Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5.

Glucocorticoids play an important role in the treatment of inflammation and immune disorders, despite side effects, which include metabolic derangements such as central adiposity. These studies examine the role of protein phosphatase 5 (Ppp5) in glucocorticoid receptor (GR) complexes which mediate response to glucocorticoids. Mice homozygous for inactivated Ppp5 (Ppp5D274A/D274A) exhibit decreased adipose tissue surrounding the gonads and kidneys compared with wild-type mice. Adipocyte size is smaller, more preadipocytes/stromal cell are present in their gonadal fat tissue and differentiation of preadipocytes to adipocytes is retarded. Glucocorticoid levels are raised and the GR is hyperphosphorylated in adipose tissue of Ppp5D274A/D274A mice at Ser212 and Ser220 (orthologous to human Ser203 and Ser211) in the absence of glucocorticoids. Preadipocyte cultures from Ppp5D274A/D274A mice show decreased down regulation of Delta-like protein-1/preadipocyte factor-1, hyperphosphorylation of extra-cellular signal regulated kinase 2 (ERK2) and increased concentration of (sex determining region Y)-box 9 (SOX9), changes in a pathway essential for preadipocyte differentiation, which leads to decreased concentrations of the transcription factors CEBPß and CEBPα necessary for the later stages of adipogenesis. The data indicate that Ppp5 plays a crucial role in modifying GR-mediated initiation of adipose tissue differentiation, suggesting that inhibition of Ppp5 may potentially be beneficial to prevent obesity during glucocorticoid treatment.

Impact of Adolescent Personality Disorders on Obesity 17 Years Later.

OBJECTIVES: To investigate associations between adolescent personality disorder (PD) and obesity 17 years later. METHODS: The Children in the Community is a longitudinal study based on a randomly sampled cohort of families, in effect since 1975. PDs were assessed in youths by self-report and mother report in 1985 to 1986, when participants were at an average age of 16 years. Obesity was assessed in 2001 to 2004 when participants were an average age of 33 years (n = 621). RESULTS: Prevalence of obesity was 16.59% (103/621) at an average age of 33 years. Prevalence of any adolescent PD was 17.55% (109/621) at an average age of 16 years. Adolescents who had any PD were 1.84 (95% confidence interval [CI] = 1.05-3.22) times as likely to be obese 17 years later after adjusting for demographic variables and known risk factors. Paranoid, histrionic, and obsessive-compulsive PDs in adolescence were significantly associated with obesity in adulthood, with odds ratios of 3.45 (95% CI = 1.46-8.17), 4.49 (95% CI = 1.91-10.53), and 6.80 (95% CI = 2.50-18.55), respectively. CONCLUSIONS: This is the first study to report a significant independent long-term association based on prospective data between adolescent PDs and adult obesity in a community-based sample. Findings will contribute to the design of preventive measures against the development of obesity.

The efficacy of religious service attendance in reducing depressive symptoms.

PURPOSE: To examine whether religiosity may help people ward off depression, we investigated the association between religious service attendance and depressive symptom scores in a community-based 30-year follow-up longitudinal study. METHODS: This study used data on 754 subjects followed over 30 years and evaluated at four time points. Linear mixed effects models were used to assess the association between religious service attendance and depressive symptoms development; frequency of attendance and age also were used as predictors. Demographic factors, life-time trauma, family socioeconomic status, and recent negative events were considered as control variables. RESULTS: Depressive symptom scores were reduced by an average of 0.518 units (95 % CI from -0.855 to -0.180, p < 0.005) each year in subjects who attended religious services as compared with subjects who did not. The more frequent the religious service attendance, the stronger the influence on depressive symptoms when compared with non-attendance. Yearly, monthly, and weekly religious service attendance reduced depression scores by 0.474 (95 % CI from -0.841 to -0.106, p < 0.01), 0.495 (95 % CI from -0.933 to -0.057, p < 0.05) and 0.634 (95 % CI from -1.056 to -0.212, p < 0.005) units on average, respectively, when compared with non-attendance after controlling for other covariates. CONCLUSION: Religious service attendance may reduce depressive symptoms significantly, with more frequent attendance having an increasingly greater impact on symptom reduction in this 30-year community-based longitudinal study.

