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Primary Epstein-Barr virus (EBV) infection may present with self-limiting abdominal involvement, characterized by hepatitis with mild elevation of aminotransferases, splenomegaly, and rarely with acute acalculous cholecystitis (AAC). Usually, treatment of EBV related AAC is symptomatic, without the need for surgery. Here, we describe a severe case of AAC occurring as the first manifestation of infectious mononucleosis in a young adult woman, receiving treatment with interleukin 6 receptor (IL-6r) inhibitor for rheumatoid arthritis (RA); moreover, we have performed a review of the literature on EBV-related AAC., Competing Interests: Conflicts of interest statement The authors declare no conflict of interest., (©2021 Pacini Editore SRL, Pisa, Italy.)

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.

Background: Interleukin (IL)-27 is a member of the IL-6/IL-12 family of cytokines. It is a potent cytokine, with potential antiviral impact, and has been shown to play a role in modulating functions of diverse cell types, including Th1, Th2, and NK and B cells, demonstrating both pro- and anti-inflammatory roles.  In hepatocytes, it is capable of inducing signal transducer and activator of transcription (STAT)1, STAT3 and interferon-stimulated genes. Methods: To address its role in viral hepatitis, the antiviral activity of IL-27 against hepatitis C virus (HCV) and hepatitis B virus (HBV) was tested in vitro using cell-culture-derived infectious HCV (HCVcc) cell culture system and the HepaRG HBV cell culture model. To further investigate the impact of IL-27 on hepatocytes, Huh7.5 cells were treated with IL-27 to analyse the differentially expressed genes by microarray analysis. Furthermore, by quantitative PCR, we analyzed the up-regulation of chemokine (CXCL)-10 in response to IL-27. Results: In both HCV and HBV infection models, we observed only a modest direct antiviral effect. Microarray analysis showed that the up-regulated genes mostly belonged to antigen presentation and DNA replication pathways, and involved strong up-regulation of CXCL-10 , a gene associated with liver inflammation. Overall, gene set enrichment analysis showed a striking correlation of these genes with those up-regulated in response to related cytokines in diverse cell populations. Conclusion: Our data indicate that IL-27 can have a significant pro-inflammatory impact in vitro , although the direct antiviral effect is modest. It may have a potential impact on hepatocyte function, especially chemokine expression and antigen presentation., Competing Interests: No competing interest were disclosed.

Pancreatic rat islets are encapsulated by a siliceous layer deposited on the surface of single islets upon reaction with gaseous siliceous precursors. The process preserves original islet dimensions and does not suppress viability or function. The encapsulated material is homogeneously distributed on the islet surface, and layer thickness can be controlled in the 0.1–2.0 μm interval. Dynamic perfusion experiments with glucose stimulation were carried out in both encapsulated and non-encapsulated islets. Results were treated according to a kinetic model presented here for the analysis of perfusion data; the model tested by literature data, was used to substantiate the diffusion features of the siliceous layer, which does not affect mass transfer of insulin but which modifies the texture of the islet surface tissue. The clinical potential of silica encapsulation was demonstrated by in vivo experiments using encapsulated islets transplanted into diabetic rats. Transplantation was carried out in both inbred and outbred rats and indicated prolonged restoration of normal glycaemia levels and protection from immunological attack. [Copyright &y& Elsevier]

Objective: Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population., Methods: 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment., Results: Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events., Conclusions: In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment., Trial Registration Number: http://ClinicalTrials.gov registration number: NCT01095835.

Objectives: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome., Methods: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome., Results: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043)., Conclusions: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.

In recent years, a worsening outcome of hepatitis C virus (HCV)-positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre- and post-liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV-positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post-LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow-up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan-Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV-related recurrent severe fibrosis (Ishak score 4-6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence.