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PubMed2003

A longitudinal behavioral genetic analysis of the etiology of aggressive and nonaggressive antisocial behavior.

Developmental studies of antisocial behavior (ASB) have found two subgroups of behaviors, roughly described as aggressive and nonaggressive ASB. Theoretical accounts predict that aggressive ASB, which shows greater stability, should have high heritability. In contrast, nonaggressive ASB is very common in adolescence, shows less continuity, and should be influenced both by genes and shared environment. This study explored the genetic and environmental influences on aggressive and nonaggressive ASB in over 1,000 twin pairs aged 8-9 years and again at 13-14 years. Threshold models were fit to the data to incorporate the skew. In childhood, aggressive ASB was highly heritable and showed little influence of shared environment, whereas nonaggressive ASB was significantly influenced both by genes and shared environment. In adolescence, both variables were influenced both by genes and shared envirnmment. The continuity in aggressive antisocial behavior symptoms from childhood to adolescence was largely mediated by genetic influences, whereas continuity in nonaggressive antisocial behavior was mediated both by the shared environment and genetic influences. These data are in agreement with the hypothesis that aggressive ASB is a stable heritable trait as compared to nonaggressive behavior, which is more strongly influenced by the environment and shows less genetic stability over time.

Adolescent↗

PubMed2004

Instruments to assess decision-making capacity: an overview.

OBJECTIVE: The main objective of this article is to evaluate and describe instruments for assessing decision-making capacity in psychiatry and psychogeriatrics, and to evaluate them for use in daily practice. METHODS: The instruments were selected in Medline articles. We focus on the relationship between these instruments and the concept of competence, represented in the following elements: context in which an instrument is developed, disclosure of information, standards to assess decision-making capacity, the scale or threshold model, and validity and reliability. RESULTS: The developmental context influences how information is provided and standards defined. Although it is not clear how decision-making capacity relates to competency judgments, most instruments provide good reliability. CONCLUSIONS: Comparison of the different instruments opens directions for future research. Although instruments can never replace a physician's judgment, they may provide a clear starting point for a discussion on competence. In daily practice assessments, attention should be given to information disclosure, the influence of our own normative values in evaluating standards of decision-making capacity, and the relation between decision-making capacity and competence.

Aged↗

PubMed1998

Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRI) correlations.

During detailed visual function testing, pattern-reversal visual evoked potentials (VEP), generated by different spatial frequencies (3 c/d, 1 c/d and 0.6 c/d) and visual contrasts (100% and 10%) were recorded in 21 adolescent and young adult phenylketonuric (PKU) patients (11 females and 10 males; mean age 14.8 years, range 9-22.8) on and off diet. In 14 of the 21 patients, disease had been detected at neonatal screening and in 7 later. Ten age-matched healthy subjects acted as controls. Recordings in more than 40% of eyes in the whole group and 30% of eyes in the screening subgroup showed a prolonged P100 latency. All visual pattern stimuli elicited a significantly longer P100 latency in PKU patients than in controls. VEP latencies to 3 c/d, 1 c/d and 1 c/d with 10% contrast--but not to 0.6 c/d--were longer in patients off diet than in patients on diet. No differences were found between VEP latencies in early- and later-detected subjects. To study the link between biochemical variables and VEP latencies, we envisaged either a linear relationship between recent exposure to phenylalanine (Phe) and VEP abnormalities or a threshold model considering phenylalanine (Phe) concentrations among the factors influencing VEP latencies. The correlation analysis detected an association between plasma Phe concentrations and abnormal VEP latencies, predicting that plasma Phe concentrations > 901 mumol/L would prolong VEP latencies to 1 c/d; concentrations > 879 mumol/L would prolong latencies to 3 c/d; and concentrations > 898 mumol/L would prolong latencies to 1 c/d with 10% contrast.

Adolescent↗

PubMed2000

Promoter strength influences polyamine metabolism and morphogenic capacity in transgenic rice tissues expressing the oat adc cDNA constitutively.

