Changes in the spinal segmental motor output for stepping during development from infant to adult.

Human stepping movements emerge in utero and show several milestones during development to independent walking. Recently, imaging has become an essential tool for investigating the development and function of pattern generation networks in the spinal cord. Here we examine the development of the spinal segmental output by mapping the distribution of motoneuron activity in the lumbosacral spinal cord during stepping in newborns, toddlers, preschoolers, and adults. Newborn stepping is characterized by an alternating bilateral motor output with only two major components that are active at all lumbosacral levels of the spinal cord. This feature was similar across different cycle durations of neonate stepping. The alternating spinal motor output is consistent with a simpler organization of neuronal networks in neonates. Furthermore, a remarkable feature of newborn stepping is a higher overall activation of lumbar versus sacral segments, consistent with a rostrocaudal excitability gradient. In toddlers, the stance-related motor pool activity migrates to the sacral cord segments, while the lumbar motoneurons are separately activated at touchdown. In the adult, the lumbar and sacral patterns become more dissociated with shorter activation times. We conclude that the development of human locomotion from the neonate to the adult starts from a rostrocaudal excitability gradient and involves a gradual functional reorganization of the pattern generation circuitry.

Hepatitis C virus infection in the immunocompromised host: a complex scenario with variable clinical impact.

The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist.

Safety and efficacy of rituximab in patients with hepatitis C virus-related mixed cryoglobulinemia and severe liver disease.

The effectiveness of rituximab in hepatitis C virus (HCV)-related mixed cryoglobulinemia (MC) has been shown. However, the risk of an increase in viral replication limits its use in cirrhosis, a condition frequently observed in patients with MC. In this prospective study, 19 HCV-positive patients with MC and advanced liver disease, who were excluded from antiviral therapy, were treated with rituximab and followed for 6 months. MC symptoms included purpura, arthralgias, weakness, sensory-motor polyneuropathy, nephropathy, and leg ulcers. Liver cirrhosis was observed in 15 of 19 patients, with ascitic decompensation in 6 cases. A consistent improvement in MC syndrome was evident at the end-of-treatment (EOT) and end-of-follow-up (EOF-U). Variable modifications in both mean viral titers and alanine aminotransferase values were observed at admission, EOT, third month of follow-up, and EOF-U (2.62 x 10(6), 4.28 x 10(6), 4.82 x 10(6), and 2.02 x 10(6) IU/mL and 63.6, 49.1, 56.6, and 51.4 IU/L, respectively). Improvement in liver protidosynthetic activity and ascites degree was observed at EOT and EOF-U, especially in more advanced cases. This study shows the effectiveness and safety of rituximab in MC syndrome with advanced liver disease. Moreover, the depletion of CD20(+) B cells was also followed by cirrhosis syndrome improvement despite the possibility of transient increases of viremia titers.

Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcγ receptors.

OBJECTIVE: Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related immune complex disorder. Only some HCV-infected patients develop MC, which suggests that the genetic background of the host plays a key role. This study was undertaken to evaluate the contribution of host genetic factors in the pathogenesis of HCV-associated MC (HCV-MC) by analyzing allelic variants of low-affinity Fcγ receptor (FcγR) genes and BAFF promoter. METHODS: FcγR polymorphisms (FCGR2A 131 R/H, FCGR2B 232 I/T, FCGR3A 176 V/F, and FCGR3B NA1/NA2) and BAFF promoter polymorphism -871 C/T were analyzed in 102 patients with HCV-MC and 108 patients with HCV without MC, using polymerase chain reaction-based techniques. RESULTS: A higher prevalence of -871 T/T homozygosity (31% versus 16%; P = 0.001) and a greater frequency of T alleles of the BAFF promoter (80% versus 57%; P = 0.004) were found in the HCV-MC group than in the HCV group. A significant increase in serum BAFF concentration was significantly associated with the higher frequency of the T allele in HCV-MC (mean ± SD 4.12 ± 1.29 versus 2.09 ± 0.81 ng/ml; P < 0.0005). The distribution of the FcγR genotypes was not significantly different. In the 21 HCV-MC patients treated with rituximab, the response was strictly related to F allele homozygosity (significantly reduced in 5 of 5 patients with the FCGR3A F/F genotype versus 4 of 16 with V/V or V/F; P < 0.0005). CONCLUSION: These results indicate the importance of host genetic background in the development of HCV-MC, suggesting that mechanisms enhancing Ig production and B cell survival may play a relevant role. Genetic FcγR variants seem to be crucial to the effectiveness of rituximab therapy.

