Necrotizing enterocolitis (NEC) is the most common intestinal disease of premature infants. Although increased mucosal permeability and altered epithelial structure have been associated with many intestinal disorders, the role of intestinal barrier function in NEC pathogenesis is currently unknown. We investigated the structural and functional changes of the intestinal barrier in a rat model of NEC. In addition, the effect of EGF treatment on intestinal barrier function was evaluated. Premature rats were divided into three groups: dam fed (DF), formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC + EGF); all groups were exposed to asphyxia/cold stress to develop NEC. Intestinal permeability, goblet cell density, mucin production, and composition of tight junction (TJ) proteins were evaluated in the terminal ileum, the site of NEC injury, and compared with the proximal jejunum, which was unaffected by NEC. Animals with NEC had significantly increased intestinal paracellular permeability compared with DF pups. Ileal goblet cell morphology, mucin production, and TJ composition were altered in animals with NEC. EGF treatment significantly decreased intestinal paracellular permeability, increased goblet cell density and mucin production, and normalized expression of two major TJ proteins, occludin and claudin-3, in the ileum. In conclusion, experimental NEC is associated with disruption of the intestinal barrier. EGF treatment maintains intestinal integrity at the site of injury by accelerating goblet cell maturation and mucin production and normalizing expression of TJ proteins, leading to improved intestinal barrier function.
Background & Aims-Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. While the effect of bile acids (BAs) on intestinal mucosal injury is known, we investigated the contribution of BAs during the development of NEC in neonatal rats.
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical followup in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.Brain Pathology 30 (2020) 46-62
Background and Purpose We investigated whether brain arteriovenous malformation (bAVM) silent intralesional microhemorrhage (SIM), i.e., asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated two markers to assess the occurrence of SIM: neuroradiological assessment of evidence of old hemorrhage (EOOH)— imaging evidence of bleeding before the outcome events, and hemosiderin positivity in H&E-stained paraffin block sections. Methods We included cases from a bAVM database with recorded neuroradiological data or available surgical paraffin blocks. Using two endpoints, index ICH and new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess EOOH and hemosiderin positivity, adjusting for age, sex, deep-only venous drainage, maximal bAVM size, deep location, and associated arterial aneurysms. Results EOOH was present in 6.5% (n=975) of patients and highly predictive of index ICH (p<0.001; OR=3.97; 95% CI, 2.1-7.5), adjusting for other risk factors. In a multivariable model (n=643), EOOH was an independent predictor of new ICH (HR=3.53; 95% CI=1.35-9.23; p=.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; p=.04), and associated with index ICH in univariate (OR=2.18; 95%CI 1.03-4.61; p=.042; n=127) and multivariable models (OR=3.64; 95% CI=1.11-12.00; p=.034; n=79). Conclusions The prevalence of SIM is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect SIM during bAVM evaluation may present an opportunity to improve risk-stratification, especially for unruptured bAVMs.
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