We analyzed molecularly and biochemically a series of transgenic rice lines expressing the oat adc (arginine decarboxylase) cDNA under the control of the constitutive maize ubiquitin 1 promoter. We established baseline biochemical parameters to elucidate the role of polyamines (PAs) during morphogenesis. We measured mRNA levels, ADC enzyme activity and cellular PAs in dedifferentiated callus. Polyamine levels were also quantified in two subsequent developmental stages--regenerating tissue and differentiated shoots. We observed significant (P < 0.05) differences in the levels of individual PAs at the three developmental stages. The amounts of putrescine (Put) and spermidine (Spd) in dedifferentiated transgenic callus were lower than those in the wild type or in hpt (hygromycin resistant)-controls, whereas the amount of spermine (Spm) was increased up to two-fold. In regenerating tissue, this trend was reversed, with significantly higher levels of Put and Spd (P < 0.05), and lower levels of Spm (P < 0.05) compared to non-transformed or hpt-control tissues at the same developmental stage. In differentiated shoots, there was a general increase in PA levels, with significant increases in Put, Spd, and Spm (P < 0.05); on occasion reaching six times the level observed in wild type and hpt-control tissues. These results contrast those we reported previously using the weaker CaMV 35S promoter driving adc expression. mRNA measurements and ADC enzyme activity were consistently higher (P < 0.01) in all tissues expressing pUbiadcs compared to equivalent tissues engineered with 35Sadc. Our findings are consistent with a threshold model which postulates that high adc expression leading to production of Put above a basal level is necessary to generate a big enough metabolic pool to trigger PA flux through the pathway leading to an increase in the concentration of Spd and Spm. This can be best accomplished by a strong constitutive promoter driving adc. We discuss our results in the context of flux through the PA pathway and its impact on morphogenesis.

Avena↗

PubMed1999

The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins.

Not much is known about the genetic and environmental determinants of various aspects of substance use in adolescents. This study examined whether the inheritance of initiation of tobacco use in adolescents is independent of the inheritance of the number of cigarettes smoked. Alternative multifactorial threshold models were applied to data on tobacco use in 1676 Dutch adolescent twin pairs. The three models that were considered are (i) the single liability dimension model, (ii) the independent liability dimension model, and (iii) the combined model (CM). The results showed that there is not one underlying continuum of liability to smoking. The CM was the best-fitting model. This model postulates that there are separate initiation and quantity dimensions but allows for the possibility that there are some individuals who are so low on the liability to level of consumption that they are not using tobacco. There were no differences between males and females in the magnitude of the genetic and environmental influences on individual differences in smoking initiation and quantity smoked. Smoking initiation was influenced by genetic factors (39%) and shared environmental influences (54%). Once smoking is initiated genetic factors determine to a large extent (86%) the quantity that is smoked.

Adolescent↗

PubMed2003

Trophic determinants of hypopus induction in the stored-product mite Lepidoglyphus destructor (Acari: Astigmata).

A unique (synapomorphic) characteristic of astigmatic mites is the heteromorphic deuteronymph also called hypopus. It is a non-feeding and facultative instar between protonymph and tritonymph. The hypopus is adapted for dispersal and sometimes also for dormancy, as in Lepidoglyphus destructor. The experiments reveal a correlation between the composition of the foodstuff, the duration of development of homomorphic instars, the mortality of protonymphs and the production of hypopodes. As food quality decreases, development lasts longer, mortality increases and hypopodes are produced in greater numbers. Disadvantageous trophic conditions of varied chemical nature favour the induction of hypopodes. The experimental data show that hypopus incidences (as percentage individuals of a population) depend on the relative proportions of constituents of an ingested foodstuff. What matters is the ratio between nourishing foodstuff components and those that are of little or no nutritional value. When a certain ratio does not meet a presumed metabolically required level of nutrients a nutritional deficiency results and hypopus induction is triggered, provided that adequate genetic propensities for hypopus production are present (L. destructor is highly polymorphic for hypopus production). Specific key substances are apparently not involved, and composite properties of a foodstuff are crucial for hypopus induction. Decrease of food quality (not poor food per se) during the hypopus-inducible period (late larval to early protonymphal phase) promotes hypopus induction. The interpretation matches the ecological scene. When trophic deterioration of a patch habitat sets in, often as a result of overcrowding, conditions will eventually become untenable. As a response to incurring nutritional deficiencies the mites will induce hypopodes, which provide for escape from or survival at the decaying habitat patch. Experiments support the threshold model of quantitative genetics for hypopus expression as previously inferred from other experiments with L. destructor.

Acaridae↗

PubMed2000

Process dissociation as source monitoring.

