Determining causality and consequence of expression quantitative trait loci.

Expression quantitative trait loci (eQTLs) are currently the most abundant and systematically-surveyed class of functional consequence for genetic variation. Recent genetic studies of gene expression have identified thousands of eQTLs in diverse tissue types for the majority of human genes. Application of this large eQTL catalog provides an important resource for understanding the molecular basis of common genetic diseases. However, only now has both the availability of individuals with full genomes and corresponding advances in functional genomics provided the opportunity to dissect eQTLs to identify causal regulatory variants. Resolving the properties of such causal regulatory variants is improving understanding of the molecular mechanisms that influence traits and guiding the development of new genome-scale approaches to variant interpretation. In this review, we provide an overview of current computational and experimental methods for identifying causal regulatory variants and predicting their phenotypic consequences.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

Is the thrifty genotype hypothesis supported by evidence based on confirmed type 2 diabetes- and obesity-susceptibility variants?

AIMS/HYPOTHESIS: According to the thrifty genotype hypothesis, the high prevalence of type 2 diabetes and obesity is a consequence of genetic variants that have undergone positive selection during historical periods of erratic food supply. The recent expansion in the number of validated type 2 diabetes- and obesity-susceptibility loci, coupled with access to empirical data, enables us to look for evidence in support (or otherwise) of the thrifty genotype hypothesis using proven loci. METHODS: We employed a range of tests to obtain complementary views of the evidence for selection: we determined whether the risk allele at associated 'index' single-nucleotide polymorphisms is derived or ancestral, calculated the integrated haplotype score (iHS) and assessed the population differentiation statistic fixation index (F (ST)) for 17 type 2 diabetes and 13 obesity loci. RESULTS: We found no evidence for significant differences for the derived/ancestral allele test. None of the studied loci showed strong evidence for selection based on the iHS score. We find a high F (ST) for rs7901695 at TCF7L2, the largest type 2 diabetes effect size found to date. CONCLUSIONS/INTERPRETATION: Our results provide some evidence for selection at specific loci, but there are no consistent patterns of selection that provide conclusive confirmation of the thrifty genotype hypothesis. Discovery of more signals and more causal variants for type 2 diabetes and obesity is likely to allow more detailed examination of these issues.

ORegAnno: an open access database and curation system for literature-derived promoters, transcription factor binding sites and regulatory variation.

MOTIVATION: Our understanding of gene regulation is currently limited by our ability to collectively synthesize and catalogue transcriptional regulatory elements stored in scientific literature. Over the past decade, this task has become increasingly challenging as the accrual of biologically validated regulatory sequences has accelerated. To meet this challenge, novel community-based approaches to regulatory element annotation are required. SUMMARY: Here, we present the Open Regulatory Annotation (ORegAnno) database as a dynamic collection of literature-curated regulatory regions, transcription factor binding sites and regulatory mutations (polymorphisms and haplotypes). ORegAnno has been designed to manage the submission, indexing and validation of new annotations from users worldwide. Submissions to ORegAnno are immediately cross-referenced to EnsEMBL, dbSNP, Entrez Gene, the NCBI Taxonomy database and PubMed, where appropriate. AVAILABILITY: ORegAnno is available directly through MySQL, Web services, and online at http://www.oreganno.org. All software is licensed under the Lesser GNU Public License (LGPL).

cisRED: a database system for genome-scale computational discovery of regulatory elements.

We describe cisRED, a database for conserved regulatory elements that are identified and ranked by a genome-scale computational system (www.cisred.org). The database and high-throughput predictive pipeline are designed to address diverse target genomes in the context of rapidly evolving data resources and tools. Motifs are predicted in promoter regions using multiple discovery methods applied to sequence sets that include corresponding sequence regions from vertebrates. We estimate motif significance by applying discovery and post-processing methods to randomized sequence sets that are adaptively derived from target sequence sets, retain motifs with p-values below a threshold and identify groups of similar motifs and co-occurring motif patterns. The database offers information on atomic motifs, motif groups and patterns. It is web-accessible, and can be queried directly, downloaded or installed locally.

HIV risk behavior and HIV testing: a comparison of rates and associated factors among homeless and runaway adolescents in two cities.

This study examined differences in self-reported rates and predictors of HIV testing between homeless and runaway youths in San Diego (N = 1,102) and Los Angeles (N = 1,167). Youths aged 13-23 were recruited from agency and street sites using a stratified probability sampling design. Interviewers administered a structured survey instrument lasting 20 minutes, which assessed youths' involvement in HIV risk-related sexual and drug-use behaviors, contact with outreach workers, and other variables. Significantly more Los Angeles youths (78%) reported testing than did San Diego youths (52%; p < .001). Multivariable analyses controlling for risk behaviors, knowing someone with HIV, and contact with outreach workers indicated that the higher rates of these factors in Los Angeles did not account for the difference in testing rates between the cities. Youths in Los Angeles were still 1.85 times as likely to be tested as San Diego youths (p < .001), possibly a result of differing normative behavior and accessibility of testing services.