HCV and lymphoproliferation.

Hepatitis C virus (HCV) infection is a serious public health problem because of its worldwide diffusion and sequelae. It is not only a hepatotropic but also a lymphotropic agent and is responsible not only for liver injury--potentially evolving to cirrhosis and hepatocellular carcinoma--but also for a series of sometimes severely disabling extrahepatic diseases and, in particular, B-cell lymphoproliferative disorders. These latter range from benign, but prelymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas. Analogously with Helicobacter pylori related lymphomagenesis, the study of the effects of viral eradication confirmed the etiopathogenetic role of HCV and showed it is an ideal model for better understanding of the molecular mechanisms involved. Concerning these latter, several hypotheses have been proposed over the past two decades which are not mutually exclusive. These hypotheses have variously emphasized the important role played by sustained stimulation of the immune system by HCV, infection of the lymphatic cells, viral proteins, chromosomal aberrations, cytokines, or microRNA molecules. In this paper we describe the main hypotheses that have been proposed with the corresponding principal supporting data.

Involvement of PI3K in HCV-related lymphoproliferative disorders.

Hepatitis C virus (HCV) core protein has been shown to deregulate cell growth and programmed cell death in hepatoma cells, but only minimal informations are available about its possible role on B-lymphoproliferative disorders (LPDs). The aim of our work was to analyze the biological activity of HCV core protein on B-cell proliferation. We established Wil2-ns and Ramos B-cell lines that stably expressed the HCV core protein. Growth curve, thymidine incorporation analysis, as well as the expression of PCNA and activated-ERKs demonstrated that HCV core protein induced an increased growth in both cell lines. Interestingly, the HCV core protein expression determined, in our model, a downregulation of DNp73 and an upregulation of DNp63, which was essential for the maintenance of viral-dependent effects on cell growth. Finally, we have identified phosphoinositide 3-kinase (PI3K) as mediator of HCV core-dependent transcriptional increase of DNp63, which in turn correlated with the increasing of lymphocyte proliferation. In primary B-lymphocytes, derived from HCV-related low-grade non-Hodgkin's lymphoma patients, consistent results were obtained. These findings provide evidence for a possible pathogenetic role played by HCV core protein in HCV-related lymphomagenesis; it could occur through the deregulation of PI3K activity, consequent activation of Akt and overexpression of DNp63.

Gene modulation associated with inhibition of liver regeneration in hepatitis B virus X transgenic mice.

AIM: To analyze the modulation of gene expression profile associated with inhibition of liver regeneration in hepatitis B X (HBx)-expressing transgenic mice. METHODS: Microarray technology was performed on liver tissue obtained from 4 control (LacZ) and 4 transgenic mice (HBx-LacZ), 48 h after partial hepatectomy. The significance of the normalized log-ratios was assessed for each gene, using robust t-tests under an empirical Bayes approach. Microarray hybridization data was verified on selected genes by quantitative PCR. RESULTS: The comparison of gene expression patterns showed a consistent modulation of the expression of 26 genes, most of which are implicated in liver regeneration. Up-regulated genes included DNA repair proteins (Rad-52, MSH6) and transmembrane proteins (syndecan 4, tetraspanin), while down-regulated genes were connected to the regulation of transcription (histone deacetylase, Zfp90, MyoD1) and were involved in the cholesterol metabolic pathway and isoprenoid biosynthesis (farnesyl diphosphate synthase, Cyp7b1, geranylgeranyl diphosphate synthase, SAA3). CONCLUSION: Our results provide a novel insight into the biological activities of HBx, implicated in the inhibition of liver regeneration.

Hepatitis C virus-related lymphoproliferative disorders: an overview.

Hepatitis C virus (HCV) is a global health problem affecting 3% of the world's population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV-related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed.

Prevalence of bcl-2 rearrangement in patients with hepatitis C virus-related mixed cryoglobulinemia with or without B-cell lymphomas.