A 2-high-threshold model source-monitoring model (U. J. Bayen, K. Murnane, & E. Erdfelder, 1996) was applied to both source-monitoring and process-dissociation data collected varying source and distracter similarity. The model fit both sets of data using identical parameter values. The values of the detection parameter, D, and the source-discrimination parameter, d, varied in the manner expected. Also, neither the process-dissociation (L. L. Jacoby, 1991) nor the extended process-dissociation model (A. Buchner, E. Erdfelder, & B. Vaterrodt-Plünnecke, 1995) fit either type of data. The memory processes involved in recognition judgments are the same when using the process-dissociation or the source-monitoring procedure. The 4 cognitive processes in both procedures can be interpreted as item detection, source identification, recognition guessing, and source guessing. The potential role of unconscious memory influences via the 2 guessing processes is discussed.

Adolescent↗

PubMed1999

Sex differences in genetic and environmental influences on DSM-III-R attention-deficit/hyperactivity disorder.

Approximately 5% of children are affected by attention-deficit/hyperactivity disorder (ADHD), and more boys are affected than girls. This study examined the magnitude of genetic and environmental influences on ADHD and several questions regarding sex differences in its prevalence and liability. The participants were 2,391 twin and sibling pairs from Australia, ages 3-18. ADHD symptoms in the general population were highly heritable (h2 = .85-.90), as were deviant ADHD scores in the selected population. The magnitude of familial influences was similar for boys and girls, although there were shared environmental influences on ADHD in girls but not boys and dominance genetic influences on ADHD in boys but not girls. Specific genetic and environmental influences were highly similar for boys and girls. Evidence supported the polygenic multiple threshold model rather than the constitutional variability model of sex differences in ADHD.

Adolescent↗

PubMed2005

The occurrence of male-to-female intimate partner violence on days of men's drinking: the moderating effects of antisocial personality disorder.

In this study, the moderating effects of antisocial personality disorder (ASPD) on the day-to-day relationship between male partner alcohol consumption and male-to-female intimate partner violence (IPV) for men entering a domestic violence treatment program (n=170) or an alcoholism treatment program (n=169) were examined. For both samples, alcohol consumption was associated with an increased likelihood of nonsevere IPV among men without a diagnosis of ASPD but not among men with ASPD (who tended to engage in nonsevere IPV whether they did or did not drink). Drinking was more strongly associated with a likelihood of severe IPV among men with ASPD compared with those without ASPD who also drank. These results provide partial support for a multiple threshold model of intoxication and aggression.

Adult↗

PubMed1996

Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45.

Elimination of self-reactive B cells must be balanced against the need for B-cell diversity for antibody responses to pathogens. To analyse factors that determine the extent of B-cell negative selection, we crossed CD45-deficient mice with mice carrying immunoglobulin transgenes specific for hen egg lysozyme (HEL). CD45 positively regulates antigen-receptor signalling and CD45-deficient HEL-specific B cells gave diminished signalling in response to HEL. Significantly, few mature CD45-/- B cells accumulated, despite normal immature B-cell production. Circulating HEL autoantigen mediates negative selection of mature CD45+/+ HEL-binding B cells but, in striking contrast, the autoantigen positively selected CD45-/- HEL-binding B cells, promoting their accumulation as long-lived IgD(hi) cells. These findings are consistent with a signal-threshold model for B-cell selection and demonstrate that changes in antigen receptor signalling can cause high-affinity self-reactive B cells to be actively retained instead of eliminated, thus revealing a potential mechanism for inherited susceptibility to autoimmune disease.

Animals↗

PubMed2003

Evidence for joint action of genes on diabetes status and CVD risk factors in American Indians: the strong heart family study.