Contribution of family violence to the intergenerational transmission of externalizing behavior.

Research finds that early antisocial behavior is a risk for later intimate partner violence (IPV) perpetration and victimization, and that children's exposure to their parents' IPV is a risk for subsequent behavior problems. This study tests whether intimate violence (IPV) between partners contributes independently to the intergenerational transmission of antisocial behavior, using the Children in the Community Study, a representative sample (N = 821) followed for over 25 years in 6 assessments. The present study includes a subsample of parents (N = 678) and their offspring (N = 396). We test the role of three mechanisms by which IPV may influence child antisocial behavior-parental psychopathology, parenting practices, and child self-regulation. Results suggest that IPV independently increased the risk for offspring externalizing problems, net of the effects of parental history of antisocial behavior and family violence. IPV also increased the risk for parental post traumatic stress disorder (PTSD) and alcohol use disorder 2 years later, but not for major depressive disorder. Alcohol use disorder independently increased the risk for offspring externalizing behavior, but IPV continued to predict offspring externalizing net of parental alcohol use. Parenting, particularly low satisfaction with the child, was significantly associated with both IPV and externalizing behavior, but did not mediate the effects of IPV on externalizing. IPV predicted higher levels of emotional expressivity, aggression and hostile reactivity, and depressive mood in offspring. Implications for future research and prevention are discussed.

On the Origins of Disorganized Attachment and Internal Working Models: Paper II. An Empirical Microanalysis of 4-Month Mother-Infant Interaction.

A microanalysis of 4-month mother-infant face-to-face communication predicted 12-month infant disorganized (vs. secure) attachment outcomes in an urban community sample. We documented a dyadic systems view of the roles of both partners, the roles of both self- and interactive contingency, and the importance of attention, orientation and touch, and as well as facial and vocal affect, in the co-construction of attachment disorganization. The analysis of different communication modalities identified striking intrapersonal and interpersonal intermodal discordance or conflict, in the context of intensely distressed infants, as the central feature of future disorganized dyads at 4 months. Lowered maternal contingent coordination, and failures of maternal affective correspondence, constituted maternal emotional withdrawal from distressed infants. This maternal withdrawal compromises infant interactive agency and emotional coherence. We characterize of the nature of emerging internal working models of future disorganized infants as follows: Future disorganized infants represent states of not being sensed and known by their mothers, particularly in moments of distress; they represent confusion about both their own and their mothers' basic emotional organization, and about their mothers' response to their distress. This internal working model sets a trajectory in development which may disturb the fundamental integration of the person. The remarkable specificity of our findings has the potential to lead to more finely-focused clinical interventions.

R3F, a novel membrane-associated glycogen targeting subunit of protein phosphatase 1 regulates glycogen synthase in astrocytoma cells in response to glucose and extracellular signals.

Abnormal regulation of brain glycogen metabolism is believed to underlie insulin-induced hypoglycaemia, which may be serious or fatal in diabetic patients on insulin therapy. A key regulator of glycogen levels is glycogen targeted protein phosphatase 1 (PP1), which dephosphorylates and activates glycogen synthase (GS) leading to an increase in glycogen synthesis. In this study, we show that the gene PPP1R3F expresses a glycogen-binding protein (R3F) of 82.8 kDa, present at the high levels in rodent brain. R3F binds to PP1 through a classical 'RVxF' binding motif and substitution of Phe39 for Ala in this motif abrogates PP1 binding. A hydrophobic domain at the carboxy-terminus of R3F has similarities to the putative membrane binding domain near the carboxy-terminus of striated muscle glycogen targeting subunit G(M)/R(GL), and R3F is shown to bind not only to glycogen but also to membranes. GS interacts with PP1-R3F and is hyperphosphorylated at glycogen synthase kinase-3 sites (Ser640 and Ser644) when bound to R3F(Phe39Ala). Deprivation of glucose or stimulation with adenosine or noradrenaline leads to an increased phosphorylation of PP1-R3F bound GS at Ser640 and Ser644 curtailing glycogen synthesis and facilitating glycogen degradation to provide glucose in astrocytoma cells. Adenosine stimulation also modulates phosphorylation of R3F at Ser14/Ser18.

