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Integrative data analysis (IDA) was used to derive developmental models of depression, externalizing problems, and self-regulatory processes in three prevention trials of the Family Check-Up and one longitudinal, community-based study of girls over a 10-year span covering early to late adolescence (N = 4,773; 74.9% female, 41.7% white). We used moderated nonlinear factor analysis to create harmonized scores based on all available items for a given participant in the pooled dataset while accounting for potential differences in both the latent factor and the individual items as a function of observed covariates. We also conducted latent growth model analyses to examine developmental trajectories of risk. Results indicated a bidirectional relationship between depression and externalizing problems, with greater baseline externalizing problems and depression predicting growth in inhibitory control difficulties. Furthermore, initial level of inhibitory control difficulties was associated with growth in depression. We did not, however, find a relationship between early inhibitory control difficulties and growth in externalizing problems. This work illustrates the utility of IDA techniques to harmonize data across multiple studies to identify risk factors for the development of depression and externalizing problems that can be targeted by prevention efforts.

Prenatal complications are associated with poor outcomes in the offspring. Access to medical records is limited in the United States and investigators often rely on maternal report of prenatal complications.We tested concordance between maternal recall and birth records in a community-based sample of mothers participating in a longitudinal study in order to determine the accuracy of maternal recall of perinatal complications.Participants were 151 biological mothers, who were interviewed about gestational age at birth, birthweight, and the most commonly occurring birth complications: nuchal cord and meconium aspiration when the female child was on average 6years old, and for whom birth records were obtained.Concordance between reports was assessed using one-way random intra-class coefficients for continuous measures and kappa coefficients for dichotomous outcomes. Associations between maternal demographic and psychological factors and discrepancies also were tested.Concordance was excellent for continuously measured birthweight (ICC=0.85, p0.001) and good for gestational age (ICC=0.68, p0.001). Agreement was good for low birthweight (2500g) (kappa=0.67, p0.001), fair for preterm delivery (37weeks gestation) (kappa=0.44, p0.001), and poor for nuchal cord or meconium aspiration. Most discrepancies were characterized by presence according to birth record and absence according to maternal recall. Receipt of public assistance was associated with a decrease in discrepancy in report of nuchal cord.Concordance between maternal retrospective report and medical birth records varies across different types of perinatal events. There was little evidence that demographic or psychological factors increased the risk of discrepancies. Maternal recall based on continuous measures of perinatal factors may yield more valid data than dichotomous outcomes.

Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP.

Importance African American women living in urban, low-income environments are at high risk for poor nutrition during pregnancy and birth complications. Objective To test the effectiveness of prenatal docosahexaenoic acid (DHA) supplementation on birth outcomes and infant development in a sample of African American women with Medicaid insurance and living in the city of Pittsburgh. Design The Nutrition and Pregnancy Study (NAPS) is a double-blind, randomized controlled trial of prenatal DHA supplementation conducted between 2012 and 2014. Setting Participants were recruited from obstetric clinics at the University of Pittsburgh Medical Center. Participants Sixty-four pregnant, African American women were enrolled at 16–21 weeks of gestation and randomized to either 450 mg/day of DHA (22:6n-3)(n = 43) or a soybean placebo (n = 21). Four women (6.3%) withdrew from the study: two participants from each study arm; complete data were obtained for 49 infants (76.5%) at the 3-month assessment. Interventions Supplementation with DHA or placebo continued from the beginning of enrollment through delivery. Main outcome and measures Data on birth outcomes were collected from medical records. At approximately 3 months post-partum, mothers brought their infants to the laboratory where the Bayley Scales of Infant Development (BSID-III) were administered and cortisol response to the Face-to-Face Still-Face (FFSF) paradigm was assessed. Results Infants of mothers who received DHA supplementation had higher birth weight (3.174 g versus 2.890 g) than infants of mothers receiving placebo ( F [2.40] = 6.09, p = 0.018, eta = 0.36), and were more likely to have a 1-min Apgar score greater than 8 ( OR = 5.99 [95% CI = 1.25–28.75], p = 0.025). Infants of mothers who received DHA compared with infants of mothers receiving placebo had lower levels of cortisol in response to the FFSF paradigm ( F [1.32] = 5.36, p = 0.018, eta = 0.36). None of the scores on the BSID-III differed as a function of active supplement versus placebo. Conclusions Infants of women living in urban, low-income environments who received DHA supplementation had more optimal birth outcomes and more modulated cortisol response to a stressor. DHA supplementation may be effective in attenuating the negative effects of prenatal stress on offspring development.

