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PubMed2001

A longitudinal study of the effects of long-term exposure to lead among lead battery factory workers in Taiwan (1989-1999).

The objective of this study was to assess the relationship between blood-lead levels (BLL), hematological, liver and renal indicators among workers in a lead battery factory in Taiwan over a 10-year period. Blood samples were taken periodically from 30 workers and BLL, HGB (hemoglobin), RBC (red blood cells), WBC (white blood cells) and HCT (hematocrit) were measured. Levels of GPT (alanine aminotransferase) and Crea (creatinine) in the blood were assessed to indicate liver and renal function, respectively. The results showed that there was a general decrease in BLL over the 10-year period (except for 1993). There was a similar trend for HCT, RBC and Crea. There was no significant trend for the other health indicators. Four generalized estimating equation (GEE) models [correlation model (A), threshold correlation model (B), instant change model (C) and lag change model (D)] were set up to demonstrate the causal relationship between BLL and the other health indicators. Models A and C showed that BLL correlated positively with RBC, but negatively with Crea. Model B showed that BLL correlated positively with GPT. There were no significant correlations of BLL with the other indicators. Models C and D, (GEE with logit link function to analyze the association between changes BLL and the other health indicators) showed that when BLL increased, RBC and HCT increased, both longitudinally and cross-sectionally. The authors conclude that long-term exposure to lead stimulates production of RBC and HCT, but the effect on liver and renal function was unclear.

Adult↗

PubMed1976

Allelic restriction: a biologic alternative to multifactorial threshold inheritance.

Contrary to the argument regarding the conservatism of the multifactorial threshold model for describing the inheritance of congenital malformations, little biological insight has resulted from the series of tautological, albeit grandiose, mathematical assumptions currently comprising the basis for this hypothesis. The working hypothesis of this presentation is to apply the "allelic restriction" model to the genesis of common human congenital malformations. New population data concerning isolated cleft palate closely fit the predictions of the proposed hypothesis. Recognising the heterogeneity of cleft palate as well as other common congenital malformations (namely, the difference between phenocopies, definable syndromes, and true hereditary cases), the "allelic restriction" model accords with the apparent greatly "reduced penetrance" of the heriditary cases. This model is meant to apply only to those congenital malformations which have both a high population frequency and a relatively small number of families showing an atypical type of vertical transmission.

Adult↗

PubMed2003

Phosphatases in concert with kinases set the gain for signal transduction through the T cell receptor.

The 'tunable activation thresholds' model for signal transduction through the T cell receptor (TCR)/CD3 signaling complex proposes that rapid cycles of phosphorylation and dephosphorylation are integral to regulating the frequency of protein-protein interaction, thus having considerable influence over the activation of downstream signaling pathways. Co-temporal activation of kinases and phosphatases could serve to modulate the ongoing signaling response, depending on the relative balance of their opposing enzymatic activities. Although recent reports have addressed the mechanisms by which specific kinase/phosphatase pairs contribute to the initiation and termination of signaling, we sought a more global understanding of the ability of the kinase/phosphatase balance to regulate, or "tune", the very proximal steps of TCR signaling in primary human T cells. Herein, we provide biochemical evidence that phosphotyrosine induction via the TCR is subject to fine-tuning based on the overall activity of kinases and phosphatases relative to one another, leading to cycles of phosphorylation and dephosphorylation, with implications for developing the next generation of immunotherapeutic agents.

Animals↗

PubMed1989

Early-life undernutrition impairs the development of the learning and short-term memory processes mediating performance in a conditional-spatial discrimination task.

Previously undernourished and well-nourished control rats 23, 30, 40, and 90 days old were compared in a win-shift version of a conditional-spatial discrimination task. Control animals at each age were able to reach criterion on this problem. In contrast, the underfed rats were unable to solve this problem until they were at least 40 days old. The short-term memory of the 40- and 90-day-olds was further evaluated by increasing the interval between the forced run and choice run to 30, 60, and 180 s. Control animals could bridge all intervals; however, the undernourished animals' performance fell to chance when the interval was only 60 s. Thus, early-life undernutrition severely impaired the development of the ability of animals to solve spatial-conditional discrimination tasks and permanently impaired their short-term memory capacity. A simple threshold model relating undernutrition, brain development, and behavior is proposed to account for these data.

Animals↗

PubMed2001

Gender effects in hearing loss in Dalmatians.

Brainstem auditory-evoked-response data were collected from 3101 Dalmatian dogs from 1984 to 1998 at the Veterinary Medicine Teaching Hospital at the University of California, Davis. Also collected were data on eye color and the presence or absence of a color-patch at birth. Our objective was to evaluate the role of gender in hearing loss, including the possibility that the probability of suffering unilateral or bilateral deafness was greater if the dam was hearing impaired than if the sire was hearing impaired. Results of a multiple-trait threshold-model analysis support the commonly held observation that females were more likely to be deaf than males. In addition, females were also more likely to have two blue eyes (a condition associated with an increased prevalence of deafness). However, gender differences in hearing loss were limited to these direct observations. There was no detectable difference in the prevalence of hearing loss between offspring of deaf mothers and the offspring of deaf fathers. Finally, there was no detectable decrease in the prevalence of hearing loss over the years covered in the data set - suggesting that Dalmatian breeders are not yet selecting against hearing problems.

Animals↗

PubMed1998

Reducing the incidence of epileptic seizures in the Belgian Tervuren through selection.

There is growing evidence that idiopathic epilepsy in the Belgium Tervuren has a genetic foundation. Reducing the incidence of this disorder, which may afflict as much as 17% of the breed, will rely upon the wise selection of parents. Seizure data on 997 dogs from the American Belgian Tervuren Club were collected through questionnaires in which animals were classified into one of four mutually exclusive categories: 1) no seizures observed, 2) one seizure observed, 3) two to five seizures, and 4) more than five seizures. The analysis of this ordered data made use of a threshold model of Bayesian inference. Integration of posterior densities was accomplished through Gibbs sampling. Through this analysis we are able to predict that the offspring of the mating of two non-epileptic dogs has a probability of 0.99 of never suffering from a seizure. The offspring of the mating of two dogs who have each had 1 seizure has a predicted probability 0.58 of never suffering from a seizure. Prevention of this disease is best prescribed through the selection of non-epileptic dogs as parents of future generations.

Animals↗

PubMedDate not supplied

Contribution of human data to the analysis of human carcinogenesis.

Human data strongly suggest that small doses or low concentrations of genotoxic agents cause only a relatively small number of human cancers. They emphasize the role of promotion, in particular that associated with cell proliferation. There is therefore a qualitative difference between high doses of genotoxic agents which provoke cell death and a compensatory increase in cell division, and low doses which do not. During the promotion phase, human data demonstrate the importance of induced genetic instability and defects in apoptosis as well as that of cell immortalization which play a main role for the accumulation in a cell genome of several specific lesions. Carcinogenesis is a complex process in which initial mutations do not appear to be a limiting or crucial step. This view is supported by the paramount influence of age on the induction by radiation of thyroid and breast cancer. It is also compatible with practical thresholds observed in subjects whose bones or liver were exposed to alpha-emitters, as well as with the curvilinearity in the leukemia incidence dose-response in the Japanese atomic bomb survivors. The linear no threshold model assumes that: 1) the probability of DNA lesion repair is constant whatever the dose and, hence, the number of lesions provoked in the same cell and the surrounding cells; 2) the probability for a damaged cell to evolve toward an invasive cancer is not influenced by the possible promotional effect of further irradiation or induced tissue proliferation, nor the control exerted by surrounding cells. These assumptions deserve a critical analysis.

Age Distribution↗

PubMed1995

Uncovering and managing denial during the research process.

This article describes experiences of geropsychiatric nurses examining the effectiveness of the Progressively Lowered Stress Threshold Model for caregivers of persons with Alzheimer's disease and related disorders, and briefly reviews the literature on coping and denial. This research project, and those of many other psychiatric nurses, is predicated on the expectation that subjects will be able to acknowledge and report to investigators their personal and intimate responses to the challenges and everyday experiences of caregiving. Clearly, the research findings will be most valid if subjects are completely open about all aspects of their experiences, no matter how painful; yet this is often an idealized expectation. Therefore, this article also explores the concerns of geropsychiatric nurse researchers attempting to balance sensitivity to the needs of subjects and the reliability and validity of the data.

Adaptation, Psychological↗

PubMed2001

Sustained and selective attention as measures of genetic liability to schizophrenia.

We tested for a relationship between attention and genetic liability to schizophrenia. Samples of probands with DSM-IV schizophrenia (n=20), their well first-degree relatives (n=40) and healthy controls (n=82) were tested using measures of sustained attention (degraded-stimulus continuous performance test: DS-CPT) and selective attention (spatial negative priming task). Assuming a liability-threshold model, we predicted that probands would display greater attentional decrements than controls and that the relatives would show intermediate levels of decrement. We did not observe the predicted pattern of effect using either measure, although the probands showed a trend towards less negative priming. However, our results may have been affected by self-selection bias in probands and relatives and clinical heterogeneity among probands, which could have reduced our power to detect effects.

Adolescent↗

PubMed2000

DNA damage and repair: consequences on dose-responses.

Damage to DNA is considered to be the main initiating event by which genotoxins cause hereditary effects and cancer. Single or double strand breaks, bases modifications or deletions, intra- or interstrand DNA-DNA or DNA-protein cross-links constitute the major lesions formed in different proportions according to agents and to DNA sequence context. They can result in cell death or in mutational events which in turn may initiate malignant transformation. Normal cells are able to repair these lesions with fidelity or by introducing errors. Base excision (BER) and nucleotide excision (NER) repair are error-free processes acting on the simpler forms of DNA damage. A specialized form of BER involves the removal of mismatched DNA bases occurring as errors of DNA replication or from miscoding properties of damaged bases. Severe damage will be repaired according to several types of recombinational processes: homologous, illegitimate and site-specific recombination pathways. The loss of repair capacity as seen in a number of human genetic diseases and mutant cell lines leads to hypersensitivity to environmental agents. Repair-defective cells show qualitative (mutation spectrum) and quantitative alterations in dose-effect relationships. For such repair-deficient systems, direct measurements at low doses are possible and the extrapolation from large to low doses fits well with the linear or the linear-quadratic no-threshold models. Extensive debate still takes place as to the shape of the dose-response relationships in the region at which genetic effects are not directly detectable in repair-proficient normal cells. Comparison of repair mutants and wild-type organisms pragmatically suggests that, for many genotoxins and tissues, very low doses may have no effect at all in normal cells.

Animals↗

PubMed1997

Prevalence and correlates of susceptibility to motion sickness.

Data on susceptibility to motion sickness were collected on a sample of 535 individuals divided into eight groups. The prevalence of motion sickness among Tibetans and Northeast Indians (28%) was slightly higher than Northwest Indians (26%). Generally speaking, females (27.3%) were more susceptible than males (16.8%). Among different groups, the highest incidence of susceptibility to motion sickness (SMS) was recorded in schizophrenic patients (30%), while the lowest in rowers (zero percent). Ears and eyes are the most potent receptors of provocative motion that causes sickness. Individuals with greater spatial and motor control, reflected in sports like rowing, athletics and professions like armed and paramilitary forces, were less susceptible to motion sickness. The SMS was significantly higher in individuals who suffered from spatial disorientation (35.05%), migraine (26.31%), gastrointestinal disorders (26.82%) and those who were more sensitive to unpleasant odours (24.64%) and preferred sweet flavours (24.48%) than their counterparts. These correlates have been utilized to explain the genesis of sickness using threshold model. Genetic and environmental pathways are strongly advocated. Past episodes of motion sickness acted as a strong psychological attribute in determining further episodes. The roadway buses and trucks proved more effective passive transportation types that caused sickness. The voluntary stabilization of the head and neck movements and gaze control proved very effective natural measures adopted by 38% subjects to avoid or limit motion sickness. About 50% of susceptible individuals became less susceptible or fully acclimatized to motion sickness due to habituation. The mean age at acclimatization was 21.98 +/- 5.93 years.

