The effects of temporally secondary co-morbid mental disorders on the associations of DSM-IV ADHD with adverse outcomes in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).

BACKGROUND: Although DSM-IV attention deficit hyperactivity disorder (ADHD) is known to be associated with numerous adverse outcomes, uncertainties exist about how much these associations are mediated temporally by secondary co-morbid disorders. METHOD: The US National Comorbidity Survey Replication Adolescent Supplement (NCS-A), a national survey of adolescents aged 13-17 years (n = 6483 adolescent-parent pairs), assessed DSM-IV disorders with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Statistical decomposition was used to compare direct effects of ADHD with indirect effects of ADHD through temporally secondary mental disorders (anxiety, mood, disruptive behavior, substance disorders) in predicting poor educational performance (suspension, repeating a grade, below-average grades), suicidality (ideation, plans, attempts) and parent perceptions of adolescent functioning (physical and mental health, interference with role functioning and distress due to emotional problems). RESULTS: ADHD had significant gross associations with all outcomes. Direct effects of ADHD explained most (51.9-67.6%) of these associations with repeating a grade in school, perceived physical and mental health (only girls), interference with role functioning and distress, and significant components (34.5-44.6%) of the associations with school suspension and perceived mental health (only boys). Indirect effects of ADHD on educational outcomes were predominantly through disruptive behavior disorders (26.9-52.5%) whereas indirect effects on suicidality were predominantly through mood disorders (42.8-59.1%). Indirect effects on most other outcomes were through both mood (19.8-31.2%) and disruptive behavior (20.1-24.5%) disorders, with anxiety and substance disorders less consistently important. Most associations were comparable for girls and boys. CONCLUSIONS: Interventions aimed at reducing the adverse effects of ADHD might profitably target prevention or treatment of temporally secondary co-morbid disorders.

Mental disorders as risk factors for later substance dependence: estimates of optimal prevention and treatment benefits.

BACKGROUND: Although mental disorders have been shown to predict subsequent substance disorders, it is not known whether substance disorders could be cost-effectively prevented by large-scale interventions aimed at prior mental disorders. Although experimental intervention is the only way to resolve this uncertainty, a logically prior question is whether the associations of mental disorders with subsequent substance disorders are strong enough to justify mounting such an intervention. We investigated this question in this study using simulations to estimate the number of substance disorders that might be prevented under several hypothetical intervention scenarios focused on mental disorders. METHOD: Data came from the National Comorbidity Survey Replication (NCS-R), a nationally representative US household survey that retrospectively assessed lifetime history and age of onset of DSM-IV mental and substance disorders. Survival analysis using retrospective age-of-onset reports was used to estimate associations of mental disorders with subsequent substance dependence. Simulations based on the models estimated effect sizes in several hypothetical intervention scenarios. RESULTS: Although successful intervention aimed at mental disorders might prevent some proportion of substance dependence, the number of cases of mental disorder that would have to be treated to prevent a single case of substance dependence is estimated to be so high that this would not be a cost-effective way to prevent substance dependence (in the range 76-177 for anxiety-mood disorders and 40-47 for externalizing disorders). CONCLUSIONS: Treatment of prior mental disorders would not be a cost-effective way to prevent substance dependence. However, prevention of substance dependence might be considered an important secondary outcome of interventions for early-onset mental disorders.

Enhancing immune responses using suicidal DNA vaccines.

We describe a DNA vaccine strategy that allows antigens to be produced in vivo in the context of an alphaviral replicon. Mice immunized with such vectors developed humoral and cellular immune responses at higher levels than mice that received a conventional DNA vaccine vector. Immunized animals acquired protective immunity to lethal influenza challenge. Compared with traditional DNA vaccine strategies in which vectors are persistent and the expression constitutive, the expression mediated by the alphaviral vector was transient and lytic. As a result, biosafety risks such as chromosomal integration, and the induction of immunological tolerance, could be circumvented.

Patterns and predictors of treatment seeking after onset of a substance use disorder.