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.

MATERNAL ANXIETY SYMPTOMS AND MOTHER-INFANT SELF- AND INTERACTIVE CONTINGENCY.

Associations of maternal self-report anxiety-related symptoms with mother-infant 4-month face-to-face play were investigated in 119 pairs. Attention, affect, spatial orientation, and touch were coded from split-screen videotape on a 1-s time base. Self- and interactive contingency were assessed by time-series methods. Because anxiety symptoms signal emotional dysregulation, we expected to find atypical patterns of mother-infant interactive contingencies, and of degree of stability/lability within an individual's own rhythms of behavior (self-contingencies). Consistent with our optimum midrange model, maternal anxiety-related symptoms biased the interaction toward interactive contingencies that were both heightened (vigilant) in some modalities and lowered (withdrawn) in others; both may be efforts to adapt to stress. Infant self-contingency was lowered ("destabilized") with maternal anxiety symptoms; however, maternal self-contingency was both lowered in some modalities and heightened (overly stable) in others. Interactive contingency patterns were characterized by intermodal discrepancies, confusing forms of communication. For example, mothers vigilantly monitored infants visually, but withdrew from contingently coordinating with infants emotionally, as if mothers were "looking through" them. This picture fits descriptions of mothers with anxiety symptoms as overaroused/fearful, leading to vigilance, but dealing with their fear through emotional distancing. Infants heightened facial affect coordination (vigilance), but dampened vocal affect coordination (withdrawal), with mother's face-a pattern of conflict. The maternal and infant patterns together generated a mutual ambivalence.

Earlier stress exposure and subsequent major depression in aging women.

OBJECTIVE: Despite evidence that stress exposure earlier in the life course may have long-term consequences for psychopathology, most models of vulnerability for late life depression are limited to current stressors or to retrospective reports of stress history. This study estimates the influences of earlier stressors assessed longitudinally on subsequent major depressive disorder (MDD) in women at average age 60 (range 50-75). METHOD: MDD, negative life events (NLE), and marital stress were assessed multiple times in a community-based sample of 565 women followed for three decades. Adverse events experienced in childhood also were assessed prior to outcome. RESULTS: Greater childhood adversity, earlier high levels of NLE and marital stress, and a more rapid increase in marital stress over time elevated the odds of MDD at average age 60 independent of all stressors and other salient risk factors. Childhood adversity was mediated in part by intervening risks. Prior depression, earlier poor health status, a more rapid deterioration in health with age, and current disability owing to physical problems also were related independently to later MDD. CONCLUSIONS: These findings support the enduring effects of earlier stress burden on MDD in women into old age and, in light of the increasing proportion of older women in the population, have important clinical implications for identification and treatment of those at risk for depression. Findings also underscore the need to develop resources to counteract or buffer similar stress exposure in younger generations of women.

An adult myometrial pluripotential precursor that promotes healing of damaged muscular tissues.

The use of adult stem cells for tissue and organ regeneration constitutes a promising alternative therapy in many human diseases that are currently not treatable. We have isolated a new cell type from mouse adult uterine biopsies (murine adult myometrial precursors or mAMPs) by means of using a simple and non-invasive approach. These cells have been characterized by surface markers, being positive for CD31, CD34, CD44, CD117, Stro-1 and Sca-1. A similar cell population (hAMPs) was isolated from human biopsies. AMPs can differentiate in vitro into a number of mesodermal (smooth and skeletal muscle, osteoblasts and adipocytes) as well as epidermal lineages (all neural lineages). AMPs are unusual adult stem cells as they still express some embryonic antigens and remain undifferentiated through a high number of passages before entering senescence. Importantly, when injected into animal models of muscular disease, AMPs can regenerate new muscle fibers, and promote functional muscular recovery. Moreover, these cells can regenerate the uterine lining after wound healing, reconstructing the uterine muscular architecture. In addition, these cells can form new vessels both in vitro and in vivo. We believe that these cells have superior features to other known adult stem cells and, consequently, their use holds great promise for regenerative medicine, drug development and basic research.