Adaptation, Physiological↗

PubMed1979

Holzinger's Hc revised.

The formula H'C = 1 - CDZ/CMZ is suggested as a better summary of twin concordance data than the familiar Holzinger concordance formula, HC = (CMZ - CDZ)/(1 - CDZ). The new formula better estimates degree of genetic determination, G, as calculated from a threshold model, but never exceeds unity, as G sometimes does. For high concordance rates, if CMZ + CDZ greater than 1, HC may be more useful than either G or H'C.

Female↗

PubMed2002

Mapping quantitative trait loci with epistatic effects.

Epistatic variance can be an important source of variation for complex traits. However, detecting epistatic effects is difficult primarily due to insufficient sample sizes and lack of robust statistical methods. In this paper, we develop a Bayesian method to map multiple quantitative trait loci (QTLs) with epistatic effects. The method can map QTLs in complicated mating designs derived from the cross of two inbred lines. In addition to mapping QTLs for quantitative traits, the proposed method can even map genes underlying binary traits such as disease susceptibility using the threshold model. The parameters of interest are various QTL effects, including additive, dominance and epistatic effects of QTLs, the locations of identified QTLs and even the number of QTLs. When the number of QTLs is treated as an unknown parameter, the dimension of the model becomes a variable. This requires the reversible jump Markov chain Monte Carlo algorithm. The utility of the proposed method is demonstrated through analysis of simulation data.

Algorithms↗

PubMed2003

An EM algorithm for mapping binary disease loci: application to fibrosarcoma in a four-way cross mouse family.

Many diseases show dichotomous phenotypic variation but do not follow a simple Mendelian pattern of inheritance. Variances of these binary diseases are presumably controlled by multiple loci and environmental variants. A least-squares method has been developed for mapping such complex disease loci by treating the binary phenotypes (0 and 1) as if they were continuous. However, the least-squares method is not recommended because of its ad hoc nature. Maximum Likelihood (ML) and Bayesian methods have also been developed for binary disease mapping by incorporating the discrete nature of the phenotypic distribution. In the ML analysis, the likelihood function is usually maximized using some complicated maximization algorithms (e.g. the Newton-Raphson or the simplex algorithm). Under the threshold model of binary disease, we develop an Expectation Maximization (EM) algorithm to solve for the maximum likelihood estimates (MLEs). The new EM algorithm is developed by treating both the unobserved genotype and the disease liability as missing values. As a result, the EM iteration equations have the same form as the normal equation system in linear regression. The EM algorithm is further modified to take into account sexual dimorphism in the linkage maps. Applying the EM-implemented ML method to a four-way-cross mouse family, we detected two regions on the fourth chromosome that have evidence of QTLs controlling the segregation of fibrosarcoma, a form of connective tissue cancer. The two QTLs explain 50-60% of the variance in the disease liability. We also applied a Bayesian method previously developed (modified to take into account sex-specific maps) to this data set and detected one additional QTL on chromosome 13 that explains another 26% of the variance of the disease liability. All the QTLs detected primarily show dominance effects.

Algorithms↗

PubMed2001

Life events and depression in a community sample of siblings.