The impact of the women's centre of Jamaica foundation programme for adolescent mothers on repeat pregnancies

A random sample (n=260) of primiparous Jamaican adolescent mothers (12-16 years old) who gave birth in 1994 in the parishes of Kingston and St Andrew, St Catherine and Manchester was selected from vital records and interviewed in 1998 for this historical cohort study. Among programme participants, the incidence of repeat pregnancy was 37 percent compared with 60 percent among non-participants. Programme participation reduced the risk of one or more repeat pregnancies by 45 percent with 95 percent confidence interval (0.22, 0.91). Programme participants were also 1.5 times (1.005, 2.347) more likely to complete high school than non-participants; however, this effect did not achieve statistical significance. The results confirmed that the WCJF Programme exerts a considerable effect on the incidence of repeat pregnancy among participants. The benefits of programme participation were greatest among residents of the Kingston Metropolitan Area from single parent, female headed households with average incomes below J$10,000, who wanted to continue their education after the first live birth.(Au)

The impact of the Women's Centre of Jamaica Foundation programme for adolescent mothers on repeat pregnancies

A random sample (n = 260) of primiparous Jamaican adolescent mothers (12-16 years old) who gave birth in 1994 in the parishes of Kingston and St Andrew, St Catherine and Manchester was selected from vital records and interviewed in 1998 for this historical cohort study. Among programme participants, the incidence of repeat pregnancy was 37 per cent compared with 60 percent among non-participants. Programme participation reduced the risk of one or more repeat pregnancies by 45 per cent with 95 confidence interval (0.22, 0.91). Programme participants were also 1.5 times (1.005, 2.347) more likely to complete high school than non-participants; however, this effect did not achieve statistical significance. The results confirmed that the WCJF Programme exerts a considerable effect on the incidence of repeat pregnancy among participants. The benefits of programme participation were greatest among residents of the Kingston Metropolitan Area from single-parent, female-headed households with average monthly incomes below J$10,000, who wanted to continue their education after the first live birth.

The impact of the Women's Centre of Jamaica Foundation programme for adolescent mothers on repeat pregnancies

OBJECTIVES: To assess the effect of the Women's Centre of Jamaica Foundation Programme for adolescent mothers (WCJF) on the incidence of repeat pregnancies occurring between 1995 and 1998, and on the educational attainment of programme participants. DESIGN AND METHODS: A random sample (n=260) of primiparous Jamaican adolescent mothers, 12-16 years, who gave birth in 1994 in the parishes of Kingston and St Andrew, St Catherine and Manchester was selected from vital records and interviewed in 1998 for this historical cohort study. RESULTS: Only 23.5 percent of all repeat pregnancies in the entire study population were among programme participants compared with 76.5 percent among non-participant. Programme participation reduced the risk of one or more repeat pregnancies by 45 percent (0.22-0.9). Programme participants were also 1.5 times (1.00-2.3) more likely to complete high school than non-participants. CONCLUSION: The results confirmed that WCJF Programme exerts a beneficial effect on the incidence of repeat pregnancy among participants. The benefits of programme participation were greatest among residents of the Kingston Metropolitan Area from single parent, female-headed households with average monthly incomes below J$10,000, who wanted to continue their education after the first live birth.(AU)

The impact of the Women's Centre of Jamaica Foundation programme for adolescent mothers on repeat pregnancies.

A random sample (n = 260) of primiparous Jamaican adolescent mothers (12-16 years old) who gave birth in 1994 in the parishes of Kingston and St Andrew, St Catherine and Manchester was selected from vital records and interviewed in 1998 for this historical cohort study. Among programme participants, the incidence of repeat pregnancy was 37 per cent compared with 60 percent among non-participants. Programme participation reduced the risk of one or more repeat pregnancies by 45 per cent with 95% confidence interval (0.22, 0.91). Programme participants were also 1.5 times (1.005, 2.347) more likely to complete high school than non-participants; however, this effect did not achieve statistical significance. The results confirmed that the WCJF Programme exerts a considerable effect on the incidence of repeat pregnancy among participants. The benefits of programme participation were greatest among residents of the Kingston Metropolitan Area from single-parent, female-headed households with average monthly incomes below J$10,000, who wanted to continue their education after the first live birth.

Service utilization among homeless and runaway youth in Los Angeles, California: rates and reasons.

