Early-Life Antibiotic-Driven Dysbiosis Leads to Dysregulated Vaccine Immune Responses in Mice.

Antibody-mediated responses play a critical role in vaccine-mediated immunity. However, for reasons that are poorly understood, these responses are highly variable between individuals. Using a mouse model, we report that antibiotic-driven intestinal dysbiosis, specifically in early life, leads to significantly impaired antibody responses to five different adjuvanted and live vaccines. Restoration of the commensal microbiota following antibiotic exposure rescues these impaired responses. In contrast, antibiotic-treated adult mice do not exhibit impaired antibody responses to vaccination. Interestingly, in contrast to impaired antibody responses, immunized mice exposed to early-life antibiotics display significantly enhanced T cell cytokine recall responses upon ex vivo restimulation with the vaccine antigen. Our results demonstrate that, in mice, antibiotic-driven dysregulation of the gut microbiota in early life can modulate immune responses to vaccines that are routinely administered to infants worldwide.

Methylation of Gata3 protein at Arg-261 regulates transactivation of the Il5 gene in T helper 2 cells.

Gata3 acts as a master regulator for T helper 2 (Th2) cell differentiation by inducing chromatin remodeling of the Th2 cytokine loci, accelerating Th2 cell proliferation, and repressing Th1 cell differentiation. Gata3 also directly transactivates the interleukin-5 (Il5) gene via additional mechanisms that have not been fully elucidated. We herein identified a mechanism whereby the methylation of Gata3 at Arg-261 regulates the transcriptional activation of the Il5 gene in Th2 cells. Although the methylation-mimicking Gata3 mutant retained the ability to induce IL-4 and repress IFNγ production, the IL-5 production was selectively impaired. We also demonstrated that heat shock protein (Hsp) 60 strongly associates with the methylation-mimicking Gata3 mutant and negatively regulates elongation of the Il5 transcript by RNA polymerase II. Thus, arginine methylation appears to play a pivotal role in the organization of Gata3 complexes and the target gene specificity of Gata3.

Prevalence and sociodemographic correlates of lifetime substance use among a rural and diverse sample of adolescents.

BACKGROUND: Data are limited regarding the prevalence of substance use among adolescents in rural and ethnically diverse communities. This study examined rates and sociodemographic correlates of lifetime substance use among adolescents in Mississippi, a rural state that is the poorest in the country (21.3% poverty rate) and has the largest proportion of African Americans per capita (36.3%). METHODS: Participants in this cross-sectional study were 6349 adolescents (6th through 12th grade) who reported on lifetime tobacco, alcohol, marijuana, cocaine, inhalant, hallucinogen, and methamphetamine use. RESULTS: Lifetime smoking (10.2% to 44.5%), alcohol (23.2% to 72.0%), and marijuana use (7.9% to 39.2%) increased steadily when comparing students in 6th to 12th grade. Substances with more serious abuse potential (cocaine [6.7% to 11.1%], inhalants [12.2% to 17.9%], hallucinogens [4.4% to 12.1%], and methamphetamine [3.0% to 6.7%]) displayed more modest increases across grade. Adolescents who classified their race/ethnicity as "Other" (i.e., not white, black/African American, Asian, or Hispanic/Latino/Latina) demonstrated more than 2-fold increased likelihood of methamphetamine use (odds ratio [OR] = 2.42), and increased risk for use of any illicit substance (OR = 1.49). In general, males demonstrated an increased risk for use across substances (OR = 1.15-1.94), and higher income was associated with a decreased likelihood of illicit substance use (OR = 0.51-0.67). Living in a more populated area was associated with an increased likelihood of alcohol (OR = 1.43), marijuana (OR = 2.11), and cocaine use (OR = 2.06), and use of any illicit substance (OR = 1.54). CONCLUSIONS: Mississippi adolescents reported higher rates of lifetime cocaine, inhalant, hallucinogen, and methamphetamine use across all grade levels compared with national surveys. Male gender, low income, and residence in more populated areas were associated with increased use of several substances. Findings demonstrate the need for prevention and intervention programs targeting impoverished rural and ethnically diverse communities.

Functionally distinct Gata3/Chd4 complexes coordinately establish T helper 2 (Th2) cell identity.

GATA binding protein 3 (Gata3) is a GATA family transcription factor that controls differentiation of naïve CD4 T cells into T helper 2 (Th2) cells. However, it is unknown how Gata3 simultaneously activates Th2-specific genes while repressing those of other Th lineages. Here we show that chromodomain helicase DNA-binding protein 4 (Chd4) forms a complex with Gata3 in Th2 cells that both activates Th2 cytokine transcription and represses the Th1 cytokine IFN-γ. We define a Gata3/Chd4/p300 transcriptional activation complex at the Th2 cytokine loci and a Gata3/Chd4-nucleosome remodeling histone deacetylase repression complex at the Tbx21 locus in Th2 cells. We also demonstrate a physiological role for Chd4 in Th2-dependent inflammation in an in vivo model of asthmatic inflammation. Thus, Gata3/Chd4 forms functionally distinct complexes, which mediate both positive and negative gene regulation to facilitate Th2 cell differentiation.