BACKGROUND: We studied survey respondents aged 18 through 54 years to determine consistent predictors of treatment seeking after onset of a DSM-III-R substance use disorder. METHODS: Survey populations included a regional sample in Ontario (n = 6261), a national sample in the United States (n = 5388), and local samples in Fresno, Calif (n = 2874) and Mexico City, Mexico (n = 1734). The analysis examined the effects of demographics, symptoms, and types of substances on treatment seeking. RESULTS: Between 50% (Ontario) and 85% (Fresno) of people with substance use disorders seek treatment but the time lag between onset and treatment seeking averages a decade or more. Consistent predictors of treatment seeking include: (1) late onset of disorder (odds ratio [OR], 3.8; 95% confidence interval [CI], 2.6-5.6 for late [> or =30 years] vs early [1-15 years] age at first symptom of disorder); (2) recency of cohort (OR, 3.4; 95% CI, 2.3-5.0 for most recent [aged 15-24 years at interview] vs earliest [aged > or =45 years] cohorts); (3) 4 specific dependence symptoms (using larger amounts than intended, unsuccessful attempts to cut down use, tolerance, and withdrawal symptoms), with ORs ranging between 1.6 (95% CI, 1.3-2.0) and 2.7 (95% CI, 2.1-3.6) for people with vs without these symptoms; and (4) use vs nonuse of cocaine (OR, 2.1; 95% CI, 1.6-2.7) and heroin (OR, 2.6; 95% CI, 1.1-6.0). CONCLUSIONS: Although most people with substance use disorders eventually seek treatment, treatment seeking often occurs a decade or more after the onset of symptoms of disorder. While treatment seeking has increased in recent years, it is not clear whether this is because of increased access, increased demand, increased societal pressures, or other factors.

Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys.

BACKGROUND: To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD). METHOD: Nationally or regionally representative epidemiological interviews were administered to 74 045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: 45.7% of respondents with lifetime MDD (32.0-46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8-54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9-47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v. 46.0%; χ 2 1 = 187.0, p < 0.001) and suicide ideation (19.5 v. 8.9%; χ 2 1 = 71.6, p < 0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v. 45.4%; χ 2 1 = 108.8, p < 0.001) than low/middle-income countries (30.3 v. 20.6%; χ 2 1 = 11.7, p < 0.001). CONCLUSIONS: Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6-74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v. causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.

Alphaviruses as vectors for gene delivery.

Alphavirus vectors have become an important complement to the systems available for transient expression of cloned sequences in cell culture and in vivo. They express foreign sequences from cytoplasmically self-replicating RNA, which can be delivered into the cell either as RNA or DNA. This article outlines some of the properties of alphavirus expression systems, and discusses the pros and cons underlying their present use in basic research and for in vivo applications.

Alphavirus expression vectors and their use as recombinant vaccines: a minireview.

Alphavirus vectors have become widely used in basic research to study the structure and function of proteins and for protein production purposes. Development of a variety of vectors has made it possible to deliver foreign sequences as naked RNA or DNA, or as suicide virus particles produced using helper vector strategies. Preliminary reports also suggest that these vectors may be useful for in vivo applications where transient, high-level protein expression is desired, such as recombinant vaccines. The initial studies have already shown that alphavirus vaccines can induce strong humoral and cellular immune responses with good immunological memory and protective effects.

Patterns and predictors of treatment contact after first onset of psychiatric disorders.

OBJECTIVE: The authors used self-report data to study patterns and predictors of treatment contact after the first onset of DSM-III-R mood, anxiety, and addictive disorders. METHODS: Data from the National Comorbidity Survey, a general population survey of 8,098 respondents, were used. Disorders were assessed by using a modified version of the Composite International Diagnostic Interview. Age at onset and age at first treatment contact were assessed retrospectively. RESULTS: There was great variation across disorders in lifetime probability of treatment contact. Most treatment contact was delayed; the median delay time was between 6 and 14 years across the disorders considered here. Probability of treatment contact was inversely related to age at onset and increased in younger cohorts. The effects of sociodemographic variables were modest and inconsistent across disorders. CONCLUSIONS: The majority of people with the disorders considered here eventually make treatment contact. However, delay was pervasive. Further research is needed on the determinants of delay and on the low probability of lifetime treatment contact among people with early-onset psychiatric disorders.

Social phobia subtypes in the National Comorbidity Survey.

OBJECTIVE: This article presents epidemiologic data on the distinction between social phobia characterized by pure speaking fears and that characterized by other social fears. METHOD: The data come from the National Comorbidity Survey (N = 8,098). Social phobia was assessed with a revised version of the Composite International Diagnostic Interview. RESULTS: Latent class analysis showed that the brief set of social fears assessed in the survey can be disaggregated into a class characterized largely by speaking fears and a second class characterized by a broader range of social fears. One-third of the people with lifetime social phobia exclusively reported speaking fears, while the other two-thirds also had at least one of the other social fears assessed. The vast majority of the latter had multiple social fears including, in most cases, both performance and interactional fears. The two subtypes were similar in age at onset distribution, family history, and certain sociodemographic correlates. However, the social phobia characterized by pure speaking fears was less persistent, less impairing, and less highly comorbid with other DSM-III-R disorders than was social phobia characterized by other social fears. CONCLUSIONS: Further general population research assessing more performance and interaction fears is needed to determine whether social phobia subtypes can be refined and whether the subtypes are better conceptualized as distinct disorders. In the meantime, people who have social phobia with multiple fears, some of which are nonspeaking fears, appear to have the most impairment and should be the main focus of prevention and intervention efforts.