BACKGROUND: Hepatitis C virus (HCV) infection is strictly associated with mixed cryoglobulinemia, a benign B-cell lymphoproliferative disorder that may evolve to lymphoma. An increased prevalence of bcl-2 rearrangement (the t(14;18) translocation) has been shown in patients infected with HCV. OBJECTIVE: To evaluate the prevalence of bcl-2 rearrangement in patients with HCV-related mixed cryoglobulinemia and patients with chronic hepatitis but no cryoglobulinemia. DESIGN: Prospective study. SETTING: Two university hospitals. PATIENTS: 37 consecutively recruited patients with HCV-related mixed cryoglobulinemia and 101 patients with chronic HCV infection but without mixed cryoglobulinemia. MEASUREMENTS: Clinical and serologic characteristics; liver biopsy; bcl-2 rearrangement, Bcl-2 expression, and the ratio of Bcl-2 to Bax in total peripheral blood mononuclear cells and cell subgroups; and sequence analysis of the junction of bcl-2 and IgH joining segments in positive samples. RESULTS: Rearrangement of bcl-2 was observed in 28 of 37 (75.7%) patients with mixed cryoglobulinemia (65% of those with type III disease and 85% of those with type II disease, including 3 of 4 patients with lymphoma) and in 38 of 101 (37.6%) patients with chronic HCV infection but not mixed cryoglobulinemia (P < 0.001). Overexpression of Bcl-2 protein and a high ratio of Bcl-2 to Bax were observed in samples from patients with bcl-2 rearrangement. In 2 patients followed over time, peripheral blood cells bearing the t(14;18) translocation disappeared after antiviral therapy. CONCLUSIONS: Rearrangement of bcl-2 was found with increased frequency in patients with chronic HCV infection and mixed cryoglobulinemia. The frequency was greatest in patients with type II mixed cryoglobulinemia. The high ratio of Bcl-2 to Bax in patients with bcl-2 rearrangement and disappearance of the rearrangement with antiviral therapy suggest that the translocation is associated with the antiapoptotic function of Bcl-2 and that HCV infection is linked to inhibition of B-cell apoptosis.

Role of microRNA profile modifications in hepatitis C virus-related mixed cryoglobulinemia.

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin's lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders.

The hepatitis C virus infection as a systemic disease.

Hepatitis C Virus (HCV) is a major health problem, infecting about 3 % of people worldwide and leading to liver as well as extrahepatic diseases. This justifies the definition of HCV infection as a systemic disease. Based on available data, the link between the virus and some of these extrahepatic disorders is certain, whereas for some others needs further confirmation. HCV-related lymphoproliferative disorders, ranging from benign, but pre-lymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas, represent the extrahepatic manifestations most closely related to HCV. The primary involvement of the liver and lymphatic system corresponds to the double viral tropism, being HCV able to infect both hepatic and lymphatic cells. Other HCV-associated disorders include renal, endocrine, dermatological, cardiovascular, rheumatologic and central nervous system diseases. On the whole, the HCV disease appears a very important, mainly hidden, public health problem leading to heavy direct and indirect costs. The possibility that HCV may be eradicated following antiviral therapy is important for both the therapeutic and preventive points of view, making the HCV disease an ideal model for pathogenetic studies.

Locomotor primitives in newborn babies and their development.

How rudimentary movements evolve into sophisticated ones during development remains unclear. It is often assumed that the primitive patterns of neural control are suppressed during development, replaced by entirely new patterns. Here we identified the basic patterns of lumbosacral motoneuron activity from multimuscle recordings in stepping neonates, toddlers, preschoolers, and adults. Surprisingly, we found that the two basic patterns of stepping neonates are retained through development, augmented by two new patterns first revealed in toddlers. Markedly similar patterns were observed also in the rat, cat, macaque, and guineafowl, consistent with the hypothesis that, despite substantial phylogenetic distances and morphological differences, locomotion in several animal species is built starting from common primitives, perhaps related to a common ancestral neural network.

Hepatitis C virus RNA localization in human carotid plaques.

BACKGROUND: Hepatitis C virus (HCV) infection has certain characteristics that enable it to play an important role in atherosclerosis. Some studies report its association with an increased risk of carotid artery plaque. OBJECTIVES: The aim of this study was to evaluate the presence of HCV genomic sequences and replicative intermediates in plaque tissues. STUDY DESIGN: A cohort of consecutive, prospectively recruited patients with HCV infection and chronic ischemic heart disease from the Cardiology, Vascular Surgery and Hepatology Units of a University Hospital in Florence, Italy, were studied. RESULTS: Positive-strand HCV RNA was detected in seven carotid plaque tissues from anti-HCV-positive patients and was not detected in the nine carotid plaque tissues obtained from anti-HCV-negative patients. In three patients, HCV RNA was found in carotid plaque and not in serum. HCV replicative intermediates were detected in three plaque samples. Direct sequencing of HCV RNA from the plaque and serum showed HCV genotypes 2 (five cases) and 1 (two cases). CONCLUSIONS: The novel finding of HCV RNA sequences in plaque tissue strongly suggests an active local infection. This in turn makes it conceivable that the virus may exert local action in carotid atherosclerosis.

HBV and HCV chronic infection: autoimmune manifestations and lymphoproliferation.

Hepatitis B (HBV) and C (HCV) viruses differ both in viral structure and in natural history of chronic infection. However, they seem to share, although to a different extent, some characteristics, like the possibility to infect not only hepatic but also lymphatic cells and to associate with some hepatic and/or extrahepatic disorders of an autoimmune and/or lymphoproliferative nature. These characteristics have been more widely studied in the case of chronic HCV infection, where they are more evident, but they have been described also in the case of HBV infection.

HCV patients, psychopathology and tryptophan metabolism: analysis of the effects of pegylated interferon plus ribavirin treatment.

AIMS: Depression and other psychiatric disorders are frequent in HCV-infected patients, especially during interferon treatment. The molecular mechanism(s) underlying this finding is still unknown but it has been suggested that HCV and/or interferon administration may increase indoleamine 2,3-dioxygenase (IDO) activity, and reduce plasma tryptophan (TRP) levels and brain serotonin synthesis thus leading to psychopathological disorders. METHODS: We studied 89 subjects: (a) 39 patients with chronic hepatitis C virus (HCV) infection and mild liver damage; (b) 39 healthy controls; and (c) 10 patients with chronic hepatitis B virus (HBV) infection. 15 of the patients with HCV infection were re-evaluated after antiviral treatment with pegylated interferon alpha-2a plus ribavirin leading to viral eradication. We measured serum TRP and kynurenine levels and IDO activity in macrophages. Furthermore, each patient had an accurate psychopathological evaluation. RESULTS: HCV-infected patients had lower (-28%) serum TRP and kynurenine levels than healthy volunteers or HBV-infected patients with comparable liver damage. Depression and anxiety symptoms were particularly common in HCV patients. After viral clearance, macrophage IDO activity, plasma TRP and kynurenine levels returned toward normal values and psychopathology improved. CONCLUSION: Our study shows that HCV patients have reduced serum TRP levels and confirms that they frequently suffer from anxiety and depression-related symptoms. The reduced IDO activity found in the macrophages of these patients suggests that HCV infection may hamper macrophage functions. After successful antiviral treatment, in spite of the expected increase of IDO activity in macrophages, we noticed that TRP and kynurenine plasma levels returned toward physiological levels and psychopathology decreased significantly.

Improvement in liver cirrhosis after treatment of HCV-related mixed cryoglobulinemia with rituximab.

Mixed cryoglobulinemia (MC) is the most strictly virus-related extrahepatic HCV disease. Antiviral therapy is considered the first therapeutic option; however, MC patients are frequently excluded from treatment due to contraindications. The effectiveness of B-cell depletion by anti-CD20 monoclonal antibody (rituximab) has recently been described, but the possibility of an immunodepression- related increase in viral replication and aminotransferase values limits its use in patients with advanced liver disease. Unfortunately, MC patients frequently also have cirrhosis. To our knowledge, no data are available regarding the effect of rituximab therapy in patients with decompensated cirrhosis. We report the successful treatment with rituximab (4 weekly infusions of 375 mg/m 2) of two patients (a 58-year-old man, and a 65-year-old woman) with HCV-related MC syndrome and decompensated liver cirrhosis. These patients underwent at least 6 months of post-treatment follow-up. In both cases a consistent improvement of MC syndrome was evident after treatment. In addition, improvement of liver protidosynthetic activity, increased prothrombin time, impressive reduction or disappearance of ascites and encephalopathy were also observed, in spite of some increase in viral titers or in ALT values. The Child-Pugh score improved from B8 to A6 and from Cll to B7, respectively. Pre- and post-treatment transjugular liver biopsies were available in 1 patient, showing disappearance of lymphocytic infiltration after treatment. These case reports show the effectiveness and safety of rituximab in patients with HCV-related MC and advanced cirrhosis, and strongly suggest that the depletion of CD20+ B-cells induced by rituximab treatment may be responsible for liver function improvement. The mechanisms involved are unknown. Interesting working hypotheses may implicate a role played by B-cell infiltrates in conditioning liver damage. The improvement of Kupffer cell function due to the cryocrit value reduction might also play a role.

