risks present, the worse the child outcome. Moreover, the presence of multiple risks in early childhood continues to explain variations in predicting adolescent behavior outcomes even after including the effects of risk in middle childhood. CONCLUSIONS: The results support the need for comprehensive prevention and early intervention efforts with high-risk children, such that there does not appear to be a point beyond which services for children are hopeless, and that every risk factor we can reduce matters.

Adolescent↗

PubMed1987

Ordered categorical sire evaluation for dystocia in Holsteins.

New statistical procedures for analysis of ordered categorical data were investigated. In using the standardized threshold model, scores are transformed to estimate unknown boundary points and fixed and random effects on an underlying scale of continuous response. The model for calving ease included sex of calf, parity of dam, and the unknown boundary points as fixed effects; herd-year-seasons and sires were random. Data were 5029 dystocia scores on a scale of 1 to 5 collected from June 1982 to January 1984 through the Mid-States Dairy Records Processing Center. The predicted probability of a difficult birth by an average sire indicated that twice as many males as females are born with difficulty. Difficult births declined between first and second parity by a factor of 5. Herd-year-seasons accounted for 13.3% of the variance and sires 3.2%. Heritability on the underlying scale was higher (.147) than on the observed scale (.061). Rank correlations among the threshold model sire solutions and best linear unbiased predictions were .94 when herd-year-seasons were fixed, .98 with random herd-year-seasons, and .99 with normalized scores. Predicted percentage of difficult births for all sires in the analysis ranged from 6 to 18%.

Animals↗

PubMed1981

Cell adhesion on model substrata: threshold effects and receptor modulation.

Trypsinized BHK cells become attached to glass that has been derivatized with a variety of lectins with well-defined specificity for cell-surface carbohydrates. Provided a threshold concentration of glass-immobilized protein is present the cells undergo a transformation to a well-spread morphology. The matrix density of lectins (ricin and concanavalin A) required to trigger this morphological transformation is higher by 10 to 40-fold thant the value determined earlier (Hughes, Pena, Clark & Dourmashkin, 1979) for fibronectin. Cells resistant to the toxic lectin, ricin, and expressing 10% or less of ricin-binding carbohydrate groups at their cell surfaces require correspondingly greater matrix densities of ricin to promote active cell spreading. All cell lines spread equally well on concanavalin A-based matrices consistent with their similar binding properties. The quantitative interaction of complementary molecules on the cell surface and matrix, promoting cell adhesion, is demonstrated by these results and a model is proposed for the events leading to a well-spread cell morphology on a protein-coated substratum.

Animals↗

PubMed1998

Activation-induced apoptosis of mature T cells is dependent upon the level of surface TCR but not on the presence of the CD3 zeta ITAM.

Activation-induced cell death (AICD) occurs primarily in recently activated T cells after a second TCR triggering. Since a threshold in the activation status may be critical for AICD, it is likely that the CD3 ITAM, docking sites for tyrosine kinases, regulate AICD. A 'threshold model' for AICD was tested by using two targeted mutant mouse strains lacking either the zeta chain (CD3zeta-/-) or the ITAM of the zeta chain (CD3zeta-/-:Tgzetadelta67-150). Although the T cells from the CD3zeta-/- mice express extremely low levels of surface TCR, a subpopulation (approximately 18%) of activated T cells could be induced to express TCR/FcepsilonRI gamma by using a powerful polyclonal activation protocol. These activated TCR/FcRI gamma T cells were capable of undergoing AICD, but its induction required 10 times as much anti-CD3epsilon mAb as that required for AICD of wild-type T cells. Thus, the intensity of AICD correlated with the level of CD3 expression and was less efficient with activated, CD3zeta(-/-)-derived T cells. By contrast, AICD of T cells from the CD3zeta-/-:Tgzetadelta67-150 mice could be induced with low doses of anti-CD3epsilon mAb and the extent of AICD was comparable to T cells from wild-type mice. The AICD induced in T cells from CD3-/-, CD3zeta-/-:Tgzetadelta67-150 and normal controls was specifically inhibited by Fas-Ig fusion proteins. Our data support the 'threshold model' of AICD by demonstrating that AICD is controlled by the strength of T cell activation.

Animals↗

PubMed2006

Interval estimates for epidemic thresholds in two-sex network models.

Epidemic thresholds in network models of heterogeneous populations characterized by highly right-skewed contact distributions can be very small. When the population is above the threshold, an epidemic is inevitable and conventional control measures to reduce the transmissibility of a pathogen will fail to eradicate it. We consider a two-sex network model for a sexually transmitted disease which assumes random mixing conditional on the degree distribution. We derive expressions for the basic reproductive number (R(0)) for one and heterogeneous two-population in terms of characteristics of the degree distributions and transmissibility. We calculate interval estimates for the epidemic thresholds for stochastic process models in three human populations based on representative surveys of sexual behavior (Uganda, Sweden, USA). For Uganda and Sweden, the epidemic threshold is greater than zero with high confidence. For the USA, the interval includes zero. We discuss the implications of these findings along with the limitations of epidemic models which assume random mixing.

Acquired Immunodeficiency Syndrome↗