BACKGROUND: The overall aim of the GENESiS project is to identify quantitative trait loci (QTLs) for anxiety/depression, and to examine the interaction between these loci and psychosocial adversity. Here we present life-events data with the aim of clarifying: (i) the aetiology of life events as inferred from sibling correlations; (ii) the relationship between life events and measures of anxiety and depression, as well as neuroticism; and (iii) the interaction between life events and neuroticism on anxiety/depression indices. METHODS: We assessed the occurrence of one network and three personal life-event categories and multiple indices of anxiety/depression including General Health Questionnaire, Anhedonic Depression, Anxious Arousal and Neuroticism in a large community-based sample of2150 sib pairs, 410 trios and 81 quads. Liability threshold models and raw ordinal maximum likelihood were used to estimate within-individual and between-sibling correlations of life events. The relationship between life events and indices of emotional states and personality were assessed by multiple linear regression and canonical correlations. RESULTS: Life events showed sibling correlations of 0-37 for network events and between 0-10 and 0.19 for personal events. Adverse life events were related to anxiety and depression and, to a less extent, neuroticism. Trait-vulnerability (as indexed by co-sib's neuroticism, anxiety and depression) accounted for 11% and life events for 3% of the variance in emotional states. There were no interaction effects. CONCLUSIONS: Life events show moderate familiality and are significantly related to symptoms of anxiety and depression in the community. Appropriate modelling of life events in linkage and association analyses should help to identify QTLs for depression and anxiety.

Adult↗

PubMed2002

Sex differences in genetic and environmental risk factors for irrational fears and phobias.

BACKGROUND: For irrational fears and their associated phobias, epidemiological studies suggest sex differences in prevalence and twin studies report significant genetic effects. How does sex impact on the familial transmission of liability to fears and phobias? METHODS: In personal interviews with over 3000 complete pairs (of whom 1058 were opposite-sex dizygotic pairs), ascertained from a population-based registry, we assessed the lifetime prevalence of five phobias and their associated irrational fears analysed using a multiple threshold model. Twin resemblance was assessed by polychoric correlations and biometrical model-fitting incorporating sex-specific effects. RESULTS: For agoraphobia, situational and blood/injury fear/phobia, the best fit model suggested equal heritability in males and females and genetic correlations between the sexes of less than +0.50. For animal fear/phobias by contrast, the best fit model suggested equal heritability in males and females and a genetic correlation of unity. No evidence was found for an impact of family environment on liability to these fears or phobias. For social phobias, twin resemblance in males was explained by genetic factors and in females by familial-environmental factors. CONCLUSION: The impact of sex on genetic risk may differ meaningfully across phobia subtypes. Sex-specific genetic risk factors may exist for agoraphobia, social, situational and blood-injury phobias but not for animal fear/phobia. These results should be interpreted in the context of the limited power of twin studies, even with large sample sizes, to resolve sex-specific genetic effects.

Adult↗

PubMed2003

Genetic and environmental influences on psychological distress in the population: General Health Questionnaire analyses in UK twins.

BACKGROUND: The General Health Questionnaire (GHQ) is the most popular screening instrument for detecting psychiatric disorders in community samples. Using longitudinal data of a large sample of UK twin pairs, we explored (i) heritabilities of the four scales and the total score; (ii) the genetic stability over time; and (iii) the existence of differential heritable influences at the high (ill) and low (healthy) tail of the distribution. METHOD: At baseline we assessed the GHQ in 627 MZ and 1323 DZ female pairs and at a second occasion (3.5 years later) for a small subsample (90 MZ and 270 DZ pairs). Liability threshold models and raw ordinal maximum likelihood were used to estimate twin correlations and to fit longitudinal genetic models. We estimated extreme group heritabilities of the GHQ distribution by using a model-fitting implementation of the DeFries-Fulker regression method for selected twin data. RESULTS: Heritabilities for Somatic Symptoms, Anxiety, Social Dysfunction, Depression and total score were 0.37, 0.40, 0.20, 0.42 and 0.44, respectively. The contribution of shared genetic factors to the correlations between time points is substantial for the total score (73%). Group heritabilities of 0.48 and 0.43 were estimated for the top and bottom 10% of the total GHQ score distribution, respectively. CONCLUSION: The overall heritability of the GHQ as a measure of psychosocial distress was substantial (44%), with all scales having significant additive genetic influences that persisted across time periods. Extreme group analyses suggest that the genetic control of resilience is as important as the genetic control of vulnerability.

Adolescent↗

PubMed1999

Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion.

Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, "experience-expectant," and "experience-dependent." Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.

Animals↗