Psychiatric disorder onset and first treatment contact in the United States and Ontario.

OBJECTIVE: The authors describe the timing of the first treatment contact following new-onset DSM-III-R mood, anxiety, and addictive disorders in community samples from the United States and Ontario, Canada, before and after passage of the Ontario Health Insurance Plan. METHOD: The authors drew data from the National Comorbidity Survey (NCS) (N=8,098) and the mental health supplement to the Ontario Health Survey (OHS) (N= 9,953). They assessed psychiatric disorders with a modified version of the Composite International Diagnostic Interview; they also assessed retrospectively age at disorder onset and first treatment contact. They used the Kaplan-Meier method to generate time-to-treatment curves and survival analysis to compare time-to-treatment intervals across the two surveys. RESULTS: The overall time-to-treatment curves revealed substantial differences between disorders that were consistent across the two surveys. In both surveys, panic disorder had the highest probability of first-year treatment (NCS, 65.6%; OHS supplement, 52.6%), while phobia (NCS, 12.0%; OHS supplement: 6.5%) and addictive disorders (NCS, 6.4%; OHS supplement, 4.2%) had the lowest in both surveys. Retrospective subgroup analysis suggests that before the passage of the Ontario public insurance plan, the likelihood of receiving treatment in the year of disorder onset was greater in Ontario than in the United States but that this relationship reversed following passage of the Ontario plan. During this period, the authors observed no significant between-country differences in the probability of prompt treatment of adults with 12 or fewer years of education. CONCLUSIONS: These results challenge the assumption that the universal health insurance plan in Ontario promotes greater access to mental health services than is available in the United States for vulnerable groups. Marked differences between disorders in the speed to first treatment suggest that in both countries, clinical factors play an important role in the timing of the initial decision to seek treatment.

Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys.

OBJECTIVE: Generalized anxiety disorder might be better conceptualized as a prodrome, residual, or severity marker of major depression or other comorbid disorders than as an independent diagnosis. The authors questioned whether generalized anxiety disorder itself is associated with role impairment or whether the impairment of patients with generalized anxiety disorder is due to depression or other comorbid disorders. METHOD: The authors assessed data from the National Comorbidity Survey and the Midlife Development in the United States Survey for generalized anxiety disorder and major depression at 12 months by using the DSM-III-R criteria with modified versions of the Composite International Diagnostic Interview. RESULTS: The prevalences of generalized anxiety disorder at 12 months were 3.1% and 3.3%, respectively, in the National Comorbidity Survey and the Midlife Development in the United States Survey; the prevalences of major depression at 12 months were 10.3% and 14.1%. The majority of respondents with generalized anxiety disorder at 12 months in the National Comorbidity Survey (58.1%) and the Midlife Development in the United States Survey (69.7%) also met the criteria for major depression at 12 months. Comparisons of respondents with one versus neither disorder showed that both disorders had statistically significant independent associations with impairment that were roughly equal in magnitude. These associations could not be explained by the other comorbid DSM-III-R disorders or by sociodemographic variables. CONCLUSIONS: These results show that a substantial amount of generalized anxiety disorder occurs independently of major depression and that the role impairment of generalized anxiety disorder is comparable to that of major depression.

Social consequences of psychiatric disorders, II: Teenage parenthood.

OBJECTIVE: The subject of this study was the relation between retrospectively reported early-onset psychiatric disorders and subsequent teenage parenthood in the general population. METHOD: The data were from 5,877 respondents aged 15-54 years in the National Comorbidity Survey, a nationally representative household survey. Information on respondents' DSM-III-R anxiety disorders, mood disorders, substance abuse disorders, and conduct disorder, age at the birth of the first child, and teenage sexual activity was collected in face-to-face interviews. RESULTS: Early-onset psychiatric disorders were associated with subsequent teenage parenthood among both females and males, with significant odds ratios of 2.0-12.0 and population attributable risk proportions of 6.2%-33.7%. Disaggregation analyses showed that disorders were associated with increased probability of sexual activity but not with decreased probability of using contraception. CONCLUSIONS: These results add to a growing body of evidence that psychiatric disorders are associated with a variety of adverse life consequences. The current policy debate concerning universal insurance coverage needs to take this into consideration. Planners of interventions aimed at preventing teenage pregnancy should consider including a mental health treatment component in their intervention packages. Mental health professionals treating adolescents need to be sensitized to their higher risk of pregnancy, while family doctors and specialists treating teenage mothers or their children need to be sensitized to the mothers' higher risk of psychiatric disorder.

