T cell protein tyrosine phosphatase protects intestinal barrier function by restricting epithelial tight junction remodeling.

Genome-wide association studies revealed that loss-of-function mutations in protein tyrosine phosphatase non-receptor type 2 (PTPN2) increase the risk of developing chronic immune diseases, such as inflammatory bowel disease (IBD) and celiac disease. These conditions are associated with increased intestinal permeability as an early etiological event. The aim of this study was to examine the consequences of deficient activity of the PTPN2 gene product, T cell protein tyrosine phosphatase (TCPTP), on intestinal barrier function and tight junction organization in vivo and in vitro. Here, we demonstrate that TCPTP protected against intestinal barrier dysfunction induced by the inflammatory cytokine IFN-γ by 2 mechanisms: it maintained localization of zonula occludens 1 and occludin at apical tight junctions and restricted both expression and insertion of the cation pore-forming transmembrane protein, claudin-2, at tight junctions through upregulation of the inhibitory cysteine protease, matriptase. We also confirmed that the loss-of-function PTPN2 rs1893217 SNP was associated with increased intestinal claudin-2 expression in patients with IBD. Moreover, elevated claudin-2 levels and paracellular electrolyte flux in TCPTP-deficient intestinal epithelial cells were normalized by recombinant matriptase. Our findings uncover distinct and critical roles for epithelial TCPTP in preserving intestinal barrier integrity, thereby proposing a mechanism by which PTPN2 mutations contribute to IBD.

Methamphetamine, Amphetamine, and MDMA Use and Emergency Department Recidivism.

BACKGROUND: Emergency department (ED) recidivism and the use of amphetamine and associated derivatives such as methamphetamine and MDMA (MAE), are intersecting public health concerns. OBJECTIVE: This study aims to determine the frequency of ED recidivism of patients who use MAE and associated factors. METHODS: The study was a retrospective 6-year electronic medical record review of patients with MAE-positive toxicology screens and single and multiple ED visits in the span of 12 months. RESULTS: There were 7844 ED visits by 5568 MAE-positive patients. Average age was 42 ± 13 years. The majority were male (65%), white (46%), tobacco smokers (55%), and in the psychiatric discharge diagnostic-related group (41%), followed by blunt trauma (20%). Admission rate was 35%, with another 17% transferred to inpatient psychiatric treatment facilities. Occasional (2-5 visits/year), heavy (6-11 visits/year), and super users (≥12 visits/year) altogether accounted for 20% of patients and 43% of visits. Heavy and super users combined represented 2% of patients and 10% of visits, with significant differences for race/ethnicity, health insurance, tobacco smoking, and psychiatric/cardiovascular/trauma discharge diagnostic-related groups. Heavy and super users were less likely to be admitted and more likely to be discharged to an inpatient psychiatric treatment facility. Regression analysis revealed racial/ethnic differences, female gender, and tobacco smoking to be associated with super and heavy use. Heavy users were more likely to have cardiovascular-related discharge diagnoses. CONCLUSIONS: The prevalence of ED recidivism in patients who use MAE is similar to published ranges for general ED users. Significant differences in demographics, discharge diagnoses, insurance, smoking, and disposition exist between nonfrequent and frequent ED users.