Posttraumatic stress disorder in the World Mental Health Surveys.

BACKGROUND: Traumatic events are common globally; however, comprehensive population-based cross-national data on the epidemiology of posttraumatic stress disorder (PTSD), the paradigmatic trauma-related mental disorder, are lacking. METHODS: Data were analyzed from 26 population surveys in the World Health Organization World Mental Health Surveys. A total of 71 083 respondents ages 18+ participated. The Composite International Diagnostic Interview assessed exposure to traumatic events as well as 30-day, 12-month, and lifetime PTSD. Respondents were also assessed for treatment in the 12 months preceding the survey. Age of onset distributions were examined by country income level. Associations of PTSD were examined with country income, world region, and respondent demographics. RESULTS: The cross-national lifetime prevalence of PTSD was 3.9% in the total sample and 5.6% among the trauma exposed. Half of respondents with PTSD reported persistent symptoms. Treatment seeking in high-income countries (53.5%) was roughly double that in low-lower middle income (22.8%) and upper-middle income (28.7%) countries. Social disadvantage, including younger age, female sex, being unmarried, being less educated, having lower household income, and being unemployed, was associated with increased risk of lifetime PTSD among the trauma exposed. CONCLUSIONS: PTSD is prevalent cross-nationally, with half of all global cases being persistent. Only half of those with severe PTSD report receiving any treatment and only a minority receive specialty mental health care. Striking disparities in PTSD treatment exist by country income level. Increasing access to effective treatment, especially in low- and middle-income countries, remains critical for reducing the population burden of PTSD.

The association between childhood adversities and subsequent first onset of psychotic experiences: a cross-national analysis of 23 998 respondents from 17 countries.

BACKGROUND: Although there is robust evidence linking childhood adversities (CAs) and an increased risk for psychotic experiences (PEs), little is known about whether these associations vary across the life-course and whether mental disorders that emerge prior to PEs explain these associations. METHOD: We assessed CAs, PEs and DSM-IV mental disorders in 23 998 adults in the WHO World Mental Health Surveys. Discrete-time survival analysis was used to investigate the associations between CAs and PEs, and the influence of mental disorders on these associations using multivariate logistic models. RESULTS: Exposure to CAs was common, and those who experienced any CAs had increased odds of later PEs [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.9-2.6]. CAs reflecting maladaptive family functioning (MFF), including abuse, neglect, and parent maladjustment, exhibited the strongest associations with PE onset in all life-course stages. Sexual abuse exhibited a strong association with PE onset during childhood (OR 8.5, 95% CI 3.6-20.2), whereas Other CA types were associated with PE onset in adolescence. Associations of other CAs with PEs disappeared in adolescence after adjustment for prior-onset mental disorders. The population attributable risk proportion (PARP) for PEs associated with all CAs was 31% (24% for MFF). CONCLUSIONS: Exposure to CAs is associated with PE onset throughout the life-course, although sexual abuse is most strongly associated with childhood-onset PEs. The presence of mental disorders prior to the onset of PEs does not fully explain these associations. The large PARPs suggest that preventing CAs could lead to a meaningful reduction in PEs in the population.

Disruptions of working memory and inhibition mediate the association between exposure to institutionalization and symptoms of attention deficit hyperactivity disorder.

BACKGROUND: Young children raised in institutions are exposed to extreme psychosocial deprivation that is associated with elevated risk for psychopathology and other adverse developmental outcomes. The prevalence of attention deficit hyperactivity disorder (ADHD) is particularly high in previously institutionalized children, yet the mechanisms underlying this association are poorly understood. We investigated whether deficits in executive functioning (EF) explain the link between institutionalization and ADHD. METHOD: A sample of 136 children (aged 6-30 months) was recruited from institutions in Bucharest, Romania, and 72 never institutionalized community children matched for age and gender were recruited through general practitioners' offices. At 8 years of age, children's performance on a number of EF components (working memory, response inhibition and planning) was evaluated. Teachers completed the Health and Behavior Questionnaire, which assesses two core features of ADHD, inattention and impulsivity. RESULTS: Children with history of institutionalization had higher inattention and impulsivity than community controls, and exhibited worse performance on working memory, response inhibition and planning tasks. Lower performances on working memory and response inhibition, but not planning, partially mediated the association between early institutionalization and inattention and impulsivity symptom scales at age 8 years. CONCLUSIONS: Institutionalization was associated with decreased EF performance and increased ADHD symptoms. Deficits in working memory and response inhibition were specific mechanisms leading to ADHD in previously institutionalized children. These findings suggest that interventions that foster the development of EF might reduce risk for psychiatric problems in children exposed to early deprivation.