The origins of 12-month attachment: a microanalysis of 4-month mother-infant interaction.

A microanalysis of 4-month mother-infant face-to-face communication revealed a fine-grained specification of communication processes that predicted 12-month insecure attachment outcomes, particularly resistant and disorganized classifications. An urban community sample of 84 dyads were videotaped at 4 months during a face-to-face interaction, and at 12 months during the Ainsworth Strange Situation. Four-month mother and infant communication modalities of attention, affect, touch, and spatial orientation were coded from split-screen videotape on a 1 s time base; mother and infant facial-visual "engagement" variables were constructed. We used contingency measures (multi-level time-series modeling) to examine the dyadic temporal process over time, and specific rates of qualitative features of behavior to examine the content of behavior. Self-contingency (auto-correlation) measured the degree of stability/lability within an individual's own rhythms of behavior; interactive contingency (lagged cross-correlation) measured adjustments of the individual's behavior that were correlated with the partner's previous behavior. We documented that both self- and interactive contingency, as well as specific qualitative features, of mother and infant behavior were mechanisms of attachment formation by 4 months, distinguishing 12-month insecure, resistant, and disorganized attachment classifications from secure; avoidant were too few to test. All communication modalities made unique contributions. The separate analysis of different communication modalities identified intermodal discrepancies or conflict, both intrapersonal and interpersonal, that characterized insecure dyads. Contrary to dominant theories in the literature on face-to-face interaction, measures of maternal contingent coordination with infant yielded the fewest associations with 12-month attachment, whereas mother and infant self-contingency, and infant contingent coordination with mother, yielded comparable numbers of findings. Rather than the more usual hypothesis that more contingency is "better," we partially supported our hypothesis that 12-month insecurity is associated with both higher and lower 4-month self- and interactive contingency values than secure, as a function of mother vs. infant and communication modality. Thus, in the origins of attachment security, more contingency is not necessarily better. A remarkable degree of differentiation was identified in the 4-month patterns of "future" C and D infants, classified as resistant and disorganized, respectively, at 12 months. The central feature of future C dyads was dysregulated tactile and spatial exchanges, generating approach-withdrawal patterns. The intact maternal contingent coordination overall safeguards the future C infant's interactive agency. However, future C infants likely come to expect maternal spatial/tactile impingement, and to expect to "dodge" as mothers "chase." They managed maternal touch by tuning it out, sacrificing their ability to communicate about maternal touch. They "approached" by vigilantly coordinating their facial-visual engagement with maternal facial-visual engagement, but they "withdrew" by inhibiting their facial-visual engagement coordination with maternal touch. We proposed that future C infants will have difficulty feeling sensed and known during maternal spatial/tactile impingements. The central feature of future D dyads is intrapersonal and interpersonal discordance or conflict in the context of intensely distressed infants. Lowered maternal contingent coordination, and failures of maternal affective correspondence, constituted maternal emotional withdrawal from distressed infants, compromising infant interactive agency and emotional coherence. The level of dysregulation in future D dyads was thus of an entirely different order than that of future C dyads. We proposed that the future D infant represents not being sensed and known by the mother, particularly in states of distress. We proposed that the emerging internal working model of future D infants includes confusion about their own basic emotional organization, about their mothers' emotional organization, and about their mothers' response to their distress, setting a trajectory in development which may disturb the fundamental integration of the person. The findings have rich implications for clinical intervention, with remarkable specificity for different kinds of mother and infant distress. Heightened and lowered self- and interactive contingency, in different modalities, as well as the specific behavioral qualities identified, provide a more differentiated set of concepts to guide clinical intervention.

