A new combined predicting model using a non-invasive score for the assessment of liver fibrosis in patients presenting with chronic hepatitis B virus infection

ObjectivesSeveral non-invasive markers have recently been proposed to predict liver fibrosis without percutaneous liver biopsy (PLB). We aimed to evaluate the performance of non-invasive scores and to highlight the value of a new combined score in the prediction of liver fibrosis in chronic hepatitis B (CHB) patients.Patients and methodsWe performed a retrospective study of patients presenting with CHB who underwent PLB between 2008 and 2016. We calculated ASAT/Platelet Ratio Index (APRI), Fibrosis-4 Score (FIB4), GGT-to-platelet ratio (GPR), and ASAT/ALAT Ratio (AAR). Then, we combined APRI and FIB-4 scores into a new combined score. We assessed their performance in predicting liver fibrosis according to the Metavir score.ResultsA total of 179 patients presenting with CHB were included. Multivariate analysis showed that the APRI score was the only independent factor of significant fibrosis (OR = 3.78; P = 0.02), whereas the FIB-4 score was the only independent factor for severe fibrosis (OR = 2.85; P < 0.001) and cirrhosis (OR = 2.5; P = 0.001). At a threshold of severe fibrosis, APRI had the best specificity (75%) and FIB-4 had the greatest sensitivity (74%). Using the combined score, we improved the diagnostic performance of APRI and FIB-4 scores at the three thresholds of liver fibrosis. With this combined score, maximum 25.1% of patients presenting with CHB would undergo PLB.ConclusionAPRI, FIB-4, and GPR scores were well performing to predict liver fibrosis during CHB. The new combined score using APRI and FIB-4 was more accurate at the three-fibrosis thresholds.     

A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation

We have identified a novel splice site mutation (IVS6-1G?>?A) in the disc-large homolog 3 (DLG3) gene, encoding the synapse-associated protein 102 (SAP102) in one out of 300 families with moderate to severe non-syndromic mental retardation. SAP102 is a member of the neuronal membrane-associated guanylate kinase protein subfamily comprising SAP97, postsynaptic density (PSD)95, and PSD93, which interacts with methyl-d-aspartate receptor and associated protein complexes at the postsynaptic density of excitatory synapses. DLG3 is the first mental retardation gene directly linked to glutamate receptor signalling and trafficking, increasingly recognised as a central mechanism in the regulation of synaptic formation and plasticity in brain and cognitive development.     

Increased reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorders patients with JAK2 (V617F) mutation

Myeloproliferative disorders are associated with increased risk of thrombosis and vascular complications. The pathogenesis of these complications is not completely known. Reactive oxygen species produced by the neutrophil NADPH oxidase could have a role in this process. The aim of this study was to evaluate reactive oxygen species production by neutrophils of myeloproliferative disorder patients. Patients with or without the JAK2 V617F mutation were characterized. Reactive oxygen species production was assessed by chemiluminescence, and phosphorylation of the NADPH oxidase subunit p47phox was analyzed by Western blots. In a comparison of controls and myeloproliferative disorder patients without the JAK2 V617F mutation, reactive oxygen species production by neutrophils from patients with the JAK2 V617F mutation was dramatically increased in non-stimulated and in stimulated conditions. This increase was associated with increased phosphorylation of the p47phox on Ser345 and of the uspstream kinase ERK1/2. In neutrophils from healthy donors, JAK2 can be activated by GM-CSF. GM-CSF-induced p47phox phosphorylation and priming of reactive oxygen species production are inhibited by the selective JAK2 inhibitors AG490 and lestaurtinib (CEP-701), supporting a role for JAK2 in the upregulation of NADPH oxidase activation. These findings show an increase in reactive oxygen species production and p47phox phosphorylation in neutrophils from myeloproliferative disorder patients with the JAK2 V617F mutation, and demonstrate that JAK2 is involved in GM-CSF-induced NADPH oxidase hyperactivation. As neutrophil hyperactivation could be implicated in the thrombophilic status of patients with myeloproliferative disorders, aberrant activation of JAK2 V617F, leading to excessive neutrophil reactive oxygen species production might play a role in this setting.     

