Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus.

The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two-promoter regulon with allelic variability that produces a quorum-sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum-sensing pathway has fueled tremendous interest in understanding the structure-activity relationships underlying the AIP-AgrC interaction. The defining structural feature of the AIP is a 16-membered, thiolactone-containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogues featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function by using both established cell-based reporter gene assays and newly developed in vitro AgrC-I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, three-points-of-contact interaction between the AIP macrocycle and AgrC.

Parenting behaviours associated with the development of adaptive and maladaptive offspring personality traits.

OBJECTIVES: To investigate the associations of beneficial parenting behaviours with adaptive and maladaptive offspring personality traits that persist into adulthood among individuals in the community. METHODS: Families (n = 669) participating in the Children in the Community Study were interviewed during the childhood, adolescence, emerging adulthood, and adulthood of the offspring at the mean ages of 6, 14, 16, 22, and 33 years. RESULTS: Twelve types of beneficial maternal and paternal child-rearing behaviour, reported by offspring at the mean age of 16 years, were associated with elevated offspring personality resiliency, at the mean ages of 22 and 33 years, and with low offspring personality disorder trait levels. These longitudinal associations remained significant when histories of childhood behaviour problems and parental psychiatric disorder were controlled statistically. Similar linear (that is, dose-dependent) associations were observed between the number of beneficial parenting behaviours during childhood and adaptive and maladaptive offspring traits at the mean ages of 22 and 33 years. Maternal and paternal behaviours were independently associated with both adaptive and maladaptive offspring traits. CONCLUSIONS: Beneficial maternal and paternal child-rearing behaviours may promote the development of adaptive offspring personality traits that endure into adulthood, and they may be prospectively associated with reduced levels of maladaptive offspring traits. These associations may not be attributable to childhood behaviour problems or parental psychiatric disorders, and they may be equally evident during early and middle adulthood.

Depressed parents' treatment needs and children's problems in an urban family medicine practice.

OBJECTIVE: The study examined interest in treatment and treatment preferences and obstacles of low-income depressed parents. METHODS: A total of 273 primarily low-income, Hispanic parents of children aged seven to 17 attending an urban family medicine practice agreed to complete a survey by interview or self-report, including screening diagnoses and treatment history. Three groups were compared: major, subthreshold, and no depression. RESULTS: Nearly one-third had major (9%) or subthreshold depression (23%), and many in the depressed groups reported recent treatment (50% and 31%, respectively). Parents with any depression were significantly more likely than nondepressed parents to report interest in receiving help, endorse treatment obstacles, and report children's problems. CONCLUSIONS: High rates of personal and child problems, interest in treatment, and treatment obstacles among low-income, depressed parents highlight the need to develop acceptable mental health services for them and their children, even when parents do not meet full diagnostic criteria for depression.

Suicidality, depression, major and minor negative life events: a mediator model.

BACKGROUND: Major negative life events are associated with higher suicidality. In this association, two mediating paths were hypothesized: (a) via minor negative life events and (b) via depression. METHODS: Ninety-six adolescent primary care patients were recruited in clinics, a physician's office, and school nurses' offices. RESULTS: (1) Minor negative life events were associated with depressive symptoms and suicidality. (2) Depressive symptoms were associated with suicidality. (3) Depressive symptoms mediated the association of minor negative life events with suicidality. CONCLUSIONS: Findings suggest that minor negative life events may be associated with suicidal ideation among adolescent primary care patients, and that depressive symptoms may mediate the association of minor negative life events with suicidality.

Patient and clinician perceptions of therapeutic alliance as predictors of improvement in depression.

