The Campo de Dalias GNSS Network Unveils the Interaction between Roll-Back and Indentation Tectonics in the Gibraltar Arc.

The Gibraltar Arc includes the Betic and Rif Cordilleras surrounding the Alboran Sea; it is formed at the northwest-southeast Eurasia-Nubia convergent plate boundary in the westernmost Mediterranean. Since 2006, the Campo de Dalias GNSS network has monitored active tectonic deformation of the most seismically active area on the north coast of the Alboran Sea. Our results show that the residual deformation rates with respect to Eurasia range from 1.7 to 3.0 mm/year; roughly homogenous west-southwestward displacements of the northern sites occur, while the southern sites evidence irregular displacements towards the west and northwest. This deformation pattern supports simultaneous east-northeast-west-southwest extension, accommodated by normal and oblique faults, and north-northwest-south-southeast shortening that develops east-northeast-west-southwest folds. Moreover, the GNSS results point to dextral creep of the main northwest-southeast Balanegra Fault. These GNNS results thus reveal, for the first time, present-day interaction of the roll-back tectonics of the Rif-Gibraltar-Betic slab in the western part of the Gibraltar Arc with the indentation tectonics affecting the eastern and southern areas, providing new insights for improving tectonic models of arcuate orogens.

Preliminary evidence of sustained expression of angiopoietin-2 during monocyte differentiation in chronic hepatitis C.

BACKGROUND: Monocytes are essential precursors of antigen-presenting cells, such as macrophages and dendritic cells, and contribute to the pathogenesis of chronic inflammatory diseases and cancer. AIMS: As Tie2-expressing monocytes (TEMs) are increased in the peripheral blood of patients with chronic hepatitis C (CHC), we aimed to examine the expression of Tie2 and angiopoietins (Ang1 and Ang2) during monocyte differentiation and maturation in CHC. METHODS: The expression of Tie2, CD11b, CD80, CD83, CD86 and MHC-II was measured by flow cytometry in peripheral blood monocytes and monocytes-derived cells (Mo-DCs) from nine healthy subjects and eight CHC patients whose HCV infection was unresolved after combination therapy. Ang1 and Ang2 levels were measured in cellular supernatants by ELISA. RESULTS: Mo-DCs from CHC patients expressed differential patterns of maturation markers compared with controls--primarily with regard to CD80. Tie2 was downregulated during monocyte differentiation in controls and CHC patients, whereas Ang1 expression was constant. However, Ang2 levels fell significantly during the differentiation of control monocytes, in contrast with those from CHC patients in whom Ang2 expression remained stable throughout differentiation. CONCLUSIONS: Altered expression of the Ang/Tie2 system in monocytes and Mo-DCs from CHC patients might account for the inflammatory and angiogenic disorders that are related to CHC. An increased understanding of Ang/Tie2 system regulation might be helpful in designing strategies to prevent CHC progression.

Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV x protein.

The progression of chronic hepatitis B (CHB) is related to fibrosis and to the emergence of intrahepatic anomalous vascular structures. Hepatitis B virus (HBV) X protein transactivator (HBx) may play a significant role in both processes. To analyze how HBV induces vascular growth and remodeling in vivo, we assessed the expression of angiopoietin-2 (Ang2) in liver biopsies from CHB patients by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry because of the relevant role of Ang2 in vascular development, remodeling, and tumor promotion. In addition, we analyzed the influence of HBx in the expression of Ang2 in HBx-expressing hepatocyte cell lines and in hepatic stellate cells stimulated with conditional medium from HBx-hepatocytes. Ang2 expression was clearly up-regulated at both mRNA and protein levels in the liver of CHB patients, showing an intense staining of inflammatory infiltrates and vascular structures at inflamed portal areas. HBx-expressing hepatocytes and stimulated stellate cells showed a significant induction of Ang2 expression. PI3K inhibitor and antioxidants repressed the 64-kd Ang2 form but further enhanced the inflammation-related 50-kd molecular species. Therefore, HBx could account for the induction of Ang2 observed in CHB, especially the 50-kd form, contributing to pathological angiogenesis and hepatocellular carcinoma progression.

The potential of angiogenesis soluble markers in chronic hepatitis C.