The relationship between anxiety disorders and substance use among adolescents in the community: specificity and gender differences.

Using a sample of 781 adolescents (ages 13-17, 52.8% male) from a community survey, this study examined gender differences in the co-occurrence of specific anxiety disorders with substance use in adolescents. The associations between anxiety disorders and substance use differed according to the particular anxiety disorders and forms of substance use being examined, as well as by gender. Social phobia was associated with cigarette smoking among boys only. For girls, social phobia appeared to be negatively associated with drug use. For the other anxiety disorders, the associations with substance use tended to be stronger among girls. These findings highlight the need to improve clinical recognition of the anxiety disorders and to improve treatment access for afflicted adolescents. Future studies based on longitudinal data could further elucidate the relationships among anxiety disorders, gender, and substance use.

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.

Maternal depression and mother-child interaction patterns: association with toddler problems and continuity of effects to late childhood.

OBJECTIVE: Increased behavior problems have been reported in offspring of mothers with depression. In-home observations link maternal depressive symptoms (MDS) and mother-child interaction patterns with toddler behavior problems and examine their persistence into late childhood. METHOD: Maternal characteristics (N = 153) and behaviors of two-year-old offspring (N = 215) were assessed in families from a randomly selected population cohort. Maternal self-reported depressive symptoms and observed maternal-toddler interaction patterns were evaluated as risks for toddler problem behaviors. Follow-up CBCL assessments about a decade later assessed persistence of effects identified in the toddler data. RESULTS: Maternal negativity toward her toddler was related to toddler problems, regardless of maternal depressive symptoms. MDS in combination with positive mother-toddler interaction showed only marginal ill effects on toddler offspring and no long-term effects. Depressive symptoms of less responsive/emotion teaching dyads were related to offspring tantrums and to mother and observer rated fearfulness, independent of family contextual risks. Analyses of Child Behavior Checklist (CBCL) problem scales obtained on these children in late childhood showed persistent effects similar to those shown at the younger age. CONCLUSIONS: In sum, these findings suggest that for mothers with high levels of depressive symptoms, demonstrations of affection and responsiveness to toddler offspring may mitigate both current and long-term consequences on offspring behavior.

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.

Early maternal separation and the trajectory of borderline personality disorder symptoms.

Extended maternal separations before age 5 were evaluated as a predictor of long-term risk for offspring borderline personality disorder (BPD) symptoms in longitudinal data from a large random community sample. Early separations from mother predicted elevations in BPD symptoms assessed repeatedly from early adolescence to middle adulthood. Early separations also predicted a slower than normal rate of decline in symptoms with age. Other theoretically grounded risks were examined and shown to predict elevated BPD symptoms over the developmental trajectory. Long-term effects of early separations were largely independent of childhood temperament, child abuse, maternal problems, and parenting risks. These data provide the first prospectively collected data on the developmental course of BPD symptoms and suggest a series of environmental and other influences on these very disabling problems.

Pathways from adolescent parent-child conflict to substance use disorders in the fourth decade of life.

This 24-year community longitudinal study provides important information regarding parent-child conflict in adolescence (mean ages 14-16), vulnerable personality attributes and peer deviance in the twenties (mean age 22), and marital conflict and partner's illicit drug use in the late twenties and early thirties (mean ages 27-32) as related to a later diagnosis of substance use disorders (SUDs) in the thirties (mean ages 32-37). A community-based sample was interviewed between 1975 and 2007. Results based in structural equation modeling indicated that a weak parent-child bond was related to the development of drug-conducive personality traits, which was associated with the selection of drug-using peers and partners, which in turn, predicted SUDs. Both peer deviance and partner's illicit drug use had the greatest effects on SUDs. The findings should aid in formulating prevention and treatment programs targeting specific risk factors in adolescents, young adults, and adults.

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.