BACKGROUND: Meta-analyses have consistently concluded that a positive therapeutic alliance is associated with better clinical outcomes and progress. To date, however, very few studies have focused on sociodemographic or clinical patient characteristics as moderators of alliance. METHOD: A multicenter longitudinal treatment outcome study was conducted to investigate the associations of patient and clinician perceptions of the therapeutic alliance with improvement in depression, and to investigate whether these associations were influenced by sociodemographic or clinical characteristics of the patient. Clinician-rated Montgomery Åsberg Depressive Rating Scale scores and both patient- and therapist-rated Helping Alliance Questionnaire (HAQ-I) scores were obtained from 567 outpatients with major depressive disorder who received 6 months of combined psycho- and pharmacotherapy. RESULTS: Multilevel repeated-measures analyses indicated that patient- and therapist-rated HAQ-I scores, 4 weeks after treatment began, positively predicted subsequent clinical change, controlling for the effect of early improvement and a range of patient characteristics. Next to alliance, early improvement, initial depressive symptom severity, a history of psychiatric disorders, and occupational status affected the rate of clinical improvement. Personality pathology comorbidity, marital and occupational status, and the atypical character of the major depressive episode (MDE) moderated the alliance-outcome relationship, depending on the informant (patient or therapist) of therapeutic alliance. CONCLUSIONS: The present findings suggest that therapist and patient ratings of therapeutic alliance predict therapeutic progress, and that this relation may be moderated by client characteristics, including personality pathology comorbidity, marital status, occupational status, and the atypical character of the MDE.

Minor depression during adolescence and mental health outcomes during adulthood.

Data from a community-based prospective longitudinal study were used to investigate the association of minor depressive disorder during adolescence with adverse mental health outcomes during adulthood. Structured diagnostic interviews were administered to a community-based sample of 755 individuals during adolescence and adulthood. Results indicated that minor depressive disorder during adolescence was associated with elevated risk for subsequent psychiatric disorders during adulthood, including major depressive disorder, >or= 1 disruptive disorders and clinically relevant impairment after corresponding and co-occurring disorders were controlled statistically.

Stigmatization and receptivity to mental health services among recently bereaved adults.

Severe grief symptoms, treatment receptivity, attitudes about grief, and stigmatization concerns were assessed in a community-based sample of 135 widowed participants in the Yale Bereavement Study. There was a statistically significant association between the severity of grief symptoms and reported negative reactions from friends and family members. However, more than 90% of the respondents with complicated grief, a severe grief disorder, reported that they would be relieved to know that having such a diagnosis was indicative of a recognizable psychiatric condition, and 100% reported that they would be interested in receiving treatment for their severe grief symptoms.

Prolonged grief disorder: Psychometric validation of criteria proposed for DSM-V and ICD-11.

BACKGROUND: Bereavement is a universal experience, and its association with excess morbidity and mortality is well established. Nevertheless, grief becomes a serious health concern for a relative few. For such individuals, intense grief persists, is distressing and disabling, and may meet criteria as a distinct mental disorder. At present, grief is not recognized as a mental disorder in the DSM-IV or ICD-10. The goal of this study was to determine the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and potential treatment of bereaved individuals at heightened risk of persistent distress and dysfunction. METHODS AND FINDINGS: A total of 291 bereaved respondents were interviewed three times, grouped as 0-6, 6-12, and 12-24 mo post-loss. Item response theory (IRT) analyses derived the most informative, unbiased PGD symptoms. Combinatoric analyses identified the most sensitive and specific PGD algorithm that was then tested to evaluate its psychometric validity. Criteria require reactions to a significant loss that involve the experience of yearning (e.g., physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) and at least five of the following nine symptoms experienced at least daily or to a disabling degree: feeling emotionally numb, stunned, or that life is meaningless; experiencing mistrust; bitterness over the loss; difficulty accepting the loss; identity confusion; avoidance of the reality of the loss; or difficulty moving on with life. Symptoms must be present at sufficiently high levels at least six mo from the death and be associated with functional impairment. CONCLUSIONS: The criteria set for PGD appear able to identify bereaved persons at heightened risk for enduring distress and dysfunction. The results support the psychometric validity of the criteria for PGD that we propose for inclusion in DSM-V and ICD-11. Please see later in the article for Editors' Summary.

School climate and continuity of adolescent personality disorder symptoms.

