Genetic and environmental contributions to retrospectively reported DSM-IV childhood attention deficit hyperactivity disorder.

BACKGROUND: A variety of methodologies and techniques converge on the notion that adults and children with attention deficit hyperactivity disorder (ADHD) have similar deficits, but there is limited knowledge about whether adult retrospective reports reflect similar genetic and environmental influences implicated in childhood ADHD. METHOD: DSM-IV ADHD symptoms were collected retrospectively from 3896 young adults participating in the National Longitudinal Study of Adolescent Health. Responses from this genetically informative sample of same- and opposite-sex twins and siblings were used to determine the magnitude of genetic and environmental influences. Possible gender differences in these effects were also examined. The degree of familial specificity of the genetic and environmental influences on the Inattentive and Hyperactive-Impulsive symptom dimensions was also determined. RESULTS: Additive genetic effects contributed moderately to DSM-IV Inattentive, Hyperactive-Impulsive and Combined ADHD subtypes (heritability estimates of 0.30-0.38). Individual-specific influences accounted for the remaining proportion of the variance. Both genetic and individual-specific environmental effects contributed to the covariation of Inattentive and Hyperactive-Impulsive symptomologies. CONCLUSIONS: Results from our genetic analyses agree with previous findings based on self-assessment of current and retrospectively reported ADHD symptoms in adolescents and adults. Large individual-specific environmental influences as identified here suggest that current questionnaires used for retrospective diagnoses may not provide the most accurate reconstruction of the etiological influences on childhood ADHD in general population samples.

Genetic and environmental influences on age at sexual initiation in the Colorado Adoption Project.

Whereas the majority of research on adolescent sexual initiation has focused solely on environmental factors, the present study used behavioral genetic analyses to investigate the relative contributions of genetic and environmental influences. Structural equation models were fitted to data from adoptive and non-adoptive sibling pairs (231 biologically related pairs and 169 unrelated pairs) from the Colorado Adoption Project. Information from censored individuals who had not yet experienced sexual initiation was maximized by adapting the twin survival analysis method of Pickles et al. (Behav Genet 24(5):457-468, 1994) to accommodate adoptive and non-adoptive siblings. Point estimates of variance components from an ACE model, including additive genetic (A), shared environmental (C), and non-shared environmental (E) influences were 28%, 24%, and 48%, respectively. Despite the lower point estimate for shared environmental effects than additive genetic effects, a CE model provided the best fit to the data. However, because adoptive siblings provide a direct estimate of shared environmental influences there is greater power to detect shared environmental effects in adoption designs. Evidence for genetic influences from our data were somewhat lower than those obtained in previous twin studies, possibly reflecting a return to more socially conservative sexual attitudes, changing sexual behaviors, or ambiguities in the wording of questions commonly used in research on adolescent sexuality.

Physical mapping of autonomic/sympathetic candidate genetic loci for hypertension in the human genome: a somatic cell radiation hybrid library approach.

Allelic variation at multiple genetic loci may contribute to hypertension. Since autonomic/sympathetic dysfunction may play an early, pathogenic, heritable role in hypertension, we evaluated candidate loci likely to contribute to such dysfunction, including catecholamine biosynthetic enzymes, catecholamine transporters, neuropeptides, and adrenergic receptors. Since chromosomal locations and physical map positions of many of these loci had not yet been identified, we used the GeneBridge4 human/hamster radiation (somatic cell) hybrid library panel (resolution approximately 1 to approximately 1.5 Mb), along with specifically designed oligonucleotide primers and PCR (200-400 bp products) to position these loci in the human genome. Primers were designed from sequences outside the coding regions (3'-flanking or intronic segments) to avoid cross-species (hamster) amplification. Chromosomal positions were assigned in cR (centi-Ray) units ( approximately 270 Kbp/cR(3000) for GeneBridge 4). A total of 13 loci were newly assigned chromosomal positions; of particular interest was a cluster of adrenergic candidate loci on chromosome 5q (including ADRB2, ADRA1A, DRD1, GPRK6, and NPY6R), a region harbouring linkage peaks for blood pressure. Such physical map positions will enable more precise selection of polymorphic microsatellite and single nucleotide polymorphism markers at these loci, to aid in linkage and association studies of autonomic/sympathetic dysfunction in human hypertension.

Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy.

