Clinicopathologic Features of Primary Immunodeficiency Monogenic Disease-related Very Early Onset Inflammatory Bowel Disease: Focus on Gastrointestinal Histologic Features in IFIH1 Mutations.

Very early onset inflammatory bowel disease (VEO-IBD) is a clinical term referring to IBD-like symptomatology arising in children younger than 6 years. VEO-IBD may be due to polygenic etiology in "pure" IBD (Crohn disease-CD and ulcerative colitis-UC), or it may be caused by primary immunodeficiency underlined by monogenic disease. Primary immunodeficiency monogenic diseases have a Mendelian inheritance and affect the immune system with multiorgan morbidity and possible effects on the gastrointestinal system. Primary Immunodeficiency monogenic diseases differ from "pure" IBD as the latter primarily affect the gastrointestinal tract with mitigated extraintestinal symptomatology. Since their first description, primary immunodeficiency monogenic diseases, although rare, have been the subject of increasing interest due to their dramatic phenotype, difficulty in reaching a timely diagnosis, and specific therapeutic approach. In this paper, we present a brief review of primary immunodeficiency monogenic diseases, focusing on to their clinicopathologic features as well as delving, in greater detail, into monogenic diseases caused by IFIH1 mutations. The clinicopathologic features of 4 patients with IFIH1, a gene involved in interferon pathway deficiency, will be described using a histologic pattern of damage approach confirming the need to avoid the histologic diagnosis of VEO-IBD in children younger than 6 years.

Thrombotic Features as the Primary Cause of SARS-CoV-2 Related Acute Abdomen in Children.

OBJECTIVES: We performed a retrospective case control study to evaluate the histological characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive pediatric patients undergoing laparoscopic exploration for acute abdomen symptoms. To our knowledge this is the first study that analyzes histopathological characteristics of abdominal tissues in SARS-CoV-2 children. STUDY DESIGN: We enrolled 8 multisystem inflammatory syndrome in children (MIS-C) patients and 4 SARS-CoV-2 positive patients who underwent intestinal resection versus 36 control appendectomies from 2 pediatric tertiary referral centers between March 2020 and July 2021. Surgical resection samples were evaluated on several histological sections focusing on general inflammatory pattern and degree of inflammation. Peculiar histological features (endotheliitis and vascular thrombosis) were semi-quantitatively scored respectively in capillary, veins, and arteries. RESULTS: All SARS-CoV-2 related surgical samples showed thrombotic patterns. Those patterns were significantly less frequent in SARS-CoV-2 negative appendectomies ( P = 0.004). The semi-quantitative score of thrombosis was significantly higher ( P = 0.002) in patients with SARS-CoV-2 related procedures. CONCLUSIONS: Our results showed that SARS-CoV-2 can cause thrombotic damage in abdominal tissues both in the acute phase of the infection (SARS-CoV-2 related appendectomies) and secondary to cytokine storm (MIS-C).

The chromatin remodelling component SMARCB1/INI1 influences the metastatic behavior of colorectal cancer through a gene signature mapping to chromosome 22.

BACKGROUND: INI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known. METHODS: We examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines. RESULTS: Herein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients' survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1. CONCLUSION: Our findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.

Rhabdomyolysis and coeliac disease: A causal or casual association? A case report and review of literature.

BACKGROUND: Rhabdomyolysis is a rare, potentially life-threatening condition, caused by multiple disorders. The association with Coeliac Disease (CD) has been rarely reported and in these cases muscular damage was imputed to hypokalemia. Herein we describe a new case of severe rhabdomyolysis in a child subsequently diagnosed as affected by CD, and review previous reports. CASE PRESENTATION: A 3-year-old boy was referred for diarrhea, brown urine, muscular pain/weakness, and no history of muscular trauma. At entry, laboratory tests showed elevated levels of creatine kinase (CK) (x100 unv) and aspartate aminotransferase (AST) (x10 unv), alanine aminotrasferase (ALT) (x5 unv); electrolytes were within the reference range. Twenty-four hours after admission serum CK peaked 115,000 U/L and transaminases increased up to 30 times unv. Hyperhydration treatment was started with renal function monitoring. Urine output decreased little, while serum creatinine and urea nitrogen stayed within the reference range. Serum potassium levels went down to 2.8 mEq/L at day 3, in spite of supplementation. The patient completely recovered at day 16. Main metabolic causes of rhabdomyolysis were ruled out by appropriate tests. Because of rarely reported cases of CD/rhabdomyolysis, anti-tissue transglutaminase (tTG) antibodies were measured and found positive (IgA 34 U/mL, unv <9). HLA typing was DQA1 05:02, DQB1 03:02. As jejunal biopsy showed patchy villous atrophy, gluten free diet (GFD) was prescribed. One year after starting GFD, histology was normal. REVIEW OF LITERATURE: Literature (search engines: PUB MED and GOOGLE SCHOLAR) from 1980 to 2016 retrieved 8 cases (age range: 12 to 75 years old) previously described. CONCLUSION: The present case suggests to check for CD in children with severe rhabdomyolysis. Because severe rhabdomyolysis itself may elevate the serum potassium levels, hypokalemia might go unrecognized as the cause of muscular damage.

Large eddy simulations for blood dynamics in realistic stenotic carotids.

In this paper, we consider large eddy simulations (LES) for human stenotic carotids in presence of atheromasic plaque, a pathological condition where transitional effects to turbulence may occur, with relevant clinical implications such as plaque rupture. We provide a reference numerical solution obtained at high resolution without any subgrid scale model, to be used to assess the accuracy of LES simulations. In the context we are considering, ie, hemodynamics, we cannot refer to a statistically homogeneous, isotropic, and stationary turbulent regime; hence, the classical Kolmogorov theory cannot be used. For this reason, a mesh size and a time step are deemed fine enough if they allow to capture all the features of the velocity field in the shear layers developed after the bifurcation. To assess these requirements, we consider a simplified model of the evolution of a 2D shear layer, a relevant process in the formation of transitional effects in our case. Then, we compare the results of LES σ model (both static and dynamic) and mixed LES models (where also a similarity contribution is considered). In particular, we consider a realistic scenario of a human carotid, and we use the reference solution as gold standard. The results highlight the accuracy of the LES σ models, especially for the static model.