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Genetic and environmental influences on drug use and abuse/dependence in male and female twins.

Twins were recruited through alcohol and drug treatment programs. With structural equation modeling, genetic and environmental estimates were obtained for use and DSM-III abuse/dependence of sedatives, opioids, cocaine, stimulants, and cannabis as well as any illicit drug. Analyses were conducted separately for males and females. Models included thresholds based on population prevalence of use or abuse/dependence and ever having been in treatment. Genetic influences were found for most measures. They were generally stronger for males than females and for clinical diagnoses of abuse/dependence compared to use. Common environmental influences played a greater role in use than abuse/dependence.

Adolescent↗

A nursing intervention to decrease depression in family caregivers of persons with dementia.

The goal of this study was to evaluate a community-based psychoeducational-nursing intervention designed to teach home caregivers to manage behavioral problems of persons with Alzheimer's disease and related dementias (ADRD) using the Progressively Lowered Stress Threshold (PLST) model, and to compare this intervention with routine information and referrals for case management, community-based services, and support groups. Previous caregiver studies have overwhelmingly pointed to the adverse effects of caregiving on the caregivers' physical and mental health, and high prevalence rates of depression among caregivers of persons with ADRD have consistently been reported. Therefore, a primary aim was to evaluate the impact of the intervention on caregivers' affective responses, especially depression. Data from both the Profile of Moods States and the Geriatric Depression Rating Scale support the effectiveness of this intervention in decreasing depression among caregivers who received the experimental training. Additional analysis of factors associated with caregiver depression are also reported. The pivotal role of psychiatric nurses in the assessment and treatment of depression among caregivers of persons with ADRD is discussed.

Adaptation, Psychological↗

Dynamics of neuronal responses in macaque MT and VIP during motion detection.

We examined how the relationship between neuronal activity and behavior evolved over time during a motion-detection task. Recording from two regions of visual cortex that process motion, the middle temporal (MT) and ventral intraparietal (VIP) areas, we used the time it took subjects to detect a motion stimulus to evaluate the dynamics of the underlying neuronal signals. Single-neuron activity was correlated with stimulus detection and reaction time (RT) in both areas. The rising edge of the population response from both areas was highly predictive of RT using a simple threshold-detection model. The time course of the population responses, however, differed between MT and VIP. For MT, the onset of the neuronal response was relatively constant, whereas for VIP the onset of the neuronal responses increased with RT. In contrast to previous studies, we found that single neurons were not reliable detectors of the motion signal when constrained by realistic detection times.

Action Potentials↗

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain.

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.

Animals↗

A pilot study of immune and mood outcomes of a community-based intervention for dementia caregivers: the PLST intervention.

Providing care to a family member with dementia is conceptualized as a chronic stressor with adverse psychological and physical effects. The purpose of this pilot study was to evaluate mood and immune outcomes of caregivers exposed to a community-based psychoeducational nursing intervention based on the progressively lowered stress threshold (PLST) model. The PLST intervention is designed to strengthen the psychological resources of dementia caregivers by teaching methods of preventing and/or managing behavioral problems exhibited by the person with dementia. Mood and immune outcomes were compared between caregivers randomly assigned to receive either the PLST or a comparison intervention. Results of this pilot study suggest that caregivers who received the PLST intervention showed significantly stronger T-cell proliferative responses to both PHA and ConA, indicating an improvement in T-cell immune function immediately after the in-home intervention (T2) and again after 6 months of telephone support for application of the PLST model (T3). Findings do not support the hypothesis that the PLST intervention had a significant effect on total mood disturbance or natural killer cell cytotoxicity over the course of the study.

Aged↗

The relevance of genetic susceptibility in Graves' disease and immune thyroiditis.

It has been known for a long time that there is an increased incidence of Graves' disease and immune thyroiditis in certain families. Genetic research of this disease has shown that it is most probably transmitted in a multifactorial way, i.e. that environmental as well as genetic factors play a role in the genesis of the diseases. This hypothesis is supported by the fact that the rate of concordance is maximally 50% in identical twins. The following model of threshold values is conceivable for the formal genetics of Graves' disease and immune thyroiditis: the diseases break out whenever the sum of environmental (viruses, bacteria, iodine excess, hormones, stress) and genetic (MHC and non MHC-restricted) factors is higher than a given threshold. One of the major genes influencing the genesis of the diseases seems to be HLA-DR3 (or a closely linked gene in strong linkage disequilibrium). If this gene is present, fewer environmental factors are possibly needed.

Disease Susceptibility↗

Partitions with short sequences and mock theta functions.