BACKGROUND: Schools are key social contexts for shaping development and behavior in youths; yet, little is known of their influence on adolescent personality disturbance. METHOD: A community-based sample of 592 adolescents was assessed for family and school experiences, Axis I psychiatric disorders, and Axis II personality disorder (PD) symptoms, and followed into young adulthood. Multiple regression analysis was used to estimate associations between adolescent-reported school climate and young adult PD symptoms independent of age, sex, family socioeconomic status; childhood maltreatment; Axis I disorder, PD symptoms, academic grades, and parental punishment in adolescence; and four dimensions of school climate. RESULTS: Schools characterized as high in learning focus were related to cluster B (antisocial, borderline, histrionic, and narcissistic PD) symptom declines, whereas schools characterized as high in opportunities for student autonomy were related to cluster A (paranoid, schizoid, and schizotypal PD) symptom declines. In contrast, schools characterized as conflictual or supporting interpersonal informality/familiarity among students and teachers were related to increases in cluster A symptoms and cluster C (avoidant, dependent, and obsessive-compulsive PD) symptoms. CONCLUSIONS: Schools may exert both positive and negative influences on continuity of adolescent personality disturbance. The role of the school in guiding young people toward more favorable developmental pathways and alleviating personality disturbance is discussed.

Psychiatric disorders during adolescence and relationships with peers from age 17 to age 27.

OBJECTIVE: To investigate normative patterns of peer relationships from ages 17 to 27, and to examine the impact of adolescent psychiatric disorders on peer relationships. METHOD: Psychiatric disorders were measured at a mean age 16 years. At mean age 29, 200 participants completed detailed narrative interviews about their transition to adulthood. Monthly contact and conflict with peers were described in narratives covering ages 17-27. RESULTS: Adolescent psychiatric disorders did not predict the frequency of peer contact in the young adult period. However, adolescent disruptive disorders predicted greater peer conflict regardless of contact frequency. Adolescents with major depressive or substance abuse disorders and subsequent high frequency of peer contact reported elevated peer conflict during the transition to adulthood. In contrast, among study participants with frequent peer contact during this period, those with adolescent anxiety disorders reported less peer conflict than did those without such a diagnostic history. CONCLUSIONS: Adolescents with major depressive, disruptive, and substance abuse disorders may be at risk for long-term negative peer relationships, whereas those with anxiety disorders may subsequently avoid peer conflict.

Problematic eating behaviors in adolescents with low self-esteem and elevated depressive symptoms.

Previous research has indicated that low self-esteem may be an important risk factor for the development of eating disorders. Few longitudinal studies have examined the relationships between low self-esteem, depressive symptoms, and eating disorders in adolescents. The present study investigated whether low self-esteem was associated with depressive symptoms and problematic eating behaviors. Measures of low self-esteem and problematic eating behaviors were administered to a sample of 197 adolescent primary-care patients. Depressive symptoms and problematic eating behaviors were assessed ten months later. Youths with low self-esteem were at greater risk for high levels of depressive symptoms and eating disorder symptoms. In addition, depressive symptoms mediated the association of low self-esteem with problematic eating behaviors.

The association between anxiety and alcohol versus cannabis abuse disorders among adolescents in primary care settings.

BACKGROUND: Both clinical and population-based studies show that anxiety disorders and substance misuse frequently co-occur in adults, whereas among adolescents, less examination of this association has been done. Adolescence is frequently the time of substance use initiation and its subsequent interaction with anxiety disorders has not been fully explored. It is unknown in adolescents whether anxiety is more related to alcohol abuse versus cannabis abuse. In addition, as depression has been implicated in adolescents with both anxiety and substance misuse, its role in the association should also be considered. OBJECTIVE: To test the association between current anxiety with alcohol versus cannabis abuse disorders. METHOD: Cross-sectional, clinician-administered, structured assessment--using the Primary Care Evaluation of Mental Disorders--to evaluate anxiety, mood and substance abuse disorders among 632 adolescents recruited from primary care settings. RESULTS: Results show a strong association between current anxiety and alcohol [odds ratio = 3.8; 95% confidence interval (CI) 1.2-11.8], but not cannabis (odds ratio = 1.4; 95% CI 0.4-4.7) abuse. CONCLUSION: This association in adolescents reflects the importance for increased awareness of anxiety symptoms and alcohol use patterns in primary care. The lack of association of anxiety with cannabis abuse in this group may reflect differences in cannabis' anxiolytic properties or that this young group has had less exposure thus far. Given adolescence is a time of especially rapid psychosocial, hormonal and brain development, primary care may provide an opportunity for further investigation and, potentially, early screening and intervention.