Objective To evaluate peripheral blood T-helper (T H ) cell-associated cytokine and chemokine profiles in localized scleroderma (LS), and correlate them with clinical disease features, including disease activity parameters. Methods A 29-plex Luminex platform was used to analyze the humoral profile of plasma samples from 69 pediatric LS patients and 71 healthy pediatric controls. Cytokine/chemokine levels were compared between these two groups and within LS patients, focusing on validated clinical outcome measures of disease activity and damage in LS. Results Plasma levels of IP-10, MCP-1, IL-17a, IL-12p70, GM-CSF, PDGF-bb, IFN-α2, and IFN-γ were significantly higher in LS subjects compared to healthy controls. Analysis within the LS group demonstrated IP-10, TNF-α, and GM-CSF correlated with clinical measures of disease activity. Several cytokines/chemokines correlated with anti-histone antibody, while only a few correlated with positive ANA and single-stranded DNA antibody. Conclusion This is the first time that multiple cytokines and chemokines have been examined simultaneously in LS. In general, a T H 1 (IFN-γ) and T H 17 (IL-17a) predominance was demonstrated in LS compared to healthy controls. There is also an IFN-γ signature with elevated IP-10, MCP-1, and IFN-γ, which has been previously demonstrated in systemic sclerosis, suggesting a shared pathophysiology. Within the LS patients, those with active disease demonstrated IP-10, TNF-α, and GM-CSF, which may potentially serve as biomarkers of disease activity in the clinical setting.

Colipase is essential for efficient fat digestion. An arginine-to-cysteine polymorphism at position 92 of colipase (Arg92Cys) associates with an increased risk for developing type-2 diabetes through an undefined mechanism. To test our hypothesis that the extra cysteine increases colipase misfolding, thereby altering its intracellular trafficking and function, we expressed Cys92 colipase in HEK293T cells. Less Cys92 colipase is secreted and more is retained intracellularly in an insoluble form compared with Arg92 colipase. Nonreducing gel electrophoresis suggests the folding of secreted Cys92 colipase differs from Arg92 colipase. Cys92 colipase misfolding does not trigger the unfolded protein response (UPR) or endoplasmic reticulum (ER) stress. The ability of secreted Cys92 colipase to stimulate pancreatic triglyceride lipase (PTL) is reduced with all substrates tested, particularly long-chain triglycerides. The reaction of Cys92 colipase with triolein and Intralipid has a much longer lag time, reflecting decreased ability to anchor PTL on those substrates. Our data predicts that humans with the Arg92Cys substitution will secrete less functional colipase into the duodenum and have less efficient fat digestion. Whether inefficient fat digestion or another property of colipase contributes to the risk for developing diabetes remains to be clarified.

Introduction The purpose of this study was to evaluate the presence and levels of interferon-gamma inducible protein-10 (IP-10) in the plasma and skin of pediatric localized scleroderma (LS) patients compared to those of healthy pediatric controls and to determine if IP-10 levels correlate to clinical disease activity measures. Methods The presence of IP-10 in the plasma was analyzed using a Luminex panel in 69 pediatric patients with LS and compared to 71 healthy pediatric controls. Of these patients, five had available skin biopsy specimens with concurrent clinical and serological data during the active disease phase, which were used to analyze the presence and location of IP-10 in the skin by immunohistochemistry (IHC). Results IP-10 levels were significantly elevated in the plasma of LS patients compared to that of healthy controls and correlated to clinical disease activity measures in LS. Immunohistochemistry staining of IP-10 was present in the dermal infiltrate of LS patients and was similar to that found in psoriasis skin specimens, the positive disease control. Conclusions Elevation of IP-10 levels in the plasma compared to those of healthy controls and the presence of IP-10 staining in the affected skin of LS patients indicates that IP-10 is a potential biomarker in LS. Furthermore, significant elevation of IP-10 in LS patients with active versus inactive disease and correlations between IP-10 levels and standardized disease outcome measures of activity in LS strongly suggest that IP-10 may be a biomarker for disease activity in LS.