Associations Between Secretory Immunoglobulin A and Social Network Structure.

PURPOSE: This study investigates the social determinants of health by examining how mucosal immunity is associated with the patterning of social connections in a network. Studies have suggested that social networks have biological underpinnings, but investigations at the scale of networks, rather than individuals, have remained elusive. We integrate salivary bioscience methods with advanced social network modeling to explore the association between salivary secretory immunoglobulin A (SIgA), a key component of mucosal immunity, and social network structure. METHOD: Friendship network data and saliva samples (later assayed for SIgA) were obtained from a large mixed-gender social organization (n = 155, 55% female, M age = 19.5 years). RESULTS: Exponential random graph modeling revealed that SIgA levels were positively associated with reporting more friendship ties with community members (i.e., social network activity), after controlling for other processes associated with network structure including preference to befriend others of the same age, gender, and extraversion, increased network popularity of agreeable individuals and those with lower levels of perceived stress, as well as network structural and organizational processes. CONCLUSION: By examining a wider range of associations between SIgA and network structure, we pinpoint that SIgA is positively associated with respondent's sociability. Our findings are consistent with social integration theories linking social relationships to health and highlight the role of humoral immunity as a possible mediator of these associations.

Adrenocortical regulation, eating in the absence of hunger and BMI in young children.

The purpose of this study was to examine relations among adrenocortical regulation, eating in the absence of hunger, and body mass index (BMI) in children ages 5-9years (N=43). Saliva was collected before and after the Trier Social Stress Test for Children (TSST-C), and was later assayed for cortisol. Area under the curve with respect to increase (AUCi) was used as a measure of changes in cortisol release from baseline to 60min post-TSST-C. Age- and sex-specific BMI scores were calculated from measured height and weight, and eating in the absence of hunger was assessed using weighed food intake during a behavioral procedure. We also included a measure of parents' report of child impulsivity, as well as family demographic information. Participants were stratified by age into younger (5-7years) and older (8-9years) groups. In younger children, parents' reports of child impulsivity were significantly and positively associated with BMI; cortisol AUCi was not associated with BMI or eating in the absence of hunger. In older children, however, greater stress-related cortisol AUCi was related to higher BMI scores and greater energy intake in the absence of hunger. The results suggest that cortisol AUCi in response to psychosocial stress may be linked to problems with energy balance in children, with some variation by age.

Salivary uric acid across child development and associations with weight, height, and body mass index.

Introduction: Obesity during childhood is a serious and growing chronic disease with consequences for lifelong health. In an effort to advance research into the preclinical indicators of pediatric obesity, we examined longitudinal assessments of uric acid concentrations in saliva among a cohort of healthy children from age 6-months to 12-years (n's per assessment range from 294 to 727). Methods: Using data from a subsample of participants from the Family Life Project (an Environmental influences on Child Health Outcomes Program cohort), we: (1) characterized salivary uric acid (sUA) concentrations from infancy to early adolescence by sex and race; (2) assessed changes in sUA levels across development; and (3) evaluated associations between sUA concentrations and measures of child weight, height, and body mass index (BMI). Across four assessments conducted at 6-, 24-, 90-, and 154-months of age, 2,000 saliva samples were assayed for UA from 781 participants (217 participants had sUA data at all assessments). Results: There were no significant differences in sUA concentrations by sex at any assessment, and differences in sUA concentrations between White and non-White children varied by age. At the 90- and 154-month assessments, sUA concentrations were positively correlated with measures of child weight, height, and BMI (90-month: weight- ρ(610) = 0.13, p < 0.01; height- ρ(607) = 0.10, p < 0.05; BMI- ρ(604) = 0.13, p < 0.01; 154-month: weight- ρ(723) = 0.18, p < 0.0001; height- ρ(721) = 0.10, p < 0.01; BMI- ρ(721) = 0.17, p < 0.0001). Group based trajectory modeling identified two groups of children in our sample with distinct patterns of sUA developmental change. The majority (72%) of participants showed no significant changes in sUA across time ("Stable" group), while 28% showed increases in sUA across childhood with steep increases from the 90- to 154-month assessments ("Increasing" group). Children in the Increasing group exhibited higher sUA concentrations at all assessments (6-month: t(215) = -5.71, p < 0.001; 24-month: t(215) = -2.89, p < 0.01; 90-month: t(215) = -3.89, p < 0.001; 154-month: t(215) = -19.28, p < 0.001) and higher weight at the 24- and 90-month assessments (24-month: t(214) = -2.37, p < 0.05; 90-month: t(214) = -2.73, p < 0.01). Discussion: Our findings support the potential utility of sUA as a novel, minimally-invasive biomarker that may help advance understanding of the mechanisms underlying obesity as well as further surveillance and monitoring efforts for pediatric obesity on a large-scale.