BACKGROUND: The introduction of expensive but very effective antiviral medications has led to questions about the effects on the total use of resources for the care of patients with human immunodeficiency virus (HIV) infection. We examined expenditures for the care of HIV-infected patients since the introduction of highly active antiretroviral therapy. METHODS: We interviewed a random sample of 2864 patients who were representative of all American adults receiving care for HIV infection in early 1996, and followed them for up to 36 months. We estimated the average expenditure per patient per month on the basis of self-reported information about care received. RESULTS: The mean expenditure was $1,792 per patient per month at base line, but it declined to $1,359 for survivors in 1997, since the increases in pharmaceutical expenditures were smaller than the reductions in hospital costs. Use of highly active antiretroviral therapy was independently associated with a reduction in expenditures. After adjustments for the interview date, clinical status, and deaths, the estimated annual expenditure declined from $20,300 per patient in 1996 to $18,300 in 1998. Expenditures among subgroups of patients varied by a factor of as much as three. Pharmaceutical costs were lowest and hospital costs highest among underserved groups, including blacks, women, and patients without private insurance. CONCLUSIONS: The total cost of care for adults with HIV infection has declined since the introduction of highly active antiretroviral therapy. Expenditures have increased for medications but have declined for other services. However, there are large variations in expenditures across subgroups of patients.

Molecular genetics of essential hypertension: recent results and emerging strategies.

Efforts to identify hypertension-predisposition genetic loci have focused largely on candidate gene strategies, in which specific candidates have been tested for linkage and association with blood pressure or the diagnosis of hypertension. A variety of candidate genes have been investigated, including loci involving the renin-angiotensin-aldosterone system, sodium epithelial channel, catecholaminergic/adrenergic function, renal kallikrein system, alpha-adducin, and others involving lipoprotein metabolism, hormone receptors, and growth factors. These studies, and more recently, several genome-wide scans, have yielded highly promising results suggesting a number of potential candidate genes and genomic regions that may contribute to blood pressure variation. The results also point to the need for more robust phenotypes that are intermediate in the pathogenetic development of high blood pressure. Additional methods and strategies for improving genetic studies of human hypertension include comparative genomics, in which results from animal studies are used to target potential blood pressure loci, the use of newly developed quantitative tests of linkage and association, comprehensive single-nucleotide polymorphism discovery in candidate loci, and the use of single-nucleotide polymorphisms in cladistic/haplotype analyses and genome-wide searches.

Propensity of HIV patients to seek urgent and emergent care. HIV Cost and Services Utilization Study Consortium.

OBJECTIVE: To assess the propensity of HIV-infected adults to seek care for common symptoms, and to determine whether they would seek care in the emergency department (ED) or with their primary care provider. DESIGN: Cross-sectional interview study. SETTING: Patients in care in the 48 contiguous United States. PARTICIPANTS: A nationally representative group of HIV- infected adults selected using multistage probability sampling. MEASUREMENTS: Subjects were interviewed between January 1996 and April 1997. Patients with advanced disease (past AIDS diagnosis and/or CD4 cell count <200/microL) and early disease were asked how they would seek care for key HIV-associated symptom complexes. Three advanced disease and 3 early disease symptom scenarios were used. MAIN RESULTS: Most advanced disease patients (78% to 87%) would seek care right away from the ED or primary care provider for the symptoms asked. Most early disease patients (82%) would seek care right away for new respiratory symptoms; fewer would do so for headache (46%) or oral white patches (62%). In a multivariate model, independent predictors of propensity to use the ED for advanced disease symptoms included African-American ethnicity (adjusted odds ratio [OR], 2.5; 95% confidence interval [95% CI], 1.8 to 3.4); less education (adjusted OR, 1.4; 95% CI, 1.1 to 1.7); drug dependence (adjusted OR, 1.4; 95% CI, 1.1 to 1.7); annual income less than $5,000 (adjusted OR, 1.5; 95% CI, 1.0 to 2.3); and lower psychological well-being (adjusted OR, 0.9; 95% CI, 0.9 to 1.0). In early disease, the following independently predicted ED use: African American (adjusted OR, 4.7; 95% CI, 3.1 to 7.1) or Hispanic ethnicity (adjusted OR 2.4; 95% CI, 1.4 to 4.3), female gender (adjusted OR, 1.6; 95% CI, 1.2 to 2.2), annual income less than $5,000 (adjusted OR, 1.8; 95% CI, 1.1 to 3. 0), and lower psychological well-being (adjusted OR, 0.9; 95% CI, 0. 8 to 1.0). CONCLUSIONS: Many patients would use the ED instead of same-day primary care for several common symptoms of HIV disease. African Americans, the poor, and patients with psychological symptoms had a higher propensity to use the ED.

Genome scan for blood pressure loci in mice.

Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with Mus spretus were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the M spretus backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse.

Estimating prevalence of type 1 and type 2 diabetes in a population of African Americans with diabetes mellitus.

