Developing effective treatments for posttraumatic disorders among people with severe mental illness.

OBJECTIVE: The purpose of the study was to examine strategies for developing effective interventions for clients who have both serious mental illness and posttraumatic symptoms. METHODS: The authors conducted searches for articles published between 1970 and 2000, using MEDLINE, PsycLIT, and PILOTS. They assessed current practices, interviewed consumers and providers, and examined published and unpublished documents from consumer groups and state mental health authorities. RESULTS AND CONCLUSIONS: Exposure to trauma, particularly violent victimization, is endemic among clients with severe mental illness. Multiple psychiatric and behavioral problems are associated with trauma, but posttraumatic stress disorder (PTSD) is the most common and best-defined consequence of trauma. Mental health consumers and providers have expressed concerns about several trauma-related issues, including possible underdiagnosis of PTSD, misdiagnosis of other psychiatric disorders among trauma survivors, incidents of retraumatization in the mental health treatment system, and inadequate treatment for trauma-related disorders. Despite consensus that trauma and PTSD symptoms should be routinely evaluated, valid assessment techniques are not generally used by mental health care providers. PTSD is often untreated among clients with serious mental illness, or it is treated with untested interventions. It is important that policy makers, service system administrators, and providers recognize the prevalence and impact of trauma in the lives of people with severe mental illness. The development of effective treatments for this population requires a rational, orderly process, beginning with the testing of theoretically grounded interventions in controlled clinical trials.

An abridged history of sex steroid hormone receptor action.

The field of steroid hormone action is well established, although it is barely more than four decades old. Pivotal experiments in the late 1950s and 1960s showed that hormone-binding components exist within nuclei of target tissues and that steroid hormones act by regulating gene expression, rather than directly influencing enzymatic processes. The understanding that steroid hormone receptors interact with the general transcription machinery and alter chromatin structure came in the 1970s and 1980s, and details of this mechanism continue to be elucidated. In addition, the discovery of rapid cellular responses to steroid hormones has led to the identification of putative membrane-bound steroid receptors that act without affecting gene transcription. As noted in the recent Institute of Medicine report "Exploring the Biological Contributions to Human Health: Does Sex Matter?", the effects of steroid hormones and defects in steroid hormone receptor action have a profound impact on human health and disease. Future research directives include the development of potent, selective steroid receptor modulators, the elucidation of nongenomic steroid hormone effects, and further exploration of hormone-genome interactions.

Determinants of risk behavior for human immunodeficiency virus/acquired immunodeficiency syndrome in people with severe mental illness.

We examined the prevalence and correlates of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) risk behaviors in a large sample of severely mentally ill (SMI) patients. Risk levels were correlated with demographic factors, diagnosis, symptom severity, trauma history, post-traumatic stress disorder (PTSD), substance use disorder (SUD), and sexual orientation. SMI clients from urban and rural settings (N = 275) were assessed regarding HIV/AIDS risk behaviors, and hypothesized risk factors. Patients exhibited substantial levels of risky behavior, particularly sexual risk. Correlates of increased risk included SUD, trauma, male homosexual orientation, younger age, and symptom severity. Structural equation modeling identified SUD and sexual orientation as the primary determinants of both drug and sexual risk behavior. We conclude that specific illness related variables appear to have less impact on risk behavior among people with SMI than previously hypothesized. Substance abuse prevention and treatment may be the most effective means of reducing HIV risk in this population.

Women subjects in NIH-funded clinical research literature: lack of progress in both representation and analysis by sex.

The National Institutes of Health (NIH) issued guidelines in 1990 requiring the inclusion of women and minorities in all NIH-sponsored clinical research and revised these guidelines in 1994 to require analysis of clinical trial outcomes by sex of the subjects. To ascertain whether these guidelines are yet reflected in the scientific literature, we performed a survey of research articles published in major medical journals. All original research articles in the New England Journal of Medicine, the Journal of the American Medical Association, the Journal of the National Cancer Institute, and Circulation from the years 1993, 1995, 1997, and 1998 were examined. Articles were assessed for use of human subjects, source of funding, type of study (clinical trial or not), sex-relatedness of the disease or condition, inclusion of women as study subjects, and analysis of outcomes by sex of the subjects. Among NIH-funded, non-sex-specific studies, approximately one fifth of the studies published each year failed to include women as research subjects. This number did not improve significantly over the 5-year period analyzed. Only one quarter to one third of the studies that included women analyzed data by sex of the subjects, with no significant change over the time period studied. Although most clinical trials included women as study subjects, in only a small percentage of the trials were results analyzed by sex of the subjects, with no significant improvement over time. These data clearly show the need for increased awareness and monitoring of recruitment and retention of women in clinical research and for analysis of data by sex of the subjects to be carried out consistently.