A measurement invariance examination of the Revised Child Anxiety and Depression Scale in a Southern sample: differential item functioning between African American and Caucasian youth.

This study examined the psychometric properties of the Revised Child Anxiety and Depression Scale in a large sample of youth from the Southern United States. The authors aimed to determine (a) if the established six-factor Revised Child Anxiety and Depression Scale structure could be replicated in this Southern sample and (b) if scores were associated with measurement invariance across African American and Caucasian youth representative of youth from this region of the United States. The established six-factor model evidenced the best fit in comparison to one-, two-, and five-factor models in the total sample (N = 12,695), as well as in the African American (n = 4,906) and Caucasian (n = 6,667) subsamples. Multigroup confirmatory factor analysis also supported measurement invariance across African American and Caucasian youth at the levels of equal factor structure and equal factor loadings. Noninvariant item intercepts were identified, however, indicating differential functioning for a subset of items. Clinical and measurement implications of these findings are discussed and new norms are presented.

Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo.

To develop more effective vaccines and strategies to regulate chronic inflammatory diseases, it is important to understand the mechanisms of immunological memory. Factors regulating memory CD4(+) T helper (Th)-cell pool size and function remain unclear, however. We show that activation of type I invariant natural killer T (iNKT) cells with glycolipid ligands and activation of type II natural killer T (NKT) cells with the endogenous ligand sulfatide induced dramatic proliferation and expansion of memory, but not naïve, CD4 T cells. NKT cell-induced proliferation of memory Th1 and Th2 cells was dependent largely on the production of IL-2, with Th2-cell proliferation also affected by loss of IL-4. Type II NKT cells were also required for efficient maintenance of memory CD4 T cells in vivo. Activation of iNKT cells resulted in up-regulation of IFN-γ expression by memory Th2 cells. These IFN-γ-producing memory Th2 cells showed a decreased capability to induce Th2 cytokines and eosinophilic airway inflammation. Thus, activated NKT cells directly regulate memory CD4 T-cell pool size and function via the production of cytokines in vivo.

Non-medical use of prescription drugs among Mississippi youth: constitutional, psychological, and family factors.

OBJECTIVE: The non-medical use of prescription drugs (NMUPD) among youth is a significant public health concern, ranking as the second most frequently used class of drug in youth after marijuana. Given the complex and multiple pathways that may lead to NMUPD in youth, this study examines predictors of NMUPD across constitutional, psychological, and family/peer domains. METHOD: An ethnically diverse sample of 6790 youth in the 6th-12th grades enrolled in public schools throughout Mississippi completed a battery of questionnaires as part of a broader school-based mental health screening initiative in Mississippi (Behavioral Vital Signs Project). RESULTS: The lifetime prevalence rate of NMUPD in our sample was 6.5%. Pain medications were the most commonly used (57%), followed by benzodiazepines (44%), prescription stimulants (e.g., Ritalin, Concerta, Focalin, Dexedrine; 37%), SSRIs (29%), and antipsychotics (24%). Almost a quarter of NMUPD youth used these drugs for 10days or more during the 30-day period prior to completing the survey, and 8% reported daily use. Binary logistic regression analyses revealed that race; grade level; anxiety, mood, and suicide-related symptoms; and substance use involvement significantly increased risk for NMUPD in youth. CONCLUSIONS: NMUPD among youth is a clinically-relevant and multi-determined phenomenon. Findings from this study identify factors relevant to understanding youth NMUPD and also highlight the need for additional research and targeted prevention and intervention programs for NMUPD among youth.

Deliberate self-harm among underserved adolescents: the moderating roles of gender, race, and school-level and association with borderline personality features.

Despite increasing research on the correlates and functions of deliberate self-harm (DSH) among community youth, less is known about the subsets of youth most at-risk for DSH or the relevance of borderline personality (BP) pathology to DSH within this population. This study sought to extend research on the characteristics associated with DSH by examining the ways in which gender, racial/ethnic background, and school-level interact to influence DSH among ethnically diverse youth in a relatively poor and underserved area, as well as the extent to which levels of BP features account for differences in rates of DSH across subsets of youth. Middle- and high-school students (N = 1931) from six public schools in Mississippi completed self-report measures of DSH and BP features. Consistent with past research, 39% of the youth in our sample reported engaging in DSH. However, rates of DSH varied as function of gender, racial/ethnic background, and school-level (as well as their interactions), with African American boys reporting higher rates of most DSH behaviors than their peers (particularly in middle-school). One notable exception to this pattern pertains to the specific behavior of cutting, for which both White girls and African American boys reported the highest rates. Further, although BP features were reliably associated with DSH status (above and beyond these demographic characteristics), they did not account for the interactive effect of gender and race on rates of DSH. Findings highlight the importance of continuing to examine DSH and its correlates among more diverse groups of youth.

The Loneliness Questionnaire-Short Version: an evaluation of reverse-worded and non-reverse-worded items via item response theory.