The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium.

BACKGROUND: Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs. METHOD: General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure. RESULTS: Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types - witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury - accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events. CONCLUSIONS: Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization.

Contributions of the social environment to first-onset and recurrent mania.

In treated cohorts, individuals with bipolar disorder are more likely to report childhood adversities and recent stressors than individuals without bipolar disorder; similarly, in registry-based studies, childhood adversities are more common among individuals who later become hospitalized for bipolar disorder. Because these types of studies rely on treatment-seeking samples or hospital diagnoses, they leave unresolved the question of whether or not social experiences are involved in the etiology of bipolar disorder. We investigated the role of childhood adversities and adulthood stressors in liability for bipolar disorder using data from the National Epidemiologic Survey on Alcohol and Related Conditions (n=33 375). We analyzed risk for initial-onset and recurrent DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) manic episodes during the study's 3-year follow-up period. Childhood physical abuse and sexual maltreatment were associated with significantly higher risks of both first-onset mania (odds ratio (OR) for abuse: 2.23; 95% confidence interval (CI)=1.71, 2.91; OR for maltreatment: 2.10; CI=1.55, 2.83) and recurrent mania (OR for abuse: 1.55; CI=1.00, 2.40; OR for maltreatment: 1.60; CI=1.00, 2.55). In addition, past-year stressors in the domains of interpersonal instability and financial hardship were associated with a significantly higher risk of incident and recurrent mania. Exposure to childhood adversity potentiated the effects of recent stressors on adult mania. Our findings demonstrate a role of social experiences in the initial onset of bipolar disorder, as well as in its prospective course, and are consistent with etiologic models of bipolar disorder that implicate deficits in developmentally established stress-response pathways.

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.

The importance of secondary trauma exposure for post-disaster mental disorder.

BACKGROUND: Interventions to treat mental disorders after natural disasters are important both for humanitarian reasons and also for successful post-disaster physical reconstruction that depends on the psychological functioning of the affected population. A major difficulty in developing such interventions, however, is that large between-disaster variation exists in the prevalence of post-disaster mental disorders, making it difficult to estimate need for services in designing interventions without carrying out a post-disaster mental health needs assessment survey. One of the daunting methodological challenges in implementing such surveys is that secondary stressors unique to the disaster often need to be discovered to understand the magnitude, type, and population segments most affected by post-disaster mental disorders. METHODS: This problem is examined in the current commentary by analyzing data from the WHO World Mental Health (WMH) Surveys. We analyze the extent to which people exposed to natural disasters throughout the world also experienced secondary stressors and the extent to which the mental disorders associated with disasters were more proximally due to these secondary stressors than to the disasters themselves. RESULTS. Lifetime exposure to natural disasters was found to be high across countries (4.4-7.5%). 10.7-11.4% of those exposed to natural disasters reported the occurrence of other related stressors (e.g. death of a loved one and destruction of property). A monotonic relationship was found between the number of additional stressors and the subsequent onset of mental disorders CONCLUSIONS. These results document the importance of secondary stressors in accounting for the effects of natural disasters on mental disorders. Implications for intervention planning are discussed.

The prevalence and correlates of intermittent explosive disorder in Iraq.

OBJECTIVE: Intermittent explosive disorder is common, begins early in life, and is associated with considerable impairment in the United States. The epidemiology of IED outside the United States is unknown. We examined the prevalence and correlates of IED in Iraq, where exposure to violence has been widespread during the last three decades. METHOD: Data were drawn from a national survey of the Iraq population, the Iraq Mental Health Survey (IMHS), conducted in 2006-2007. The WHO Composite International Diagnostic interview was used to assess DSM-IV disorders, including IED. The response rate was 95.2%. RESULTS: Lifetime and 12-month prevalence estimates of IED were 1.7% and 1.5%. Mean age of onset was 18.5. The mean number of lifetime attacks was 141.6 attacks, and IED-related injuries occurred 61 times per 100 lifetime cases. IED was significantly comorbid with mood and anxiety, but not substance, disorders. CONCLUSION: Although the prevalence of IED is lower in Iraq than in the United States, the disorder has an early age of onset, is highly persistent, and is associated with substantial comorbidity and functional impairment. Iraq lacks national policies or systematic programmes to reduce aggression, highlighting the importance of implementing violence prevention programmes to reduce the societal burden of violence in Iraq.