OBJECTIVES: Previous research among American Indians of the strong heart family study (SHFS) has demonstrated significant heritabilities for CVD risk factors and implicated diabetes as an important predictor of several of the phenotypes. Moreover, we recently demonstrated that genetic effects on CVD risk factors differed in diabetic and nondiabetic individuals. In this paper, we investigated whether a significant genetic influence on diabetes status could be identified, and whether there is evidence for joint action of genes on diabetes status and related CVD risk factors. METHODS AND RESULTS: Approximately 950 men and women, age 18 or older, in 32 extended families, were examined between 1997 and 1999. We estimated the effects of genes and environmental covariates on diabetes status using a threshold model and a maximum likelihood variance component approach. Diabetes status exhibited a residual heritability of 22% (h2=0.22). We also estimated the genetic and environmental correlations between diabetes susceptibility and eight risk factors for CVD. All eight CVD risk factors displayed significant genetic correlations with diabetes status (BMI (rhoG=0.55), fibrinogen (rhoG=0.40), HDL-C (rhoG=-0.37), ln triglycerides (rhoG=0.65), FAT (rhoG=0.38 ), PAI-1 (rhoG=0.67), SBP (rhoG=0.57), and WHR (rhoG=0.58)). Three of eight traits (HDL-C (rhoE=-0.32), ln triglycerides (rhoE=0.33), and fibrinogen (rhoE=0.20)) displayed significant environmental correlations with diabetes status. CONCLUSIONS: These findings suggest that in the context of a high prevalence of diabetes, still unidentified diabetes genes may play an important role in influencing variation in CVD risk factors.

Adolescent↗

PubMed1996

Induction of heat shock protein 70 genes in human lymphocytes during fever therapy.

The induction of heat shock protein 70 (HSP70) genes has been studied in peripheral blood mononuclear cells of individuals undergoing fever therapy because of metastatic malignant melanoma. Induction of HSP70 was assessed at the protein level by metabolic labelling or, for the HLA-linked HSP70-1 and HSP70-2 genes, at the RNA level by in situ hybridization. However, de novo expression of HSP70 could be observed during fever (usually above 39 degrees C) in only about half of the cases. No simple threshold model for inducibility of HSP70 in vivo could be applied. The HSP70-1 gene was induced more easily than HSP70-2. Thus, heat-inducible HSP70 genes, including HLA-linked HSP70 genes, become expressed in human lymphocytes during fever, but not regularly.

Adult↗

PubMed1999

Mapping quantitative trait loci for complex binary traits in outbred populations.

Complex binary traits have a dichotomous phenotypic expression but do not show a simple Mendelian segregation ratio. These traits are considered to be jointly controlled by the actions of several genes and a random environmental effect. The binary phenotype and the underlying factor are assumed to be linked through a threshold model. The underlying factor, referred to as the liability, is treated as a regular but unobservable quantitative character. Mapping quantitative trait loci (QTL) can be performed directly on the liability. Methods of QTL mapping for the liability of a complex binary trait have been well developed in line-crossing experiments. However, such a method is not available in outbred populations which usually consist of many independent pedigrees (families). In this study, we develop a method to analyse jointly multiple families of an outbred population. The method is developed based on a fixed-model approach, i.e. the QTL effects, rather than the variance, are estimated and tested. After the test, the estimated effects are then converted into a single estimate of the QTL variance by taking into consideration errors in the estimated effects. The QTL effects and variance-covariance matrix of the estimates are obtained by a fast Fisher-scoring method. Monte Carlo simulations show that the method is not only powerful but also generates very accurate estimates of QTL variances.

Algorithms↗

PubMed1998

Risk of congenital inguinal hernia in siblings: a record linkage study.

Using data from the Oxford Record Linkage Study (ORLS), we conducted a case-control study to estimate the sex-specific risks of inguinal hernia in siblings of children with this condition. There were 1921 male and 347 female cases born during 1970-86 who were operated on for inguinal hernia at ages 0-5 years during 1970-87, with 12,886 male and 2534 female control subjects. The relative risk of inguinal hernia was 5.8 [95% confidence interval 4.0-8.4] for brothers of male cases and 4.3 [2.1-8.7] for brothers of female cases (both relative to brothers of control subjects). The relative risk was 3.7 [1.8-7.9] for sisters of male cases and 17.8 [6.9-46.3] for sisters of female cases (both relative to sisters of control subjects). The pattern of sex-dependent risks, particularly the large risk for sisters of female cases, suggests a multifactorial threshold model for the disease. Girls have much lower rates of inguinal hernia than boys, and if these rates are low because of a low susceptibility to disease due to the absence of a sex-related risk factor, then those girls who develop disease might have a potentially large contribution to susceptibility from genetic or intrauterine risk factors unrelated to sex.

Case-Control Studies↗

PubMed2004

Power of variance component linkage analysis-II. Discrete traits.