P. A. MacMahon was the first to examine integer partitions in which consecutive integers were not allowed as parts. Such partitions may be described as having sequences of length 1. Recently it was shown that partitions containing no sequences of consecutive integers of length k are of interest in seemingly unrelated problems concerning threshold growth models. The object now is to develop the subject intrinsically to both provide deeper understanding of the theory and application of partitions and reveal the surprising role of Ramanujan's mock theta functions.

Journal Article↗

Tumour induction in mouse epidermal cells irradiated by hot particles.

We have shown elsewhere that highly non-uniform exposure to ionizing radiation from authentic Chernobyl-released and artificially-produced hot particles (fragments of nuclear fuel) transform fibroblastic 10T1/2 cells in vitro effectively. We have also shown that hot-particle exposure leads to mutation and overexpression of the tumour suppressor gene p53 (and some other growth-related genes) in mouse skin in vivo at a high frequency. In the present paper it is shown that hot-particles produced by irradiating natural uranium with slow neutrons, when implanted (immobilized) under the skin of hairless and nude mice, induce epidermal tumours in excess compared with the conventional non-threshold stochastic model of radiation-induced cancer. One explanation for the effectiveness of the hot-particle exposure, under the present assay conditions, is that the same cells in which specific radiation-induced DNA damage is most likely to occur, are forced into sustained mitotic activity in the chronic wound which develops around the radiation source (combined genotoxic and nongenotoxic effects). The results are consistent with a role for cell proliferation in multistage carcinogenesis in mouse skin.

Accidents↗

Issues in the control of low-level radiation exposure.

The carcinogenic risks of exposure to low level ionizing radiation used by the International Commission on Radiation Protection (ICRP) have been challenged as being, at the same time, both too high and too low. This paper explains that the epidemiological evidence will always be limited at low doses, so that understanding the cellular mechanisms of carcinogenesis is increasingly important to assess the biological risks. An analysis is then given of the reasons why the challenges to ICRP, especially about the linear non-threshold response model, have arisen. As a result of considering the issues, the Main Commission of ICRP is now consulting on a revised, simpler, approach based on an individual oriented philosophy. This represents a potential shift by the Commission from the past emphasis on societal-oriented criteria. These proposals have been promulgated through the International Radiation Protection Association (IRPA) and an open literature publication was published in the Journal of Radiological Protection' in June 1999. On the basis of comments received and the observations presented at the IRPA 10 Conference, the Commission will begin to develop the outline of the next Recommendations. It is now more than ten years since ICRP distributed, for comment, a draft of what was to become the publication of the 1990 Recommendations. The Commission plans to develop its new Recommendations on a time scale of the next four or five years. In this paper, many of the issues that will need to be addressed in the development of the recommendations will be identified. These issues will cover biological effects, dosimetric quantities and the establishment of those levels of dose at which different protection requirements will be put into place. Concepts of exclusion and exemption will need to be clarified as well as the meaning of how to achieve what the proposal identifies as 'As Low as Reasonably Practicable' (ALARP). Finally, the Commission has decided to develop an environmental radiation protection philosophy that will need to be developed as part of the new Recommendations.

DNA Damage↗

Control of low-level radiation exposure: time for a change?

The carcinogenic risks of exposure to low-level ionising radiation used by the ICRP have been challenged as being, at the same time, both too high and too low. This paper explains that the epidemiological evidence will always be limited at low doses, so that understanding the cellular mechanisms of carcinogenesis is increasingly important to assess the biological risks. An analysis is then given of the reasons why the challenges to the ICRP, especially about the linear non-threshold response model, have arisen. As a result of considering the issues, the Main Commission of the ICRP is now proposing a revised, simpler, approach based on the concept of what is being called 'controllable dose'. This is an individual-based philosophy and represents a shift in emphasis by the Commission from societal-oriented criteria using Collective Dose. Finally the paper speculates on the consequences for radiological protection of such a change in policy. The Commission wishes its ideas to be discussed as part of its reconsideration of its recommendations.

Dose-Response Relationship, Radiation↗

The potential for bias in Cohen's ecological analysis of lung cancer and residential radon.

Cohen's ecological analysis of US lung cancer mortality rates and mean county radon concentration shows decreasing mortality rates with increasing radon concentration (Cohen 1995 Health Phys. 68 157-74). The results prompted his rejection of the linear-no-threshold (LNT) model for radon and lung cancer. Although several authors have demonstrated that risk patterns in ecological analyses provide no inferential value for assessment of risk to individuals, Cohen advances two arguments in a recent response to Darby and Doll (2000 J. Radiol. Prot. 20 221-2) who suggest Cohen's results are and will always be burdened by the ecological fallacy. Cohen asserts that the ecological fallacy does not apply when testing the LNT model, for which average exposure determines average risk, and that the influence of confounding factors is obviated by the use of large numbers of stratification variables. These assertions are erroneous. Average dose determines average risk only for models which are linear in all covariates, in which case ecological analyses are valid. However, lung cancer risk and radon exposure, while linear in the relative risk, are not linearly related to the scale of absolute risk, and thus Cohen's rejection of the LNT model is based on a false premise of linearity. In addition, it is demonstrated that the deleterious association for radon and lung cancer observed in residential and miner studies is consistent with negative trends from ecological studies, of the type described by Cohen.

