Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein Barr virus induced G protein coupled receptor 2 (EBI2) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7α,25-diHC-system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared to controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype related differences were observed in Ebi2-/- animals and animals with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype littermate controls,arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by enhanced level of 7α- hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH

Asymptomatic congenital tuberculosis: A case report.

RATIONALE: Congenital tuberculosis (TB) is described as a rare, but severe disease. In contrast to the cases with severe symptoms reported so far, we describe a child with asymptomatic congenital TB. PATIENT CONCERNS: An 8-week-old girl was investigated because of newly diagnosed TB in her mother, which complained about cough since 21 weeks gestation. Lung biopsy tissue specimens of the mother revealed necrotizing granuloma with a single acid-fast bacillus (AFB) and Mycobacterium tuberculosis (MTB) was detected by polymerase chain reaction. Bronchoalveolar lavage was negative for AFB smear and culture, arguing against postnatal transmission of MTB. TB contact investigations were negative. The child, at the age of 8 weeks at first assessment, was in an excellent general condition and diagnosed with congenital TB by culture-positive lung TB and exclusion of postnatal transmission. DIAGNOSES: The child fulfilled Cantwell criteria to diagnose congenital TB. INTERVENTIONS: Ambulatory anti-tuberculosis treatment was initiated for 6 months. OUTCOMES: The 18 months follow-up was uneventful. LESSONS: This case of asymptomatic congenital TB in a young child illustrates the diagnostic difficulties in congenital TB and raises the question whether congenital TB is underestimated

Low Frequency of FAS Mutations in Reed-Sternberg Cells of Hodgkin’s Lymphoma

Reed-Sternberg (RS) cells, the neoplastic elements of Hodgkin’s lymphoma (HL), usually lack B-cell receptor expression. Normal germinal center B cells, with lack of or low-affinity B-cell receptor expression, are eliminated via FAS-induced apoptosis. RS cells express FAS, but are rescued from apoptosis by a transforming event. It is known that HL-derived cell lines are resistant to FAS-mediated apoptosis. To investigate potential causes for this resistance, FAS mutations and c-FLIP expression were studied in four HL-derived cell lines and 20 cases of HL. L1236 was found to have a splice donor site mutation in intron 7 that resulted in an aberrantly spliced FAS transcript. Screening of microdissected RS cells revealed loss of heterozygosity for a known exon 7 polymorphism in two of six informative cases indicating loss of one FAS allele. In one of the two cases with loss of heterozygosity a hemizygous mutation was detected in exon 9. c-FLIP expression was observed in all HL cell lines and in RS cells of all HL cases. Our data show that FAS mutations are rare and suggest that overexpression of c-FLIP, which was present in all cases, is involved in the resistance to FAS-mediated apoptosis

Group A Streptococcus strains causing meningitis without distinct invasive phenotype

Abstract Group A streptococcal (GAS; aka Streptococcus pyogenes) meningitis is a fulminant disease associated with high morbidity and mortality. To elucidate the mechanisms underlying the invasiveness of GAS in meningitis, we compared GAS isolates derived from five cases of meningitis to otitis and colonizing isolates. We did not observe differences in adherence to and invasion of human brain microvascular endothelial cells, virulence factors activity, or barrier disruption. Whole genome sequencing did not reveal particular invasiveness traits. Most patients previously suffered from otitis media suggesting that meningitis likely resulted from a continuous spread of the infection rather than being attributable to changes in the pathogen's virulence

Western outcomes of circumferential endoscopic submucosal dissection for early esophageal squamous cell carcinoma

Background and aims: Circumferential endoscopic submucosal dissection (cESD) in the esophagus has been reported to be feasible in small Eastern case series. We assessed the outcomes of cESD in the treatment of early esophageal squamous cell carcinoma (ESCC) in Western countries. Methods: We conducted an international study at 25 referral centers in Europe and Australia using prospective databases. We included all patients with ESCC treated with cESD before November 2022. Our main outcomes were curative resection according to European guidelines and adverse events. Results: A total of 171 cESDs were performed on 165 patients. En bloc and R0 resections rates were 98.2% (95% CI 95.0%-99.4%) and 69.6% (95% CI 62.3%-76.0%), respectively. Curative resection was achieved in 49.1% (95% CI 41.7%-56.6%) of the lesions. The most common reason for non-curative resection was deep submucosal invasion (21.6%). The risk of stricture requiring six or more dilations or additional techniques (incisional therapy/stent) was high (71%), despite the use of prophylactic measures in 93% of the procedures. The rates of intraprocedural perforation, delayed bleeding and adverse cardiorespiratory events were 4.1%, 0.6% and 4.7%, respectively. Two patients died (1.2%) from a cESD-related adverse event. Overall and disease-free survival rates at 2 years were 91% and 79%. Conclusions: In Western referral centers, cESD for ESCC is curative in approximately half of the lesions. It can be considered a feasible treatment in selected patients. Our results suggest the need to improve patient selection and to develop more effective therapies to prevent esophageal strictures