PIP: Data from the US National Comorbidity Survey on 5877 respondents 15-54 years of age were used to assess the relationship between retrospectively identified early-onset psychiatric disorders and subsequent adolescent parenthood. Between 21-24% of the sample's male and female age cohorts reported having their first child at ages 15-19 years. The cumulative and conditional probability curves for adolescent parenthood were consistently higher among men and women with prior psychiatric diagnoses of anxiety, affective, addictive, and conduct disorders than among those without psychiatric diagnoses. The diagnosis most predictive of adolescent parenthood was addictive disorders. The population attributable risk proportions of births of first children to teenagers associated with the psychiatric disorders were 11.1% in the teenage female subsample with premarital childbearing, 6.2% in the teenage female subsample with marital childbearing, and 33.7% in the teenage male subsample with premarital parenthood. Physicians and mental health professionals who work with adolescents with psychiatric conditions should be aware of the increased risk of adolescent pregnancy and a mental health component should be added to adolescent pregnancy prevention programs.

Outcome of immunization of cynomolgus monkeys with recombinant Semliki Forest virus encoding human immunodeficiency virus type 1 envelope protein and challenge with a high dose of SHIV-4 virus.

Infection of macaques with chimeric simian-human immunodeficiency viruses (SHIVs) allows evaluation of HIV-1 envelope vaccines. SHIV-4 is based on SIVmac239 but carries the env, tat, and rev genes of HIV-1IIIB. In this study we used Semliki Forest virus (SFV) RNA vectors to express the envelope protein gp160 of HIV-1IIIB in cynomolgus macaques. Monkeys were immunized four times with recombinant suicide SFV. Whereas two of four monkeys showed T cell-proliferative responses, only one monkey had demonstrable levels of antibodies to HIV-1 gp41 and gp120 as shown by enzyme-linked immunosorbent assay (ELISA) and Western blot. The vaccinated monkeys and four control animals were challenged with 10,000 MID100 (100% minimum infectious doses) of cell-free monkey cell-grown SHIV-4 virus. As demonstrated by virus isolation, all macaques became infected after challenge. All vaccinated monkeys showed an HIV-1-specific anamnestic T cell-proliferative response. Three of four vaccines had developed HIV-1-Env-specific antibodies 2 weeks after challenge whereas none of the four controls showed any detectable immune response at this time point. Furthermore, three of four vaccinated monkeys had no demonstrable viral antigenemia and low viral load as opposed to one of the four naive control animals.

Controlling lipase enantioselectivity for organic synthesis.

Lipases are used frequently as chiral catalysts in the synthesis of various fine chemicals and intermediates. The increasing need of compounds with high stereochemical purity requires catalysts with an improved and controlled performance. This overview emphasizes some important aspects for the control of lipase enantioselectivity and some examples where the enantioselectivity has been altered or reversed are highlighted. However, in several of these cases the complete explanation for the altered or reversed enantioselectivity remains unclear and needs to be solved. Three different strategies (engineering of the reaction medium, the substrate molecule, and the enzyme) for exploring lipase enantioselectivity at a molecular level are discussed and summarized. These three different approaches represent powerful tools for understanding the molecular basis for lipase enantioselective catalysis and can guide the rational improvement and tailoring of catalyst performance. By combining approaches from chemistry and biology much is learnt about the most important parameters controlling lipase enantioselectivity for organic synthesis.

Creation of a synthetically useful lipase with higher than wild-type enantioselectivity and maintained catalytic activity.

[reaction: see text] We have found that two Geotrichum candidum lipase isozymes have remarkably different abilities to differentiate between enantiomers of ethyl 2-methyldecanoate. By rational recombination of selected portions of the two isozymes, we have created a novel lipase with an enantioselectivity superior to that of the best wild-type parent isozyme. Site-directed mutagenesis identified two key amino acid residues responsible for the improved enantioselectivity without compromised total activity of the reengineered enzyme.

The prevalence and correlates of untreated serious mental illness.