Air Pollutants, Radioactive↗

Thresholds and stability analysis of models for the spatial spread of a fatal disease.

A simple two-class (susceptibles and infectives) model describing the dynamics of a fatal disease in a variable-size population is presented and analysed. Spatial dependence is introduced into the model by considering two different mechanisms for the geographic spread of the disease: nonlocal interaction between susceptibles and infectives, and migratory spread of the animals. The steady states and their stability for these spatially dependent models are deduced; no spatially heterogeneous steady states were possible. For nonlocal interaction, there were two spatially uniform steady states: the trivial state (no infectives or susceptibles), which was unstable, and the endemic state (constant proportion of the population infected), which was locally asymptotically stable. With migratory spread, the number of spatially uniform steady states was dependent on the boundary conditions imposed. With hostile (Dirichlet) boundary conditions, only the trivial steady state was possible and its local stability found to depend on the rate of diffusion of the total population. With no-flux (Neumann) boundary conditions, the steady states are the trivial and endemic states; these were unstable and locally asymptotically stable, respectively.

Animals↗

Using high-dimensional environmental covariates to study genotype by environment interaction for reproductive traits in Duroc boars.

We investigated the potential of incorporating grid-cell-based environmental covariates (ECs) in the genetic evaluation of total sperm count (TSC), sperm motility (MOT), and sperm morphology (MOR) for Duroc boars. A total of 188,665 records derived from 3,684 genotyped boars, born between December 2018 and October 2024 and raised in three stud farms located in different U.S. states, were analyzed using multi-trait linear-threshold repeatability models. To account for genotype by environment interactions (GE), we constructed an interaction matrix as the Hadamard product of the genomic relationship matrix and an environmental (co)variance matrix. The environmental groups were defined in three ways: farm, farm-season, and farm-year-season. The (co)variance matrix was constructed based on daily ECs obtained from the NASA POWER database for each environmental group. Of all available ECs, those significantly associated with TSC, MOT, and MOR (temperature, relative humidity, atmospheric pressure, and wind speed and direction) were retained. We evaluated five models with different GE structures: M1 represented the baseline without accounting for GE, in M2 the GE included farm as environmental groups, in M3 the GE included farm-season as environmental groups, in M4 the GE included farm-year-season as environmental groups, and M5 involved M3 with an additional random effect of the farm-season. Estimates of heritability for TSC, MOT, and MOR ranged from 0.03 to 0.04, 0.05 to 0.08, and 0.04 to 0.08, respectively. Corresponding repeatability ranged from 0.15 to 0.23, 0.28 to 0.49, and 0.28 to 0.49. The proportion of phenotypic variance attributed to GE variance ranged from 0.00 to 0.32, 0.00 to 0.44, and 0.00 to 0.44. Lastly, estimates of genetic correlation, TSC-MOT, TSC-MOR, and MOT-MOR ranged from 0.27 to 0.31, 0.24 to 0.31, and 0.98 to 0.99, respectively, with minor differences across models. We assessed the predictive ability of models using the linear regression validation. Across traits and models, bias ranged from -0.05 to 0.02 standard deviations, slope varied from 0.88 to 0.99, the correlation ranged from 0.75 to 0.84, and accuracy from 0.41 to 0.53. Overall, building the GE matrix considering grid-cell-based ECs helped to account for GE, thereby reducing the proportion of phenotypic variance attributed to genetic components; however, it did not improve the validation metrics. Additional on-farm records for ECs may improve the model performance.

Animals↗

Improvement in prediction of solvent accessibility by probability profiles.

The capability of predicting folding and conformation of a protein from its primary structure is probably one of the main goals of modern biology. An accurate prediction of solvent accessibility is an intermediate step along this way. A new method for predicting solvent accessibility from single sequence and multiple alignment data is described. The method is based on probability profiles calculated on an amino acid sequence centred on the residue whose accessibility has to be predicted. A profile is constructed for each exposure category considered so as to calculate the probability of a sequence being generated by the different profiles. Prediction accuracy was tested on a variety of protein sets with two- and three-state models. Different thresholds were used according to those adopted by the authors proposing the data sets. The prediction accuracy is significantly improved over existing methods.

Algorithms↗

Stability of diagnosis: application to phenotype definition.