Cumulative prevalence of personality disorders between adolescence and adulthood.

OBJECTIVE: To investigate the cumulative prevalence of personality disorder (PD) among adults in the community, based on prospective longitudinal data from a series of psychiatric interviews. METHOD: Psychiatric interviews were administered to a regionally representative community-based sample of 568 individuals in 1983 (mean age = 14), 1985-1986 (mean age = 16), 1991-1993 (mean age = 22), and 2001-2004 (mean age 33). RESULTS: The point prevalence of any current DSM-IV PD, including depressive PD and passive-aggressive PD, varied between 12.7% and 14.6% across the four diagnostic assessments. The cumulative prevalence of PD increased at each of the follow-up assessments. At mean age 33, the estimated lifetime prevalence of PD was 28.2%. CONCLUSION: The cumulative prevalence of PD, based on a series of interviews conducted during adolescence and adulthood, may be substantially higher than the point prevalence of current PD based on a single assessment interview.

Comorbid Axis I and Axis II disorders in early adolescence: outcomes 20 years later.

CONTEXT: Although Axis II personality disorders in adolescence have been linked to psychopathology and psychosocial impairment in early adulthood, little is known about their effects over longer periods. OBJECTIVES: To evaluate and compare long-term prognoses of adolescent personality disorders and co-occurring Axis I disorders. DESIGN: Population-based longitudinal study. SETTING: Upstate New York. PARTICIPANTS: A community sample of 629 adolescents interviewed at a mean age of 13.8 years and again at a mean age of 33.2 years. MAIN OUTCOME MEASURES: Clinically assessed psychiatric disorders and self-reported attainment and function. RESULTS: Axis I (mood, anxiety, disruptive behavior, and substance use disorders) and Axis II disorders in adolescence showed risks for negative prognoses lasting 20 years. Co-occurring Axis I and Axis II disorders consistently presented the highest risk, often approximating the sum of the axis-associated risk or even several times the risk of disorders in either axis alone. CONCLUSIONS: Long-term prognoses of Axis I and Axis II disorders are of comparable magnitude and often additive when comorbid. These findings are highly relevant to the current debate over how personality disorders should be handled in DSM-V.

Development and validation of a new procedure for the diagnostic assessment of personality disorder: the Multidimensional Personality Disorder Rating Scale (MPDRS).

Data from a community-based prospective longitudinal study were used to investigate the utility of a structured assessment of the DSM-IV General Diagnostic Criteria for a Personality Disorder (PD). The Structured Clinical Interview for DSM-IV PDs (SCID-II) was administered to 154 adults. After completing the interview, an experienced clinician assessed the General Diagnostic Criteria for a PD using a structured rating scale. PD diagnoses, based solely on the rating scale data, demonstrated strong agreement with diagnoses obtained using the diagnostic thresholds for specific PDs (Kappa = 0.89). The sensitivity, specificity, predictive power, and internal reliability of the rating scale were satisfactory. PD diagnoses, based on both of the assessment procedures, were associated with substantial impairment and distress. These findings suggest that a structured assessment of the DSM-IV General Diagnostic Criteria for a Personality Disorder may constitute a useful alternative or supplement to standard assessments of the diagnostic thresholds for specific DSM-IV PDs.

Investigation of a developmental model of risk for depression and suicidality following spousal bereavement.

Data from a community-based multi-wave investigation were used to examine a developmental model of risk for depression and suicidality following the death of a spouse. Measures of perceived parental affection and control during childhood were administered to 218 widowed adults 11 months after the death of the spouse. Self-esteem, spousal dependency, depression, and suicidality were assessed 9 months later. Dependency on the deceased spouse mediated a significant association between retrospectively reported parental control during childhood and post-loss depressive symptoms. Depressive symptoms mediated significant associations of dependency on the deceased spouse and low self-esteem with suicidal ideation and behavior.

Parental concordance and offspring risk for anxiety, conduct, depressive, and substance use disorders.