We determine the power of variance component linkage analysis in the case of discrete, dichotomous traits analyzed under a classical liability threshold model. For simplicity we consider randomly ascertained samples and an additive model of variation incorporating a qtl, residual additive genetic factors, and individual-specific random environmental effects. We derive an expression for the power of variance component linkage analysis in arbitrary relative pairs, and compare the power of discrete and quantitative trait linkage analysis in the specific case of sibpairs. The predicted sample sizes required in linkage analysis of sibpairs are confirmed by analysis of simulated data. Unlike the affected-sibpair method, the power of discrete trait variance component analysis increases with trait prevalence. The relative efficiency of a discrete trait for linkage analysis increases with population trait prevalence, but does not exceed about 40% and is typically much less.

Analysis of Variance↗

PubMed2002

[Effects of sociomedical risk factors on the progression of ovarian cancer].

INTRODUCTION: The potential prognostic influence of sociomedical risk factors probably on ovarian cancer patient prognosis has yet not been intensively investigated. This study was to determine whether the general psychologic constitution has an influence on patient survival after primäry surgery and in how far it correlates to sociobiologic factors. METHOD: 695 long-term followed ovarian carcinoma patients were studied. The median follow-up was 4.8 years with a range of 63 days to 18.7 years. Tumor-associated death was recorded in 219 patients. The prognostic influence of sociomedical risk factor was determined by age and stage corrected survival analysis. RESULTS: The variables "genetic or hereditary risk", "hormone replacement therapy" and "use of tobacco or alcohol" had no significant influence on survival. However, the variables "psychic disorders" and "parity" were found to be of strong prognostic influence, alone and in combination. Patients showing psychic disorders had a clearly worse prognosis (p < 0,001), as well as those of higher parity (p < 0,001). DISCUSSION: This newly described link between patients' psychological constitution and course of disease suggests psychotherapeutic support to be helpful for ovarian carcinoma patients. Risk factors, furthermore, may have an opposite effect on both cancer incidence and prognosis. The latter is discussed on the background of an ovarian carcinogenesis threshold model.

Female↗

PubMed1993

[Diagnostic results and their clinical interpretation--or: what you never wanted to know about diagnosis].

Diagnostic test results become only relevant if clinically interpreted. A key issue in clinical interpretation is the predictive value which, however, in daily practice and even in medical literature, is frequently misunderstood, as if the predictive value would be about the same as sensitivity. Sensitivity and specificity of a test only together with the prevalence of the target disease allow estimation of the predictive values. This correlation will be exemplified with the diagnosis of chorioamnionitis measuring C-reactive protein: The predictive value is not constant, but depends on prevalence. Prevalence, however, changes with clinical situation, therefore similar test results must be clinically interpreted very differently. Finally, considering these correlations, decision analysis using the "threshold model" shows how to develop a rational, quantitative approach to the selection and interpretation of diagnostic tests. Although more and more studies on decision analysis in diagnostics are published, up to now, there is little response in day-to-day practice. This situation should be changed for the sake of our patients.

C-Reactive Protein↗

PubMed2005

Quantitative analysis of binding motifs mediating diverse spatial readouts of the Dorsal gradient in the Drosophila embryo.

Dorsal is a sequence-specific transcription factor that is distributed in a broad nuclear gradient across the dorsal-ventral (DV) axis of the early Drosophila embryo. It initiates gastrulation by regulating at least 30-50 target genes in a concentration-dependent fashion. Previous studies identified 18 enhancers that are directly regulated by different concentrations of Dorsal. Here, we employ computational methods to determine the basis for these distinct transcriptional outputs. Orthologous enhancers were identified in a variety of divergent Drosophila species, and their comparison revealed several conserved sequence features responsible for DV patterning. In particular, the quality of Dorsal and Twist recognition sequences correlates with the DV coordinates of gene expression relative to the Dorsal gradient. These findings are entirely consistent with a gradient threshold model for DV patterning, whereby the quality of individual Dorsal binding sites determines in vivo occupancy of target enhancers by the Dorsal gradient. Linked Dorsal and Twist binding sites constitute a conserved composite element in certain "type 2" Dorsal target enhancers, which direct gene expression in ventral regions of the neurogenic ectoderm in response to intermediate levels of the Dorsal gradient. Similar motif arrangements were identified in orthologous loci in the distant mosquito genome, Anopheles gambiae. We discuss how Dorsal and Twist work either additively or synergistically to activate different target enhancers.

Animals↗