Lifetime co-morbidity of DSM-IV disorders in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A).

BACKGROUND: Research on the structure of co-morbidity among common mental disorders has largely focused on current prevalence rather than on the development of co-morbidity. This report presents preliminary results of the latter type of analysis based on the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A). METHOD: A national survey was carried out of adolescent mental disorders. DSM-IV diagnoses were based on the Composite International Diagnostic Interview (CIDI) administered to adolescents and questionnaires self-administered to parents. Factor analysis examined co-morbidity among 15 lifetime DSM-IV disorders. Discrete-time survival analysis was used to predict first onset of each disorder from information about prior history of the other 14 disorders. RESULTS: Factor analysis found four factors representing fear, distress, behavior and substance disorders. Associations of temporally primary disorders with the subsequent onset of other disorders, dated using retrospective age-of-onset (AOO) reports, were almost entirely positive. Within-class associations (e.g. distress disorders predicting subsequent onset of other distress disorders) were more consistently significant (63.2%) than between-class associations (33.0%). Strength of associations decreased as co-morbidity among disorders increased. The percentage of lifetime disorders explained (in a predictive rather than a causal sense) by temporally prior disorders was in the range 3.7-6.9% for earliest-onset disorders [specific phobia and attention deficit hyperactivity disorder (ADHD)] and much higher (23.1-64.3%) for later-onset disorders. Fear disorders were the strongest predictors of most other subsequent disorders. CONCLUSIONS: Adolescent mental disorders are highly co-morbid. The strong associations of temporally primary fear disorders with many other later-onset disorders suggest that fear disorders might be promising targets for early interventions.

Home foreclosure and risk of psychiatric morbidity during the recent financial crisis.

BACKGROUND: A defining feature of the US economic downturn of 2008-2010 was the alarming rate of home foreclosure. Although a substantial number of US households have experienced foreclosure since 2008, the effects of foreclosure on mental health are unknown. We examined the effects of foreclosure on psychiatric symptomatology in a prospective, population-based community survey. METHOD: Data were drawn from the Detroit Neighborhoods and Health Study (DNHS), waves 1 and 2 (2008-2010). A probability sample of predominantly African-American adults in Detroit, Michigan participated (n=1547). We examined the association between home foreclosure between waves 1 and 2 and increases in symptoms of DSM-IV major depression and generalized anxiety disorder (GAD). RESULTS: The most common reasons for foreclosure were an increase in monthly payments, an increase in non-medical expenses and a reduction in family income. Exposure to foreclosure between waves 1 and 2 predicted symptoms of major depression and GAD at wave 2, controlling for symptoms at wave 1. Even after adjusting for wave 1 symptoms, sociodemographics, lifetime history of psychiatric disorder at wave 1 and exposure to other financial stressors between waves 1 and 2, foreclosure was associated with an increased rate of symptoms of major depression [incidence density ratio (IDR) 2.4, 95% confidence interval (CI) 1.6-3.6] and GAD (IDR 1.9, 95% CI 1.4-2.6). CONCLUSIONS: We provide the first prospective evidence linking foreclosure to the onset of mental health problems. These results, combined with the high rate of home foreclosure since 2008, suggest that the foreclosure crisis may have adverse effects on the mental health of the US population.

Stigma and treatment for alcohol disorders in the United States.

Among a nationally representative sample of adults with an alcohol use disorder, the authors tested whether perceived stigmatization of alcoholism was associated with a lower likelihood of receiving alcohol-related services. Data were drawn from a face-to-face epidemiologic survey of 34,653 adults interviewed in 2004-2005 who were aged 20 years or older and residing in households and group quarters in the United States. Alcohol abuse/dependence was diagnosed by using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, version (AUDADIS-IV). The stigma measure used was the Perceived Devaluation-Discrimination Scale. The main outcome was lifetime intervention including professional services and 12-step groups for alcohol disorders. Individuals with a lifetime diagnosis of an alcohol use disorder were less likely to utilize alcohol services if they perceived higher stigma toward individuals with alcohol disorders (odds ratio = 0.37, 95% confidence interval: 0.18, 0.76). Higher perceived stigma was associated with male gender (ß = -0.75; P < 0.01), nonwhite compared with non-Hispanic white race/ethnicity, lower income (ß = 1.0; P < 0.01), education (ß = 1.48; P < 0.01), and being previously married (ß = 0.47; P = 0.02). Individuals reporting close contact with an alcohol-disordered individual (e.g., relative with an alcohol problem) reported lower perceived stigma (ß = -1.70; P < 0.01). A link between highly stigmatized views of alcoholism and lack of services suggests that stigma reduction should be integrated into public health efforts to promote alcohol treatment.

