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Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglia and dopaminergic circuits in the brain, along with changes in the structure of the gut epithelium and microbiome. Importantly, DEP/MS-induced social deficits in males are prevented by shifting the gut microbiome by cross-fostering at birth and reversed by chemogenetic activation of the dopamine system.

Background & Aims Limited evidence suggests that proton pump inhibitors (PPI), nonsteroidal anti-inflammatory drugs (NSAID)/aspirin, and statins may be associated with a low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett's esophagus (BE) is unclear. Methods We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans' Affairs computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAIDs/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socioeconomic status. Results In a cohort of 11,823 patients with first-time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs 94%; P = .5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio, 0.64; 95% confidence interval, 0.42–0.97). Filled statin prescriptions also were associated with a reduction in EAC risk (0.55; 95% confidence interval, 0.36–0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding. Conclusions This observational study indicates that in patients with BE using PPI, NSAID/aspirin, or statin therapy might reduce the risk of developing EAC.

Barrett's esophagus (BE) in children has been examined in retrospective studies, consisting of case series and cross-sectional studies.To evaluate the prevalence and determinants of BE in children who are free from neurodevelopmental disorders and tracheoesophageal abnormalities.A prospective, cross-sectional study.Three pediatric GI Centers in Houston, Texas; Phoenix, Arizona; and Portland, Maine between February 2006 and December 2007.This study involved children and adolescents consecutively presenting for elective upper endoscopy. Patients with neurodevelopmental and tracheoesophageal disorders were excluded.Endoscopic pictures of all cases with suspected BE were independently reviewed and verified by two experienced investigators. Esophageal biopsy specimens were obtained in all patients, and targeted biopsy specimens also were obtained from suspected BE.Endoscopically suspected BE and histologically confirmed BE.A total of 840 patients (mean age 9.5 years) were enrolled and had complete questionnaire and endoscopic data. Twelve patients were suspected of having BE (prevalence of 1.43%; 95% confidence interval [CI], 0.73-2.45), and only 1 patient had intestinal metaplasia, for a prevalence of 0.12% (95% CI, 0-0.65), whereas the rest had gastric oxyntic glands (n=6) or squamous esophageal epithelium (n=5). Patients with suspected BE had a higher mean body mass index (23.0 vs 19.1, P=.05) and more chest pain (50% vs 13%, P.01) than patients without BE or reflux esophagitis. There was a trend toward a higher frequency of dysphagia, heartburn, and regurgitation in patients with suspected BE.The accuracy of BE prevalence estimates is limited by the small number of cases.BE is rare in children without neurodevelopmental delay or tracheoesophageal anomalies presenting for elective upper endoscopy.

Recent case reports suggested a link between oral bisphosphonate use and esophageal cancer. We therefore examined the association between these medications and the risk of esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE).This was a nested, matched case-control study. Cases with incident EAC at least 6 months following BE index date were matched by incidence density sampling to controls with BE without EAC. Patients with BE were found in the national Department of Veterans Affairs computerized databases, and each filled prescriptions for oral bisphosphonates between BE diagnosis and EAC diagnosis (or corresponding dates in controls). Incidence density ratios were calculated using conditional logistic regression models.In a cohort of 11,823 patients with BE, we compared 116 cases and 696 controls. Most were men (97%). Most cases and controls had at least one filled proton pump inhibitor (PPI) prescription (95 vs. 94%, P = 0.5). Filled bisphosphonate prescriptions were very uncommon (1.7 vs. 1.9%) and were not associated with EAC; the incidence density ratio was 0.92 (95% CI, 0.21-4.15).In patients with BE, oral bisphosphonates were not associated with an increased risk of EAC.

Purpose: Inflammatory breast cancer (IBC) is associated with very poor prognosis. The aims of this study are (a) to prospectively identify differential gene expression patterns associated with IBC and (b) to confirm these pathways using tissue arrays. Experimental Design: For gene expression analysis, IBC (n = 14) was clinically defined as rapid-onset cancer associated with erythema and skin changes, whereas non-IBC patients (n = 20) had stage III breast cancers, and cDNA analysis was carried out using the Affymetrix (Santa Clara, CA) HG-U133A microarrays. Tissue arrays were constructed from paraffin-embedded material, and the molecular phenotype of 75 IBC was compared with results from >2,000 non-IBC. Results: Gene expression analyses indicated that IBC has higher expression of genes associated with increased metabolic rate, lipid signaling, and cell turnover relative to non-IBC tumors. Consistent with the expression analysis, IBC had statistically higher Ki-67 (93% versus 11%; P < 0.001). BAX expression, reflecting increased apoptosis and cell turnover, was significantly uniformly higher in almost all IBC (98% versus 66%; P < 0.05), whereas the expression of Bcl-2 was not significantly different. IBC tumors were more likely to be steroid hormone receptor negative (estrogen receptor, 49% versus 30%; P = 0.002; progesterone receptor, 68% versus 42%; P = 0.001). The expression of tyrosine kinases was not significantly different. E-cadherin was found to be expressed in 87% of IBC, whereas the expression p53 was not significantly different. Conclusion: This study is one of the largest molecular analyses of IBC. Both IBC and non-IBC are genetically heterogeneous with consistent differences in the molecular phenotype of IBC.