Sex-related Differences in Stress Reactivity and Cingulum White Matter.

The prefrontal cortex and limbic system are important components of the neural circuit that underlies stress and anxiety. These brain regions are connected by white matter tracts that support neural communication including the cingulum, uncinate fasciculus, and the fornix/stria-terminalis. Determining the relationship between stress reactivity and these white matter tracts may provide new insight into factors that underlie stress susceptibility and resilience. Therefore, the present study investigated sex differences in the relationship between stress reactivity and generalized fractional anisotropy (GFA) of the white matter tracts that link the prefrontal cortex and limbic system. Diffusion weighted images were collected and deterministic tractography was completed in 104 young adults (55 men, 49 women; mean age = 18.87 SEM = 0.08). Participants also completed self-report questionnaires (e.g., Trait Anxiety) and donated saliva (later assayed for cortisol) before, during, and after the Trier Social Stress Test. Results revealed that stress reactivity (area under the curve increase in cortisol) and GFA of the cingulum bundle varied by sex. Specifically, men demonstrated greater cortisol reactivity and greater GFA within the cingulum than women. Further, an interaction between sex, stress reactivity, and cingulum GFA was observed in which men demonstrated a positive relationship while women demonstrated a negative relationship between GFA and cortisol reactivity. Finally, trait anxiety was positively associated with the GFA of the fornix/stria terminalis - the white matter pathways that connect the hippocampus/amygdala to the hypothalamus. These findings advance our understanding of factors that underlie individual differences in stress reactivity.

Effects of psychotherapy with children and adolescents revisited: a meta-analysis of treatment outcome studies.

A meta-analysis of child and adolescent psychotherapy outcome research tested previous findings using a new sample of 150 outcome studies and weighted least squares methods. The overall mean effect of therapy was positive and highly significant. Effects were more positive for behavioral than for nonbehavioral treatments, and samples of adolescent girls showed better outcomes than other Age x Gender groups. Paraprofessionals produced larger overall treatment effects than professional therapists or students, but professionals produced larger effects than paraprofessionals in treating overcontrolled problems (e.g., anxiety and depression). Results supported the specificity of treatment effects: Outcomes were stronger for the particular problems targeted in treatment than for problems not targeted. The findings shed new light on previous results and raise significant issues for future study.

Use of salivary biomarkers in biobehavioral research: cotton-based sample collection methods can interfere with salivary immunoassay results.

In a series of studies, we evaluated the susceptibility of immunoassays for saliva biomarkers to interference effects caused by cotton materials used to absorb saliva during sample collection. Salivary assay results for testosterone, DHEA, progesterone, and estradiol are artificially high, and for sIgA artificially low, when samples are collected using cotton absorbent materials. In contrast, results for salivary cortisol, DHEA-S, and cotinine are not affected by the use of cotton collection methods. The order of individual results from samples collected using cotton versus no-cotton methods for certain markers is not conserved, suggesting that for some biomarkers this collection method can be a significant source of unsystematic error. It was shown, using DHEA as an example, that the cotton interference effect is of sufficient magnitude to attenuate the association between serum and saliva levels. Awareness of this issue is critical to ensure measurement validity in future studies and analyses of archived samples collected using cotton materials.

Assessing dehydroepiandrosterone in saliva: a simple radioimmunoassay for use in studies of children, adolescents and adults.

While salivary assays for some hormones are widely used, the availability of assays for salivary DHEA is limited. By adapting a commercially available radioimmunoassay serum kit, we developed a reliable, efficient and sensitive measure of DHEA in saliva that does not require separation or extraction. The minimum detection limit was 4.0 pg/ml. Intra-assay coefficients of variation (CV%) were on average 4.05, and inter-assay CVs averaged 9.70. Method accuracy, determined by spike recovery, and linearity, determined by serial dilution, averaged 99.55 and 92.03%. Levels in matched serum and saliva samples showed strong linear relationships for adult males and females. Specific guidelines are developed for sample collection, storage, and preparation procedures. Reference ranges for salivary DHEA levels are provided for 64 children ages 8-11, 96 adolescents ages 12-17 and 48 adults ages 30-45. Salivary DHEA levels are shown to reflect developmental, gender and diurnal differences.

Corticotropin-releasing hormone and cortisol: longitudinal associations with depression and antisocial behavior in pregnant adolescents.

OBJECTIVE: To examine the concurrent and longitudinal associations between corticotropin-releasing hormone (CRH) and cortisol concentrations and depression and antisocial behavior (conduct disorder symptoms) in pregnant adolescents. METHOD: Fifty-nine adolescents were evaluated in early pregnancy (9-21 weeks' gestation), late pregnancy (32-34 weeks' gestation), and the postpartum period (4-5 weeks postpartum). Symptoms of depression and conduct disorder were obtained from the Diagnostic Interview Schedule for Children. RESULTS: Lower concentrations of CRH were related to a greater number of depression symptoms in early pregnancy (p < .05) and in late pregnancy (p < .05). Lower concentrations of CRH also were related to a greater number of conduct disorder symptoms in early pregnancy (p < .06) and in the postpartum period (p < .05). CONCLUSION: The findings support the long-standing hypothesis that stress-related products of the hypothalamic-pituitary-adrenal axis are associated with emotions and behavior during pregnancy.

Neuroendocrine reactivity, internalizing behavior problems, and control-related cognitions in clinic-referred children and adolescents.

Literature on neuroendocrine-behavior relations suggests that cortisol reactivity to social challenge may be associated with children's internalizing problem behavior. To explore this possibility, and the role of control-related beliefs, we studied 102 7-17-year-old clinic-referred children. Measures of problem behavior, depression and anxiety, and control-related beliefs were collected, and Ss' saliva was sampled before and after a parent-child conflict task. Neuroendocrine activation (i.e., cortisol increase) in response to the interaction task was associated with Ss' (a) social withdrawal, social anxiety, and social problems; (b) socially inhibited behavior during the task; and (c) low levels of perceived social contingency and high levels of external attributions for personal successes and failures. Our findings are among the first to link children's behavioral response to social challenge, neuroendocrine activation, cognitions, and psychopathology.

Testosterone and men's depression: the role of social behavior.

Medical research suggests that testosterone has positive effects on mood (thereby reducing the chances of depression), and social science research finds testosterone to be related to antisocial behavior, risk behavior, unemployment and low paying jobs, and being unmarried--factors known to be positively related to depression. Analysis of a sample of 4,393 men finds a parabolic model best fits the data. The relationship between testosterone and depression is inverse for men with below average testosterone and direct for those with above average testosterone. The relationship disappears for those with above average testosterone when controls for antisocial and risk behaviors and the absence of protective factors such as marriage and steady employment are in the equation. The relationship is unchanged for those with below average testosterone. The results help explain the difference between medical and social research findings. Mechanisms accounting for the findings are explored.

Social judgment processes in hyperactive boys: effects of methylphenidate and comparisons with normal peers.

Although there is consensus that ADHD children have serious social problems, there is little understanding of the mechanisms underlying or accompanying such problems. To examine the possibility of atypical or faulty social reasoning, we presented ADHD and normal boys with a social perception task that entailed evaluating the behaviors of unknown peers. ADHD "judges" participated under both methylphenidate and placebo conditions, and on each occasion they evaluated an unfamiliar ADHD "target" in each medication state. In contrast to placebo, methylphenidate appeared to dampen overall response rates in ADHD judges, but there was no effect on sensitivity to medication-related differences. Regardless of their own medication state, ADHD judges identified more undesirable behaviors in peers on placebo than in those taking methylphenidate. Judges with the most serious behavior problems tended to identify the greatest number of negative behaviors in peers, especially when both judge and target were unmedicated. There were no effects of target medication status on detections of positive behaviors and few differences in detection patterns of ADHD versus normal judges. Discussion focused on the need to distinguish general regulatory from specific social-cognitive processes.

Malleability of social impressions of hyperactive children.

The role of adults' social cognitions in mediating judgments of hyperactive children's medication-related behavior change was explored. Two hundred eight-eight undergraduates observed two videotaped excerpts of a hyperactive "target" boy playing a group game with two peers. Each target was taking either methylphenidate (0.6 mg/kg) during both excerpts, placebo during both excerpts, methylphenidate first followed by placebo, or placebo first followed by methylphenidate. Adults' cumulative social evaluations of the child were assessed after they viewed both video segments. Results indicated that observers combined their perceptions of the two behavior samples into composite impressions using an equal-weight averaging algorithm. Even for children whose behavior improved, adults' ratings of undercontrolled behaviors continued to meet or, in some cases exceed, research cutoff scores used to identify hyperactive children. The findings suggest that the actual behaviors of children with attention-deficit hyperactivity disorder (ADHD) play a more influential role in shaping interpersonal impressions than do perceiver social-cognitive processes such as primacy, recency, or integration biases.

Perceptions of methylphenidate effects on hyperactive children's peer interactions.

The behavioral constructs that emerge from observers' open-ended impressions of methylphenidate effects on the social behaviors of hyperactive children were examined. Ninety-six undergraduates observed videotapes of two different hyperactive "target" boys, each playing an interaction game with three peers. One target was taking methylphenidate and the other was taking placebo. The valence and content of observers' social perceptions were analyzed. Overall, more negative than positive behaviors were detected, a pattern more pronounced for the placebo than for the medication condition. Interestingly, placebo targets received negative evaluations for poorly controlled behaviors such as noncompliance, aggression, and disruption, but medicated targets received negative evaluations for social inhibition--passive and submissive behaviors. In contrast, the boys' medication state did not consistently influence observers' perceptions of positive social behaviors. Discussion focused on the extent and consequences of medication-related increases in social disengagement and on the ultimate impact of stimulant treatment on hyperactive children's social worlds.