Childhood adversities and adult psychopathology in the National Comorbidity Survey Replication (NCS-R) III: associations with functional impairment related to DSM-IV disorders.

BACKGROUND: Despite evidence that childhood adversities (CAs) are associated with increased risk of mental disorders, little is known about their associations with disorder-related impairment. We report the associations between CAs and functional impairment associated with 12-month DSM-IV disorders in a national sample. METHOD: We used data from the US National Comorbidity Survey Replication (NCS-R). Respondents completed diagnostic interviews that assessed 12-month DSM-IV disorder prevalence and impairment. Associations of 12 retrospectively reported CAs with impairment among cases (n=2242) were assessed using multiple regression analysis. Impairment measures included a dichotomous measure of classification in the severe range of impairment on the Sheehan Disability Scale (SDS) and a measure of self-reported number of days out of role due to emotional problems in the past 12 months. RESULTS: CAs were positively and significantly associated with impairment. Predictive effects of CAs on the SDS were particularly pronounced for anxiety disorders and were significant in predicting increased days out of role associated with mood, anxiety and disruptive behavior disorders. Predictive effects persisted throughout the life course and were not accounted for by disorder co-morbidity. CAs associated with maladaptive family functioning (MFF; parental mental illness, substance disorder, criminality, family violence, abuse, neglect) were more consistently associated with impairment than other CAs. The joint effects of co-morbid MFF CAs were significantly subadditive. Simulations suggest that CAs account for 19.6% of severely impairing disorders and 17.4% of days out of role. CONCLUSIONS: CAs predict greater disorder-related impairment, highlighting the ongoing clinical significance of CAs at every stage of the life course.

Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: a test of the stress sensitization hypothesis in a population-based sample of adults.

BACKGROUND: Childhood adversity (CA) is associated with adult mental disorders, but the mechanisms underlying this association remain inadequately understood. Stress sensitization, whereby CA increases vulnerability to mental disorders following adult stressful life events, has been proposed as a potential mechanism. We provide a test of the stress sensitization hypothesis in a national sample. METHOD: We investigated whether the association between past-year stressful life events and the 12-month prevalence of major depression, post-traumatic stress disorder (PTSD), other anxiety disorders, and perceived stress varies according to exposure to CA. We used data from the National Epidemiological Survey of Alcohol and Related Conditions (NESARC) (n=34 653). RESULTS: Past-year stressful life events were associated with an increased risk of major depression, PTSD, anxiety disorders, and perceived stress. However, the magnitude of the increased risk varied according to respondents' history of CA. For example, past-year major stressors were associated with a 27.3% increase in the 12-month risk of depression among individuals with 3 CAs and a 14.8% increased risk among individuals without CAs. Stress sensitization effects were present for depression, PTSD, and other anxiety disorders in women and men, although gender differences were found in the threshold of past-year stress needed to trigger such effects. Stress sensitization was most evident among individuals with 3 CAs. CONCLUSIONS: CA is associated with increased vulnerability to the deleterious mental health effects of adult stressors in both men and women. High levels of CA may represent a general diathesis for multiple types of psychopathology that persists throughout the life course.

Isolation and characterization of Xenopus Hey-1: a downstream mediator of Notch signaling.

Regulation of Notch signaling likely occurs, at least in part, at the level of basic helix-loop-helix (bHLH) transcription factors that function downstream of Suppressor of Hairless (Su(H)) in the Notch pathway. To begin to characterize modulation of Notch signaling during organogenesis, we examined the bHLH transcription factor, XHey-1 (hairy related-1) in early Xenopus laevis embryos. XHey-1 is expressed in numerous tissues during early development including the somites, head, embryonic kidneys, and heart. Importantly, the expression of XHey-1 was significantly altered in response to perturbation of Notch signaling by means of inducible constructs that served to either activate or suppress Notch signaling through Su(H) in a temporally controlled manner.

What does it take to collaborate with families affected by brain injury? A preliminary model.