Angiogenesis, the formation of new vessels, has been reported to play a significant pathogenic role in liver damage-associated hepatitis C virus infection. Most of our current knowledge derives from immunohistochemical studies of hepatic biopsy samples obtained from chronic hepatitis C (CHC) patients. We evaluated whether CHC is associated with elevated serum levels of angiogenesis markers and whether these are modulated by therapy. Vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), and soluble Tie-2 (sTie-2) were determined in the serum of 36 CHC patients, before and after receiving antiviral combination therapy with pegylated interferon alpha-2b plus ribavirin, and in 15 healthy controls. CHC patients showed elevated baseline VEGF and Ang-2 levels. After treatment, both factors were decreased, whereas antiangiogenic sTie-2 was increased, indicating a shift toward an "anti-angiogenic" profile of serum markers in CHC patients. In conclusion, this suggests that serum VEGF, Ang-2, and sTie-2 levels could be useful as noninvasive, mechanistically based markers of response to therapy and disease progression in CHC.

The prevalence of hepatitis C virus infection in patients with non-Hodgkin's lymphoma.

AIM: Lymphomagenesis is a multifactorial process in which genetic, environmental and infectious factors can be involved. The aim of the present study was to assess the prevalence of hepatitis C virus (HCV) infection among patients with non-Hodgkin's lymphoma (NHL), and to compare it with that of a control group of voluntary blood donors. METHODS: All consecutive patients with a histological diagnosis of NHL from January 1996 to December 2001 were included in this prospective study. As control group for HCV infection, voluntary blood donors recruited over the same time period from the same geographical area were considered. The presence of anti-HCV antibodies was investigated by ELISA-II and RIBA-II, and viraemia (HCV RNA) was tested by using a polymerase chain reaction (PCR). HCV genotyping was also performed. RESULTS: Ninety-nine patients (mean age 48 years) with NHL were diagnosed during the study period. Histological classification of NHL was high-intermediate grade (63 patients), and low grade (36 patients). Immunophenotype distribution was type B (86 patients) and type T (13 patients). Seven of the 99 NHL patients (7%) were infected with HCV (both using serology and PCR), five of them with immunophenotype B and two with immunophenotype T. The prevalence of HCV infection according to NHL phenotype was 5.8% in B-cell NHL and 15.4% in T-cell NHL. The HCV genotype was 1b in six cases, and 3a in one. In voluntary blood donors (mean age 45 years), HCV infection was detected in 517/55 587 (0.93%). Therefore, HCV infection was more frequent in NHL patients than in controls (odds ratio = 8.1; 95% CI = 3.7-17.6). The odds ratio for the association of HCV and B-cell NHL was 6.2 (95% CI = 2.5-15.3), and for T-cell NHL 16.4 (95% CI = 3.7-72.8). CONCLUSION: The prevalence of HCV infection in patients with NHL (both B- and T-type) is higher than that observed in controls, suggesting a role of HCV in lymphoma aetiopathogenesis.

Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis.

BACKGROUND/AIMS: Nitrosative stress resulting from increased nitric oxide (NO) synthesis contributes to the pathogenesis of chronic inflammatory diseases, including chronic viral hepatitis. Our goal was to assess the expression of inducible nitric oxide synthase (iNOS) and the formation of nitrotyrosine (NTY), as a marker of nitrosative stress, in liver biopsies from primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) patients. METHODS: Intrahepatic expression of iNOS and NTY was measured immunohistochemically and compared to histological scores of the severity of liver disease. RESULTS: Hepatocellular iNOS expression was observed in liver sections from PBC patients (with a diffuse lobular distribution) and from AIH patients (marked staining in areas of pronounced inflammation and necrosis), but not in control liver sections, including non-autoimmune cholestatic liver disease. Liver samples from PBC and AIH patients, but not from controls, showed NTY accumulation in clusters of hepatocytes and Kupffer cells. Increased iNOS expression and NTY accumulation correlated with the histological severity of PBC or AIH, especially with the degree of inflammation. CONCLUSIONS: Patients with PBC and AIH showed an enhanced intrahepatic iNOS expression and NTY accumulation, related to the histological severity of liver disease, consistent with NO-mediated nitration of hepatocellular proteins contributing to liver damage in both diseases.