OBJECTIVE: To identify the number of people in the United States with untreated serious mental illness (SMI) and the reasons for their lack of treatment. DATA SOURCE/STUDY DESIGN: The National Comorbidity Survey; cross-sectional, nationally representative household survey. DATA COLLECTION: An operationalization of the SMI definition set forth in the Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act identified individuals with SMI in the 12 months prior to the interview. The presence of SMI then was related to the use of mental health services in the past 12 months. PRINCIPAL FINDINGS: Of the 6.2 percent of respondents who had SMI in the year prior to interview, fewer than 40 percent received stable treatment. Young adults and those living in nonrural areas were more likely to have unmet needs for treatment. The majority of those who received no treatment felt that they did not have an emotional problem requiring treatment. Among those who did recognize this need, 52 percent reported situational barriers, 46 percent reported financial barriers, and 45 percent reported perceived lack of effectiveness as reasons for not seeking treatment. The most commonly reported reason both for failing to seek treatment (72 percent) and for treatment dropout (58 percent) was wanting to solve the problem on their own. CONCLUSIONS: Although changes in the financing of services are important, they are unlikely by themselves to eradicate unmet need for treatment of SMI. Efforts to increase both self-recognition of need for treatment and the patient centeredness of care also are needed.

Hazardous petrol hydrocarbons from refuelling with and without vapour recovery.

Hydrocarbons in air were determined at pioneering European service stations equipped with vapour recovery systems. Vapour recovery was found capable of eliminating 99% of exposure during refuelling and greater than 95% of emissions to air. Vapour recovery is now being rapidly introduced at Swedish service stations as a result of demands concerning environmental and health hazards. The analytical technique used permitted samples corresponding to a single refuelling procedure to be analyzed. Sampling on an adsorbent tube was followed in the laboratory by thermal desorption and capillary gas chromatography. All prominent hydrocarbons were well separated on a methylsilicone phase. These include benzene and the alkenes of special interest with respect to health hazards. The particular importance of alkenes with respect to the formation of ozone and other photooxidants is discussed. The four isomeric butenes and the six isomeric pentenes were determined and found to constitute approximately 10% by weight of the petrol vapour. The highly reactive 2-alkenes were more abundant than the 1-alkenes.

Semliki Forest virus expression system: production of conditionally infectious recombinant particles.

In the recently developed Semliki Forest virus (SFV) DNA expression system, recombinant RNA encoding the viral replicase, and helper RNA molecules encoding the structural proteins needed for virus assembly are cotransfected into cells. Since the helper RNA lacks the sequence needed for its packaging into nucleocapsids, only recombinant RNAs should be packaged. We have found, however, that small amounts of replication-proficient SFV particles can still be produced. Here we describe the construction of a helper variant with a mutation in the gene encoding the viral spike protein such that its product cannot undergo normal proteolytic processing to activate viral entry functions. Hence, the recombinant stock is noninfectious, but may be activated by cleavage with chymotrypsin. When recombinant virus produced with the new helper was examined in a variety of assays, including sensitive animal tests, we were unable to detect any replication-competent SFV particles. We therefore conclude that this conditional expression system meets extremely stringent biosafety requirements.

A comparative analysis of role attainment and impairment in binge-eating disorder and bulimia nervosa: results from the WHO World Mental Health Surveys.

Background. Cross-national population data from the WHO World Mental Health surveys are used to compare role attainments and role impairments associated with binge-eating disorder (BED) and bulimia nervosa (BN). Methods. Community surveys assessed 23 000 adults across 12 countries for BED, BN and ten other DSM-IV mental disorders using the WHO Composite International Diagnostic Interview. Age-of-onset was assessed retrospectively. Ten physical disorders were assessed using standard conditions checklists. Analyses examined reciprocal time-lagged associations of eating disorders (EDs) with education, associations of early-onset (i.e., prior to completing education) EDs with subsequent adult role attainments and cross-sectional associations of current EDs with days of role impairment. Results. BED and BN predicted significantly increased education (females). Student status predicted increased risk of subsequent BED and BN (females). Early-onset BED predicted reduced odds of current (at time of interview) marriage (females) and reduced odds of current employment (males). Early-onset BN predicted increased odds of current work disability (females and males). Current BED and BN were both associated with significantly increased days of role impairment (females and males). Significant BED and BN effects on adult role attainments and impairments were explained by controls for comorbid disorders. Conclusions. Effects of BED on role attainments and impairments are comparable with those of BN. The most plausible interpretation of the fact that these associations are explained by comorbid disorders is that causal effects of EDs are mediated through secondary disorders. Controlled treatment effectiveness studies are needed to trace out long-term effects of BED-BN on secondary disorders.