Sex differences in offspring risk and resilience following 11ß-hydroxylase antagonism in a rodent model of maternal immune activation.

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11ß-hydroxylase (11ßHSD) inhibitor used to treat hypercortisolism in pregnant, lactating, and neonatal populations. Maternal, placental, and fetal brain levels of corticosterone and placental 11ßHSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal brain corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11ßHSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in adult male ventral hippocampus, but not in females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

Maternal immune activation alters placental histone-3 lysine-9 tri-methylation, offspring sensorimotor processing, and hypothalamic transposable element expression in a sex-specific manner.

Animal models of maternal immune activation (MIA) are central to identifying the biological mechanisms that underly the association between prenatal infection and neuropsychiatric disorder susceptibility. Many studies, however, have limited their scope to protein coding genes and their role in mediating this inherent risk, while much less attention has been directed towards exploring the roles of the epigenome and transposable elements (TEs). In Experiment 1, we demonstrate the ability of MIA to alter the chromatin landscape of the placenta. We induced MIA by injecting 200 µg/kg (i.p.) of lipopolysaccharide (LPS) on gestational day 15 in Sprague-Dawley rats. We found a sex-specific rearrangement of heterochromatin 24-h after exposure to MIA, as evidenced by an increase in histone-3 lysine-9 trimethylation (H3K9me3). In Experiment 2, MIA was associated with long-term sensorimotor processing deficits as indicated by reduced prepulse inhibition (PPI) of the acoustic startle reflex in adult male and female offspring and an increased mechanical allodynia threshold in males. Analyses of gene expression within the hypothalamus-chosen for its involvement in the sex-specific pathogenesis of schizophrenia and the stress response-revealed significantly higher levels of the stress-sensitive genes Gr and Fkbp5. Deleterious TE expression is often a hallmark of neuropsychiatric disease and we found sex-specific increases in the expression of several TEs including IAP, B2 SINE, and LINE-1 ORF1. The data from this study warrant the future consideration of chromatin stability and TEs as part of the mechanism that drives MIA-associated changes in the brain and behavior.

Population health management in integrated physical and mental health care.

PURPOSE: Individuals suffering from serious mental illness (SMI) face many challenges of navigating a complex and often fragmented health care system and may die significantly earlier from co-morbid physical health conditions. Integrating mental and physical health care for individuals with SMI is an emerging trend addressing the often-neglected physical health care needs of this population to better coordinate care and improve health outcomes. DESIGN/METHODOLOGY/APPROACH: Population Health Management (PHM) provides a useful friamework for designing integrated care programs for individuals with SMI. FINDINGS: This paper examines the structure and evolution of the integrated care program in Missouri in the context of PHM, highlighting particular elements of PHM that facilitate and support development of an integrated mental and physical health care program. ORIGINALITY/VALUE: As health care reform provides external motivation to provide integrated care, this study can be useful as other states attempt to address this important issue.

Statistical software applications used in health services research: analysis of published studies in the U.S.

BACKGROUND: This study aims to identify the statistical software applications most commonly employed for data analysis in health services research (HSR) studies in the U.S. The study also examines the extent to which information describing the specific analytical software utilized is provided in published articles reporting on HSR studies. METHODS: Data were extracted from a sample of 1,139 articles (including 877 original research articles) published between 2007 and 2009 in three U.S. HSR journals, that were considered to be representative of the field based upon a set of selection criteria. Descriptive analyses were conducted to categorize patterns in statistical software usage in those articles. The data were stratified by calendar year to detect trends in software use over time. RESULTS: Only 61.0% of original research articles in prominent U.S. HSR journals identified the particular type of statistical software application used for data analysis. Stata and SAS were overwhelmingly the most commonly used software applications employed (in 46.0% and 42.6% of articles respectively). However, SAS use grew considerably during the study period compared to other applications. Stratification of the data revealed that the type of statistical software used varied considerably by whether authors were from the U.S. or from other countries. CONCLUSIONS: The findings highlight a need for HSR investigators to identify more consistently the specific analytical software used in their studies. Knowing that information can be important, because different software packages might produce varying results, owing to differences in the software's underlying estimation methods.