BACKGROUND: Collaboration refers to a process in which family expertise is acknowledged and used to direct selection, implementation, and evaluation of treatment plans. Although the skills required to create collaborative partnerships with families are a mainstay of practice for certain rehabilitation disciplines, others have traditionally worked in client-clinician dyads that emphasize the role of the professional as responsible for client change. In addition, the existing collaborative models for working with families affected by brain injury require intensive resources and supports, making collaborative partnerships difficult to create within today's clinical and educational service delivery environments. RESULT: In this article, we report our efforts to create an accessible set of collaboration procedures for rehabilitation professionals working in clinical and educational settings with individuals with brain injury and their families. A 2-year, qualitative study with eight families led to the development of a preliminary model and prescriptive manual for applying collaborative principles to practice. CONCLUSION: We review the components of the model and implications for practice.

Notch regulates cell fate in the developing pronephros.

The mechanisms that regulate cell fate within the pronephros are poorly understood but are important for the subsequent development of the urogenital system and show many similarities to nephrogenesis in the definitive kidney. Dynamic expression of Notch-1, Serrate-1, and Delta-1 in the developing Xenopus pronephros suggests a role for this pathway in cell fate segregation. Misactivation of Notch signaling using conditionally active forms of either Notch-1 or RBP-J/Su(H) proteins prevented normal duct formation and the proper expression of genetic markers of duct cell differentiation. Inhibition of endogenous Notch signaling elicited the opposite effect. Taken together with the mRNA expression patterns, these data suggest that endogenous Notch signaling functions to inhibit duct differentiation in the dorsoanterior region of the anlage where cells are normally fated to form tubules. In addition, elevated Notch signaling in the pronephric anlage both perturbed the characteristic pattern of the differentiated tubule network and increased the expression of early markers of pronephric precursor cells, Pax-2 and Wilms' tumor suppressor gene (Wt-1). We propose that Notch signaling plays a previously unrecognized role in the early selection of duct and tubule cell fates as well as functioning subsequently to control tubule cell patterning and development.

Evaluation of attention process training and brain injury education in persons with acquired brain injury.

Fourteen patients with stable acquired brain injuries exhibiting attention and working memory deficits were given 10 weeks of attention process training (APT) and 10 weeks of brain injury education in a cross-over design. Structured interviews and neuropsychological tests were used prior to rehabilitation and after both treatments to determine the influence of the interventions on tasks of daily life and performance on attentional networks involving vigilance, orienting, and executive function. The overall results showed that most patients made improvements. Some of these gains were due to practice from repetitive administration of the tests. In addition, the type of intervention also influenced the results. The brain injury education seemed to be most effective in improving self-reports of psychosocial function. APT influenced self-reports of cognitive function and had a stronger influence on performance of executive attention tasks than was found with the brain injury education therapy. Vigilance and orienting networks showed little specific improvement due to therapy. However, vigilance level influenced the improvement with therapy on some tests of executive attention. We consider the implications of these results for future studies of the locus of attentional improvement and for the design of improved interventions.

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis.

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326-340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma.

BACKGROUND: To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests' individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used. METHODS: The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard. RESULTS: Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundred-and-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p<0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive. CONCLUSIONS: PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC.

The role of oxygen in thymocyte apoptosis.

Signals generated by T cell receptor (TCR) cross-linking (or phorbol 12-myristate-13-acetate + Ca2+ ionophore), glucocorticoids or ionizing radiation all stimulate apoptotic cell death in thymocytes by signals that are initially distinct from each other. However, when these stimuli were administered to thymocyte cultures that were maintained under an atmosphere containing less than 20 ppm oxygen as opposed to one that contained 18.5% molecular oxygen, cell death was inhibited or abrogated, suggesting that the induction of death by all three different stimuli depend on the presence of molecular oxygen. Studies of the effects of the cysteine analog N-acetyl cysteine (NAC) with normal thymocytes demonstrated that this antioxidant inhibited the induction of death by each of the different stimuli in a manner the paralleled anaerobiosis. Furthermore, studies with thymocytes demonstrated that the induction of nur77, a gene shown to be involved in thymocyte apoptosis signaled through the TCR or its surrogates, is not inhibited by NAC or dependent upon molecular oxygen. The possible implications for negative selection of NAC-mediated inhibition of TCR-signaled thymocyte cell death was examined in thymic organ culture. Treatment of these cultures with NAC provided significant protection against staphylococcal enterotoxin B-mediated deletion of V beta 8-expressing thymocytes.