Using diagnostic stability data from independent diagnostic interviews conducted 6 years apart, we determine which diagnoses are predictive of diagnoses 6 years later. Logistic analysis using categorical predictors is used to establish ordinal relationships and to suggest diagnostic hierarchies. The multiple-threshold multifactorial model is used to estimate the within-person correlation over time. Rather than use a simple dichotomy of "affected" or "unaffected," we provide odds ratios for mania, hypomania, and major depressive disorder in terms of diagnostic hierarchies, allowing a ranking of these diagnoses. This division increases the information for genetic studies or studies of a phenotype with correlated biological or environmental continuous covariates. The diagnosis of schizophrenia shows remarkable specificity across occasions. We find significant error in a cross-sectional assessment in this nonclinical sample. Assuming a multifactorial model, the proportion of variance in liability due to assessment error is approximately 30 percent under all schemes considered. The use of repeated measures in family studies is thus strongly recommended.

Bipolar Disorder↗

The bell tolls for LNT.

The linear no-threshold (LNT) model has been a convenient tool in the practice of radiation protection, but it is not supported by scientific data at doses less than about 100 millisievert or at chronic dose rates up to at least 200 millisievert per year. Radiation protection practices based on the LNT model yield no demonstrable benefits to health when applied at lower annual doses. The assumption that such exposures are harmful may not even be conservative and has helped to foster an unwarranted fear of low-level radiation. For its new recommendations, to be issued probably in 2005, the International Commission on Radiological Protection (ICRP) has said that it expects to continue the application of the LNT model "above a few millisievert per year." National societies for radiation protection may wish to consider the need to lobby the ICRP, through the auspices of International Radiation Protection Association, to further relax adherence to the LNT assumption--up to "a few tens of millisievert per year."

Body Burden↗

A sex-adjusted and age-adjusted genome screen for nested alcohol dependence diagnoses.

Alcohol dependence is a complex disorder with a substantial genetic contribution to susceptibility. The Collaborative Study on the Genetics of Alcoholism is a multi-site study whose purpose is to detect, localize, and characterize genes contributing to this susceptibility. Previous linkage analyses of the trait of alcohol dependence in Collaborative Study on the Genetics of Alcoholism have used affected sib-pair methods with a dichotomous phenotype definition. In contrast, the analysis in this paper uses a sex-adjusted and age-adjusted multiple threshold liability model. The use of such a model, in that it includes unaffected as well as as affected subjects and in that it utilizes the differential severity of a diagnosis scale, should heuristically be more powerful than a straight affected sib-pair analysis. Three regions of interest are found on chromosome 1 (lod 5.17), chromosome 4 (lod 3.46), and chromosome 8 (lod 4.31). The region on chromosome 1 near the marker D1S532 is in the region previously reported as linked to alcohol dependence and correlated phenotypes in this dataset. The region on chromosome 4 near the alcohol dehydrogenase gene cluster has been reported to be linked to alcohol dependence in other studies, as well as to the alcohol consumption phenotype 'Maximum Number of Drinks in a 24-Hour Period' in this dataset. The region on chromosome 8 near the marker D8S1988 is homologous to a section of rat chromosome 5 to which an alcohol consumption phenotype has been linked.

Alcohol Drinking↗

Radiation exposure from diagnostic imaging in severely injured trauma patients.

BACKGROUND: Trauma patients often require multiple imaging tests, including computed tomography (CT) scans. CT scanning, however, is associated with high-radiation doses. The purpose of this study was to measure the radiation doses trauma patients receive from diagnostic imaging. METHODS: A prospective cohort study was conducted from June 1, 2004 to March 31, 2005 at a Level I trauma center in Toronto, Canada. All trauma patients who arrived directly from the scene of injury and who survived to discharge were included. Three dosimeters were placed on each patient (neck, chest, and groin) before radiologic examination. Dosimeters were removed before discharge. Surface doses in millisieverts (mSv) at the neck, chest, and groin were measured. Total effective dose, thyroid, breast, and red bone marrow organ doses were then calculated. RESULTS: Trauma patients received a mean effective dose of 22.7 mSv. The standard "linear no threshold" (LNT) model used to extrapolate from effects observed at higher dose levels suggests that this would result in approximately 190 additional cancer deaths in a population of 100,000 individuals so exposed. In addition, the thyroid received a mean dose of 58.5 mSv. Therefore, 4.4 additional fatal thyroid cancers would be expected per 100,000 persons. In all, 22% of all patients had a thyroid dose of over 100 mSv (mean, 156.3 mSv), meaning 11.7 additional fatal thyroid cancers per 100,000 persons would result in this subgroup. CONCLUSION: Trauma patients are exposed to significant radiation doses from diagnostic imaging, resulting in a small but measurable excess cancer risk. This small individual risk may become a greater public health issue as more CT examinations are performed. Unnecessary CT scans should be avoided.

Adult↗