Maternal depression and risk for postpartum complications: role of prenatal corticotropin-releasing hormone and interleukin-1 receptor antagonist.

The pregnancies of 58 healthy adolescents (ages 13 to 19 years) were followed to examine links between symptoms of depression, corticotropin-releasing hormone (CRH), interleukin-1 beta, (IL-1 beta), and IL-1 receptor antagonist (IL-1ra) as possible predictors of maternal and infant outcomes. Maternal psychological adjustment and medical complications during gestation, labor, delivery, and the postpartum period were monitored. Plasma samples collected during gestation were assayed for CRH, IL-1 beta, and IL-1ra. During gestation, symptoms of maternal depression were found to be associated with lower levels of CRH; lower levels of CRH were associated with lower levels of IL-1ra. In addition, lower levels of IL-1ra predicted higher rates of maternal complications after childbirth. IL-1 beta, detected in only 4 mothers, was not associated with any predictor or outcome measures. During gestation, CRH may induce circulating cytokine inhibitors without significantly affecting cytokine production or synthesis. Maternal symptoms of depression during gestation may attenuate the association between CRH and IL-1ra.

Defining MAP3 kinases required for MDA-MB-231 cell tumor growth and metastasis.

Analysis of patient tumors suggests that multiple MAP3 kinases (MAP3Ks) are critical for growth and metastasis of cancer cells. MAP3Ks selectively control the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), p38 and ERK5 in response to receptor tyrosine kinases and GTPases. We used MDA-MB-231 cells because of their ability to metastasize from the breast fat pad to distant lymph nodes for an orthotopic xenograft model to screen the function of seven MAP3Ks in controlling tumor growth and metastasis. Stable short hairpin RNA (shRNA) knockdown was used to inhibit the expression of each of the seven MAP3Ks, which were selected for their differential regulation of the MAPK network. The screen identified two MAP3Ks, MEKK2 and MLK3, whose shRNA knockdown caused significant inhibition of both tumor growth and metastasis. Neither MEKK2 nor MLK3 have been previously shown to regulate tumor growth and metastasis in vivo. These results demonstrated that MAP3Ks, which differentially activate JNK, p38 and ERK5, are necessary for xenograft tumor growth and metastasis of MDA-MB-231 tumors. The requirement for MAP3Ks signaling through multiple MAPK pathways explains why several members of the MAPK network are activated in cancer. MEKK2 was required for epidermal growth factor receptor and Her2/Neu activation of ERK5, with ERK5 being required for metastasis. Loss of MLK3 expression increased mitotic infidelity and apoptosis in vitro. Knockdown of MEKK2 and MLK3 resulted in increased apoptosis in orthotopic xenografts relative to control tumors in mice, inhibiting both tumor growth and metastasis; MEKK2 and MLK3 represent untargeted kinases in tumor biology for potential therapeutic development.

Human aggression and enumerative measures of immunity.

OBJECTIVE: A pattern of clinical, behavioral, and experimental findings suggests that individual differences in aggressive behavior may be related to immunologic processes. We evaluated two conflicting models of the relationship: 1) A positive association stems from an adaptive mechanism protecting aggressive individuals from increased exposure to immune stimuli and 2) a negative association is due to potential immunosuppressive effects of high testosterone levels. METHODS: We investigated the models using enumerative measures of cellular and humoral immunity in a sample of 4415 men aged 30 to 48 years who were interviewed and underwent a medical examination. RESULTS: Analysis revealed positive (and curvilinear) associations between aggressive behavior and enumerative measures of helper/inducer and suppressor/cytolytic T lymphocytes and B lymphocytes. The aggression-immunity relationship was independent of testosterone level, age, current health status, and negative health behaviors and was most pronounced for helper/inducer T cells. There was no evidence of a negative association between testosterone and any immune measure. CONCLUSIONS: In a large sample of men, individual differences in aggressive behavior were positively associated with enumerative measures of cellular immunity.

Testosterone and men's health.

Medical and behavioral research depicts the influence of testosterone on health in opposite ways, the former finding beneficial effects and the latter potentially detrimental ones. We investigate the relationship between testosterone and health risk behavior, indicators of disease, and overall health in a sample of 4393 men who were interviewed and medically examined. Analysis revealed that having a high level of testosterone, compared to a low level, increased the odds of health risk behavior. With respect to disease, high testosterone increased the odds of some health problems but decreased the chances of others. At very high levels testosterone loses many of its beneficial effects. Overall, men with high testosterone would be healthier if they did not engage in health risk behavior.