PURPOSE: To describe the service utilization patterns of homeless and runaway youth in a "service-rich" area of Los Angeles, California; identify demographic and other correlates of utilization; and contextualize the findings with qualitative data. METHOD: During Phase 1 of this study, survey data were collected from an ethnically diverse sample of 296 youth aged 13-23 years, recruited from both service and natural "hang-out" sites using systematic sampling methods. During Phase 2, qualitative data were collected from 46 youth of varying ethnicities and lengths of time homeless. RESULTS: Drop-in centers and shelters were the most commonly used services (reported by 78% and 40%, respectively). Other services were used less frequently [e.g., medical services (28%), substance abuse treatment (10%) and mental health services (9%)]. Utilization rates differed by ethnicity, length of time in Los Angeles, and city of first homeless episode (Los Angeles versus all others). Shelter use was strongly associated with use of all other services. Despite youths' generally positive reactions to services, barriers were described including rules perceived to be restrictive, and concerns youth had about confidentiality and mandated reporting. Youth suggested improvements including more targeted services, more long-term services, revised age restrictions, and more and/or better job training and transitional services to get them off the streets. CONCLUSIONS: Because shelters and drop-in centers act as gateways to other services and offer intervention potential for these hard-to-reach youth, it is vital that we understand the perceived barriers to service utilization.

Service utilization among homeless and runaway youth in Los Angeles, California: rates and reasons.

PURPOSE: To describe the service utilization patterns of homeless and runaway youth in a "service-rich" area (Los Angeles, California); identify demographic and other correlates of utilization; and contextualize the findings with qualitative data. METHOD: During Phase 1 of this study, survey data were collected from an ethnically diverse sample of 296 youth aged 13-23 years, recruited from both service and natural "hang-out" sites using systematic sampling methods. During Phase 2, qualitative data were collected from 46 youth of varying ethnicities and lengths of time homeless. RESULTS: Drop-in centers and shelters were the most commonly used services (reported by 78% and 40%, respectively). Other services were used less frequently [e.g., medical services (28%) and substance abuse treatment (10%) and mental health services (9%)]. Utilization rates differed by ethnicity, length of time in Los Angeles, and city of first homeless episode (Los Angeles vs. all others). Shelter use was strongly associated with use of all other services. Despite youths' generally positive reactions to services, barriers were described including restrictive rules, confidentiality and reporting problems, and negative interactions with staff members. Youth suggested improvements including more targeted services, more long-term services, revised age restrictions, and more and/or better job training and transitional services to get them off the streets. CONCLUSIONS: Because shelters and drop-in centers act as gateways to other services and offer intervention potential for these hard-to-reach youth, it is vital that barriers to use of these services are eliminated.

"Substance abuse" disorders among runaway and homeless youth.

This study used systematic sampling methods to recruit a sample of 432 homeless youth from both service and natural "hang-out" sampling sites. According to DSM-III criteria, the majority of respondents were classified as having an alcohol and/or illicit "drug abuse" disorder (71%). The results from multivariate logistic regression analyses indicate that cumulative length of time homeless is positively associated with risk for an "abuse" disorder. The implications of these findings and recommendations for service interventions are discussed.

Homeless youths and young adults in Los Angeles: prevalence of mental health problems and the relationship between mental health and substance abuse disorders.

Although understanding of the subsistence patterns, service utilization, and HIV-risk behaviors of homeless youths and young adults in increasing, relatively little is known about the epidemiology of mental health problems in this group or the relationships between mental health problems and substance use. This study measured symptoms of depression, low self-esteem, ADHD, suicidality, self-injurious behavior (SIB), and drug and alcohol use disorder in a sample of homeless youth and young adults living in Hollywood, CA. Results indicated extremely high prevalences of mental health problems as compared with corresponding rates of mental health problems found among housed youths in previous studies. Prevalence of mental health problems differed by age and ethnicity. African Americans were at lower risk of suicidal thoughts and SIB than were those of other ethnicities. Older respondents and females were at increased risk of depressive symptoms, and younger respondents were at increased risk of SIB. Previous history of sexual abuse and/or assault was associated with increased risk of suicidality and SIB. Risk factors for drug abuse disorders included ethnicity other than African American, homelessness for 1 year or more, suicidality, SIB, depressive symptoms, and low self-esteem. Risk factors for alcohol abuse disorder included male gender, white ethnicity, homelessness for 1 year or more, suicidality, and SIB. Extremely high rates of mental health problems and substance abuse disorders in this sample suggest the need for street-based and nontraditional mental health services targeted toward these youths and young adults.

Homeless youth and their exposure to and involvement in violence while living on the streets.