Although reverse-worded items have often been incorporated in scale construction to minimize the effects of acquiescent reporting biases, some researchers have more recently begun questioning this approach and wondering whether the advantages associated with incorporating reverse-worded items is worth the complexities that they bring to measures (e.g., Brown, 2003 ; Marsh, 1996 ). In this study, we used item response theory (IRT) to determine whether there is statistical justification to eliminate the reverse-worded items (e.g., "I have lots of friends") from the Loneliness Questionnaire (LQ; Asher, Hymel, & Renshaw, 1984) and retain only the non-reverse-worded items (e.g., "I'm lonely") to inform the provision of a shortened LQ version. Using a large sample of children (Grades 2-7; n = 6,784) and adolescents (Grades 8-12; n = 4,941), we examined the psychometric properties of the 24-item LQ and found support for retaining the 9 non-reverse-worded LQ items to make up a shortened measure of loneliness in youth. We found that the non-reverse-worded items were associated with superior psychometric properties relative to the reverse-worded items with respect to reliability and IRT parameters (e.g., discrimination and item information). A 3-point Likert-type scale was also found to be more suitable for measuring loneliness across both children and adolescents compared to the original 5-point scale. The relative contributions of reverse-worded and non-reverse-worded items in scale development for youth instruments are also discussed.

The importance of modeling method effects: resolving the (uni)dimensionality of the loneliness questionnaire.

This study sought to resolve the dimensionality of the Loneliness Questionnaire (LQ; Asher, Hymel, & Renshaw, 1984) by applying recommended confirmatory factor analytic procedures that control for method effects (Brown, 2003). This study was needed given that inconsistent findings have been reported recently regarding the structure of this instrument (Bagner, Storch, & Roberti, 2004) and all models to date have not accounted for method effects due to the non-reversed-worded and reversed-worded items of this instrument. Using a large sample of youth in Grades 2 through 12 (N = 11,725), we compared the previously reported 1- and 2-factor models with a newly posited 1-factor model that incorporated correlated error terms to account for method effects. We found that the 1-factor model that included correlated error terms fit the data best, and that this factor structure evidenced measurement invariance across boys and girls in childhood, but not in adolescence. The meaning of the LQ indicators was also consistent for boys across development, but evidenced differences for girls in childhood versus adolescence. More generally, it was demonstrated that modeling method effects is vital to accurately understanding the dimensionality of loneliness when reversed-worded and non-reversed-worded items are used as indicators. The measurement and clinical implications of these findings are discussed.

Racial differences in symptoms of anxiety and depression among three cohorts of students in the southern United States.

The present study aimed to extend the literature on mental health disparities in underserved areas by investigating racial differences in symptoms of anxiety and depression in three cohorts of school children in the Southern United States. White and African American students attending elementary, middle, and high school (n = 3,146) were administered a multi-dimensional measure of anxiety and depression. Racial differences were examined using categorical, dimensional, and latent-variable analytic methods. Although effect sizes were small across all levels of analysis, the categorical and dimensional approaches produced different patterns of significant anxiety-related findings. Additionally, confirmatory factor analysis indicated that the dimensional findings were not due to racial differences in the measurement of anxiety. The results of the current investigation suggest that, among school children, race has modest effects on symptoms of anxiety, but not depression. Further, the differential findings observed across analytic approaches reinforce the importance of measurement and methodology when studying psychopathology in children and adolescents.

Self-injurious thoughts and behaviors among youth in an underserved area of the Southern United States: exploring the moderating roles of gender, racial/ethnic background, and school-level.

Despite the clinical relevance of self-injurious thoughts and behaviors (SITB) among youth, little is known about the subset of youth most at-risk for SITB. This study examined the moderating roles of gender, racial/ethnic background, and school-level (and their interactions) on rates of SITB within a large (N = 2638, 52.2% female), ethnically-diverse sample of middle- and high-school youth in a relatively poor and underserved area of the Southern United States. Extending extant research in this area, findings indicated a significant interaction between gender and race for self-injurious behaviors, with African-American boys reporting higher rates than all other groups. Findings also indicated significant interactions between school-level and both gender and race for self-injurious thoughts. Whereas comparable levels of self-injurious thoughts were reported across middle- and high-schools for girls and African-American youth, the frequency of these thoughts was higher among both boys and White students in high-school (vs. middle-school). Results highlight the need for further research on SITB among diverse youth in underserved areas.

State mental health policy: Overview and goals of the Mississippi Youth Programs Around the Clock (MYPAC).

This column briefly outlines the Mississippi Youth Programs Around the Clock (MYPAC) Demonstration Project. MYPAC is a federally funded effort to examine community-based alternatives to residential placement for youths with severe emotional disturbance. The project is one of ten similarly structured grants awarded nationally and is among the first to reach implementation. Because such a large amount of funding has been dedicated to such a substantial cross-section of national public mental health services ($66,000,000 in Mississippi alone), it is important to make the field aware of developments in these projects as they occur.