Multiple functions of Saccharomyces cerevisiae splicing protein Prp24 in U6 RNA structural rearrangements.

U6 spliceosomal RNA has a complex secondary structure that includes a highly conserved stemloop near the 3' end. The 3' stem is unwound when U6 RNA base-pairs with U4 RNA during spliceosome assembly, but likely reforms when U4 RNA leaves the spliceosome prior to the catalysis of splicing. A mutation in yeast U6 RNA that hyperstabilizes the 3' stem confers cold sensitivity and inhibits U4/U6 assembly as well as a later step in splicing. Here we show that extragenic suppressors of the 3' stem mutation map to the gene coding for splicing factor Prp24. The suppressor mutations are located in the second and third of three RNA-recognition motifs (RRMs) in Prp24 and are predicted to disrupt RNA binding. Mutations in U6 RNA predicted to destabilize a novel helix adjacent to the 3' stem also suppress the 3' stem mutation and enhance the growth defect of a suppressor mutation in RRM2 of Prp24. Both phenotypes are reverted by a compensatory mutation that restores pairing in the novel helix. These results are best explained by a model in which RRMs 2 and 3 of Prp24 stabilize an extended intramolecular structure in U6 RNA that competes with the U4/U6 RNA interaction, and thus influence both association and dissociation of U4 and U6 RNAs during the splicing cycle.

Dartmouth Assessment of Lifestyle Instrument (DALI): a substance use disorder screen for people with severe mental illness.

OBJECTIVE: Despite high rates of co-occurring substance use disorder in people with severe mental illness, substance use disorder is often undetected in acute-care psychiatric settings. Because underdetection is related to the failure of traditional screening instruments with this population, the authors developed a new screen for detection of substance use disorder in people with severe mental illness. METHOD: On the basis of criterion ("gold standard") diagnoses of substance use disorder for 247 patients admitted to a state hospital, the authors used logistic regression to select the best items from 10 current screening instruments and constructed a new instrument. They then tested the validity of the new instrument, compared with other screens, on an independent group of 73 admitted patients. RESULTS: The new screening instrument, the Dartmouth Assessment of Lifestyle Instrument (DALI), is brief, is easy to use, and exhibits high classification accuracy for both alcohol and drug (cannabis and cocaine) use disorders. Receiver operating characteristic curves showed that the DALI functioned significantly better than traditional instruments for both alcohol and drug use disorders. CONCLUSIONS: Initial findings suggest the DALI may be useful for detecting substance use disorder in acutely ill psychiatric patients. Further research is needed to validate the DALI in other settings and with other groups of psychiatric patients.

An element in human U6 RNA destabilizes the U4/U6 spliceosomal RNA complex.

Large-scale changes in RNA secondary structure, such as those that occur in some of the spliceosomal RNAs during pre-mRNA splicing, have been proposed to be catalyzed by ATP-dependent RNA helicases. Here we show that deproteinized human U4/U6 spliceosomal RNA complex, which has the potential for extensive intermolecular base pairing, contains a cis-acting element that promotes its dissociation into free U4 and U6 RNAs. The destabilzing element corresponds to the bae of putative intramolecular stem in U6 RNA that includes the 3' three-quarters of the molecule. Oligonucleotides expected to compete for U6 RNA 3' stem formation promote assembly of the human U4/U6 RNA complex under conditions that otherwise result in dissociation of the U4/U6 complex. Truncation of the putative 3' stem-forming sequences in U6 RNA by oligonucleotide-directed RNase H cleavage increases the melting temperature of the U4/U6 RNA complex by almost 20 degree C, to a level commensurate with its intermolecular base-pairing potential. We conclude that the stability of the competing human U6 RNA intramolecular 3' stem, combined with a low activation energy for conformational rearrangement, causes the human U4/U6 RNA complex to be intrinsically unstable despite its base-pairing potential. Therefore a helicase activity may not be necessary for disassembly of the human U4/U6 complex during activation of the spliceosome. We propose that a previously identified base-pairing interaction between U6 and U2 RNAs may stabilize the human U4/U6 RNA complex by antagonizing U6 RNA 3' stem formation.