PURPOSE: The purpose of this research were to explore homeless youths' histories of exposure to violence, perpetration of violence, and fear of violent victimization, and to examine the extent to which these constructs are associated with demographic variables. METHODS: A sample of 432 youth (between 13 and 23 years old) who were homeless or at imminent risk for homelessness were sampled from both service and street sites. The percentage of youth who reported exposure to each type of violence was calculated. Multiple regression analyses were used to examine differences in the risk of exposure to violence across gender, ethnicity, age, and length of time homeless. RESULTS: Respondents reported a high rate of exposure to violence. Female respondents reported levels of exposure to violence that were as high as those reported by males. Females were more likely to report having been sexually assaulted and fearing victimization, and tended to be less likely to report perpetrating violence. With a few exceptions, ethnic identity was not a significant predictor of exposure to violence or fear of victimization. Age tended to be inversely associated with risk of exposure to violence. Length of time homeless was not associated with fear of victimization. CONCLUSIONS: Homeless youth are at high risk for exposure to a variety of forms violence as both witnesses and victims. The overall rates of exposure to violence and patterns of association with demographic variables are significantly higher than those reported in national samples of adolescents.

The Health Belief Model in understanding compliance with preventive recommendations for AIDS: how useful?

The Health Belief Model (HBM) has been applied to a variety of health conditions: most are less threatening and require less complex responses than those arising in the case of AIDS. The utility of the HBM in understanding preventive behaviors in AIDS is examined in a cohort of homosexual men at two different time points. Longitudinal analyses estimated the relationship of indices assessing susceptibility, severity, benefits, and barriers, as well as sociodemographic factors, to sexual behavior across the next 18 months. Analyses further defined these associations in specific subgroups of participants, such as those initially at lower or higher risk. In general, measures of severity and socioeconomic advantage had the most consistently beneficial effect on various measures of behavior. Little or no beneficial effect was observed for other components of the HBM, notably a measure of perceived susceptibility. These analyses suggest that the special features of AIDS may require development of more adequate theoretical frameworks.

Splenotoxicity associated with splenic sarcomas in rats fed high doses of D & C Red No. 9 or aniline hydrochloride.

A histopathologic review of F344 rat spleens from the National Toxicology Program-National Cancer Institute bioassays of barium salt of 5-chloro-2-(2-hydroxy-1-naphthalenyl)-azo-4-methylbenzenesulfonic acid [(D & C Red No. 9) CAS: 516-00-21] and aniline HCI (CAS: 142-04-1) was conducted to assess splenotoxic changes associated with splenic sarcomas induced by these aromatic amines. Four splenic changes--fatty metamorphosis (FM), splenic fibrosis (FIB), capsule hyperplasia (CH), and hemorrhage--were markedly increased in incidence and severity in males treated with high doses of either D & C Red No. 9 or aniline HCI. Females treated with high doses of either of these compounds showed similar but less severe changes. FIB and FM showed strong group correlations with tumor incidence (r greater than or equal to 0.87). All groups that demonstrated FM also demonstrated splenic sarcomas; groups without the FM lesions did not exhibit splenic tumors. The morphologic similarity of the FIB and CH lesions to the induced splenic sarcomas suggests that these lesions are preneoplastic. Moreover, the treatment-related splenic lesions appear to be precursors of the induced splenic sarcomas. Carcinogenicity studies with serial sacrifices at varying intervals will be required for experimental verification of these conclusions. A schema, based on the findings of the study, suggests a hypothetical pathway for the progression of the treatment-related splenic lesions from onset to tumor formation.

The role of anesthesia and catecholamines in the renal response to mild hemorrhage.

The role of the sympathoadrenal system in the renal response to mild hemorrhage was investigated in animals anesthetized with either sodium pentobarbital (Group I) or alpha-chloralose (Group II). Significantly greater decreases in renal blood flow (RBF) and increases in renal vascular resistance (RVR) were seen after hemorrhage in Group II than in Group I. Concomitant with these changes were increases both in circulating catecholamines and plasma renin activities. In Group II, however, the rise in plasma epinephrine was also significantly higher than in Group I. Additional studies were performed in pentobarbital anesthetized dogs either chemically denervated with 6-hydroxydopamine (Group III) or treated with the prostaglandin synthetase inhibitor indomethacin (Group IV). In Group III, following hemorrhage, changes in renal hemodynamics and circulating catecholamines were similar to those of Group I. In Group IV, although blood pressure was better maintained during hemorrhage than in the other groups, RVR increased to the same extent as in Group II, although increases in circulating catecholamines were comparable to those observed in Group I. Whereas pentobarbital anesthesia attenuated the sympathoadrenal response to mild hemorrhage, indomethacin appeared to sensitize the animals to adrenergic discharge by removing the modulatory effect of the prostaglandin system.