Claudin-based permeability barriers in taste buds

Tight junctions operate as semipermeable barriers in epithelial tissue, separating the apical from the basolateral sides of the cells. Membrane proteins of the claudin family represent the major tight junction constituents, and some reinforce permeability barriers, whereas others create pores based on solute size and ion selectivity. To outline paracellular permeability pathways in gustatory tissue, all claudins expressed in mouse taste buds and in human fungiform papillae have been characterized. Twelve claudins are expressed in murine taste-papillae-enriched tissue, and five of those are expressed in human fungiform papillae. A subset of the claudins expressed in mouse papillae is uniquely found in taste buds. By immunohistochemistry, claudin 4 has been found in mouse taste epithelium, with high abundance around the taste pore. Claudin 6 is explicitly detected inside the pore, claudin 7 was found at the basolateral side of taste cells, and claudin 8 was found around the pore. With the ion permeability features of the different claudins, a highly specific permeability pattern for paracellular diffusion is apparent, which indicates a peripheral mechanism for taste coding.     

Peptide-based inhibitors of the phagocyte NADPH oxidase

Phagocytes such as neutrophils, monocytes and macrophages play an essential role in host defenses against pathogens. To kill these pathogens, phagocytes produce and release large quantities of antimicrobial molecules such as reactive oxygen species (ROS), microbicidal peptides, and proteases. The enzyme responsible for ROS generation is called NADPH oxidase, or respiratory burst oxidase, and is composed of six proteins: gp91phox, p22phox, p47phox, p67phox, p40phox and Rac1/2. The vital importance of this enzyme in host defenses is illustrated by a genetic disorder called chronic granulomatous disease (CGD), in which the phagocyte NADPH oxidase is dysfunctional, leading to life-threatening recurrent bacterial and fungal infections. However, excessive NADPH oxidase activation and ROS over-production can damage surrounding tissues and participate in exaggerated inflammatory processes. As ROS production is believed to be involved in several inflammatory diseases, specific phagocyte NADPH oxidase inhibitors might have therapeutic value. In this commentary, we summarize the structure and activation of the phagocyte NADPH oxidase, and describe pharmacological inhibitors of this enzyme, with particular emphasis on peptide-based inhibitors derived from gp91phox, p22phox and p47phox.     

Epstein-Barr virus-targeted immunotherapy for nasopharyngeal carcinoma

Epstein-Barr virus (EBV) is constantly present in undifferentiated and poorly-differentiated nasopharyngeal cancer. Thus, tumour-associated viral antigens are potential targets for immunotherapy. Recently, both preclinical and early clinical studies have shown that various strategies can enhance EBV-specific immunity. Moreover, significant anti-tumour effect has been observed, and was generally correlated with biological response. The present review discusses the rational for EBV-targeted immunotherapy and summarises the latest developments in this area.     

Retrobulbar optic neuritis associated with infliximab in a patient with Crohn's disease

Background and aim:Infliximab is a chimeric human-murine monoclonal antibody with a high affinity and specificity for tumor necrosis factor α, which is nowadays widely used in Crohn's disease. An exacerbation of demyelinating disease as an adverse effect of this treatment is rare. The aim of this study was to discuss the relationship between infliximab and optic neuritis.Case report:We describe a 55-year old man with Crohn's disease who developed retrobulbar optic neuritis of the left eye after the infusion of infliximab. The outcome was favorable after systemic steroid treatment.Conclusion:Although the relationship between the onset of visual symptoms and the infusion of infliximab may have been coincidental, we believe that this case report underscores the clinical awareness of the possible association, especially in light of the increasing use of this cytokine inhibitor.