BACKGROUND: Although parental concordance for any psychiatric disorder is known to be associated with elevated risk for offspring disorder, little evidence is currently available from prospective longitudinal studies regarding the association of parental concordance with offspring risk for anxiety, conduct, depressive, and substance use disorders. SAMPLING AND METHODS: Psychiatric interviews were conducted with 593 mothers and their biological offspring at mean offspring ages 14, 16, 22, and 33. RESULTS: Offspring risk for >or=1 psychiatric disorder was significantly greater if both parents had a lifetime history of psychiatric disorder than if only one parent had a lifetime history of disorder. Parental concordance for generalized anxiety disorder (GAD) was associated with a significant increase in offspring risk for anxiety disorders, above and beyond the risk attributable to having one affected parent. In addition, parental concordance for GAD was associated with elevated risk for offspring depressive disorders, and parental concordance for substance use disorders was associated with elevated offspring risk for conduct disorder. CONCLUSIONS: Parental concordance for GAD may be associated with elevated risk for offspring anxiety disorder, above and beyond the risk associated with having one affected parent.

Personality disorder and impaired functioning from adolescence to adulthood.

BACKGROUND: Little is currently known about functioning and impairment during adulthood associated with the course of personality disorders. AIMS: To investigate the association of personality disorder stability from adolescence through middle adulthood with measures of global functioning and impairment, using prospective epidemiological data. METHOD: A community-based sample of 658 individuals was interviewed at mean ages 14, 16, 22 and 33 years. RESULTS: Individuals with persistent personality disorder had markedly poorer functioning and greater impairment at mean age 33 years than did those who had never been identified as having such disorder or who had a personality disorder that was in remission, after co-occurring Axis I disorders at age 33 years were taken into account. Remitted disorder was associated with mild long-term impairment. Adult-onset personality disorders, however, were also associated with significant impairment. CONCLUSIONS: Persistent and adult-onset personality disorders are associated with functional impairment among adults in the community. These effects are independent of co-occurring Axis I disorders.

Extensive television viewing and the development of attention and learning difficulties during adolescence.

OBJECTIVE: To investigate the association of television viewing with educational and intellectual outcomes during adolescence and early adulthood. DESIGN: Prospective epidemiological study. SETTING: Families participating in the Children in the Community Study, a prospective longitudinal investigation, were interviewed at mean offspring ages 14, 16, and 22 years. PARTICIPANTS: A community-based sample of 678 families from upstate New York. MAIN EXPOSURES: Television viewing, attention difficulties, learning difficulties, and educational achievement during adolescence and early adulthood. MAIN OUTCOME MEASURES: The Disorganizing Poverty Interview and age-appropriate versions of the Diagnostic Interview Schedule for Children. RESULTS: Frequent television viewing during adolescence was associated with elevated risk for subsequent attention and learning difficulties after family characteristics and prior cognitive difficulties were controlled. Youths who watched 1 or more hours of television per day at mean age 14 years were at elevated risk for poor homework completion, negative attitudes toward school, poor grades, and long-term academic failure. Youths who watched 3 or more hours of television per day were the most likely to experience these outcomes. In addition, youths who watched 3 or more hours of television per day were at elevated risk for subsequent attention problems and were the least likely to receive postsecondary education. There was little evidence of bidirectionality in the association of television viewing with attention and learning difficulties. CONCLUSION: Frequent television viewing during adolescence may be associated with risk for development of attention problems, learning difficulties, and adverse long-term educational outcomes.

Parental control, partner dependency, and complicated grief among widowed adults in the community.

Data from the Yale Bereavement Study, a community-based longitudinal study, were used to investigate the association of 192 widowed individuals' recollections of parenting affection and control during childhood with dependency on the deceased spouse and the development of severe grief symptoms following bereavement. The hypothesis that dependency on the deceased spouse mediates the association of parental affection and control during childhood with the development of severe grief following bereavement was investigated. Findings indicated that a high level of perceived parental control during childhood was associated with elevated levels of dependency on the deceased spouse and with symptoms of complicated grief. Dependency on the deceased spouse mediated the association of perceived parental control with the development of complicated grief following bereavement.