The pathogenesis, treatment, and outcomes of type 1 and type 2 diabetes differ. Current surveys derive population-based estimates of diabetes prevalence by type using limited clinical information and applying classification rules developed in white populations. How well these rules perform when deriving similar estimates in African American populations is unknown. For this study, data were collected on a group of African Americans with diabetes who enrolled at the Diabetes Unit of Grady Memorial Hospital in Atlanta, Georgia, from April 16, 1991, to November 1, 1996. The data were used to develop some simple classification rules for African Americans based on a classification tree and a logistic regression model. Sensitivities and specificities, in which fasting C-peptide was used as the gold standard, were determined for these rules and for two current rules developed in mostly white, non-Hispanic populations. Rules that yielded precise (minimum variance unbiased) estimates of the prevalence of type 1 diabetes were preferred. The authors found that a rule based on the logistic regression model was best for estimating type 1 prevalences ranging from 1% to 17%. They concluded that simple classification rules can be used to estimate prevalence of diabetes by type in African American populations and that the optimal rule differs somewhat from the current rules.

Neoadjuvant androgen ablation for localized prostatic cancer: pathology methods, surgical end points and meta-analysis of randomized trials.

PURPOSE: At least 7 centers or collaborative groups have performed randomized clinical trials of neoadjuvant androgen ablation and radical prostatectomy versus radical prostatectomy alone for localized prostatic cancer. Our objectives were to analyze treatment results in terms of 2 standard outcome measures, to identify patient characteristics and other factors that explain outcome differences between trials, and to use pooled data to test the hypothesis that neoadjuvant treatment alters outcomes. MATERIALS AND METHODS: Trials were identified by MEDLINE search and review of published bibliographies, and examined for pathological techniques used to assign surgical end points. An attempt was made to contact trial group members for clarification and updated information. The resulting data were transformed as needed into standardized end points of pT stage and negative surgical margin. A series of contingency tables were used to study relationships between treatment outcomes and various risk factors. RESULTS: In addition to neoadjuvant treatment, numerous risk factors related to treatment regimen and patient characteristics apparently influenced treatment outcome, and should be reanalyzed when future followup trial data become available. CONCLUSIONS: In radical prostatectomy there is a need for uniform ways to process specimens, assign surgical stage and establish standardized surgical end points. Despite differences in risk factors, the trials were similar in overall design. Within these constraints neoadjuvant androgen ablation was significantly associated with low pT stage and negative surgical margin. Longer followup is needed to validate these measures as good surrogates for tumor specific survival.

An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.

Bench-scale testing of selected remediation alternatives for contaminated sediments.

The Assessment and Remediation of Contaminated Sediments (ARCS) Program within the U.S. Environmental Protection Agency's Great Lakes National Program Office (GLNPO) contained a component for demonstrating and evaluating sediment remediation technologies. Toward this end, bench-scale tests of solvent extraction, thermal desorption, and wet air oxidation technologies were conducted. Contaminated sediments were tested from the Grand Calumet River, Indiana; Buffalo River, New York; Saginaw River, Michigan; and Ashtabula River, Ohio. The primary contaminants of concern in these sediments were polychlorinated biphenyls (PCBs) and polynuclear aromatic hydrocarbons (PAHs). The solvent extraction tests were conducted with sediments from the Grand Calumet, Buffalo, and Saginaw rivers. The thermal desorption studies were conducted with sediments from the Grand Calumet, Buffalo, and Ashtabula rivers. The wet air oxidation testing was performed with the Grand Calumet River sediment. Raw sediment contaminant concentrations ranged from 0.32-21.9 mg/kg dry mass for PCBs and 2.70-266 mg/kg dry mass for PAHs. PCB removal or destruction efficiencies ranged from approximately 6-99%. PAH removal or destruction efficiencies ranged from 65-99%. Mass balance closures ranged from 40-99% for solids; 59-139% for water; 29-3500% for oil; 16-129% for PCBs; and 69-3170% for PAHs.

Evaluation of chemical releases and worker exposures from filter press operations.

The exposures (inhalation and dermal) and releases (air, water, solids, and process streams) associated with the filtration of industrial wastewater sludge from an electronics manufacturing plant were characterized. Chemical releases and worker exposures for a target chemical (total copper) were measured over four operational cycles. Various aspects of the filtration operation believed to influence the measurement values were documented. Worker exposures associated with the discreet stages of the filter operation were measured. Ventilation patterns around the filter press were also monitored. The workers' time-weighted average exposures to total copper during the 113-minute operational cycle ranged from 3.1 to 25 micrograms/m3 (2.2 geometric standard deviation, 6.4 micrograms/m3 geometric mean concentration). The manual removal of filter cake comprised only 15% of the time in an average filtration cycle, but produced 72% of the workers' inhalation exposure. During this cake-removal stage, inhalation exposures ranged from 11 micrograms/m3 to 130 micrograms/m3 (2.5 geometric standard deviation, 30 micrograms/m3 geometric mean concentration). Differences in worker technique may account for the large range of inhalation exposures during the cake-removal stage. Exposures and releases were successfully determined for a single unit operation, as well as for the discreet stages of operation. The data generated will enable EPA to more accurately estimate worker exposures and chemical releases for new chemicals as required by the Toxic Substances Control Act. The approach utilized will benefit industrial hygienists in providing estimates of worker exposures and aid in the targeting of survey sampling.