Effect of chronic hepatitis C virus infection on inflammatory lipid mediators.

BACKGROUND: Platelet-activating factor (PAF), a powerful phospholipid mediator of inflammation, is degraded by plasma PAF-acetyl-hydxolase (pPAF-AH), an enzyme which circulates in serum mainly in a complex with lipoproteins that confer its biological activity. Hepatitis C virus (HCV) is linked to lipoproteins in serum too. Reduced pPAF-AH activity was observed in several diseases, including systemic vasculitis. AIM: To evaluate if chronic HCV infection could alter pPAF-AH physiological functions. SUBJECTS: 145 subjects were studied: 56 HCV- and 52 HBV-infected patients (pathologic controls); 37 healthy subjects (healthy controls). METHODS: pPAF-AH activity, PAF and Apo B100 titers were determined in plasma; enzyme expression levels were evaluated in monocyte-derived macrophages. HCV-RNA was detected in plasma, peripheral blood mononuclear cells and liver samples. RESULTS: HCV-infected patients showed an increase of PAF levels following a significant decrease of pPAF-AH activity. A recovery of pPAF-AH activity occurs only in patients who clear HCV after the antiviral treatment. Expression levels of pPAF-AH mRNA and Apo B100 titers were not modified in HCV patients in comparison to controls. CONCLUSION: In light of these results, it is tempting to hypothesize that during chronic HCV infection, the PAF/pPAF-AH system may be altered and this condition may contribute to HCV-related vascular damage.

Liver-stage development of Plasmodium falciparum, in a humanized mouse model.

BACKGROUND: The liver stage of the human malaria parasite Plasmodium falciparum is the least known, yet it holds the greatest promise for the induction of sterile immunity and the development of novel drugs. Progress has been severely limited by the lack of adequate in vitro and in vivo models. METHODS: Recently, it was found that immunodeficient mice transgenic for the urokinase plasminogen activator allow survival of differentiated human hepatocytes. We confirm this finding but show that hepatocyte survival is short lived unless nonadaptive defenses are simultaneously depleted. RESULTS: By controlling macrophages and NK cells, we readily effected the long-term secretion of human serum albumin and human alpha-1 antitrypsin in mouse serum (at 3 months, the proportion of repopulated mice increased from 0% to 60% and from 22% to 80%, respectively; P<.0001). P. falciparum sporozoites delivered intravenously into mice readily infected transplanted human hepatocytes and developed into liver schizonts. Their size was twice as large as what was seen in vitro and was comparable to that found in humans and chimpanzees. CONCLUSION: These results emphasize the importance of nonadaptive defenses against xenotransplantation and lead to development of small laboratory models that, because they can harbor human hepatocytes, provide novel opportunities to study intrahepatic pathogens, such as those causing malaria and hepatitis.

Hepatitis C virus core protein expression in human B-cell lines does not significantly modify main proliferative and apoptosis pathways.

Hepatitis C virus (HCV) chronic infection has been associated with many lymphoproliferative disorders. Several studies performed on hepatoma and fibroblast cell lines suggest a role of the HCV core protein in activation of cellular transduction pathways that lead to cell proliferation and inhibition of apoptosis. However, no data are available concerning the effects of HCV core expression on B-lymphocyte proliferation and apoptosis. B-lymphocyte cell lines permanently expressing full-length HCV 1b core sequences isolated from chronically infected patients were established using B-cell lines at different degrees of differentiation. Clones and pools of clones permanently expressing the HCV core were selected and characterized for protein expression by Western blot and FACS. Expression of HCV core proteins did not significantly enhance cell proliferation rates under normal culture conditions or under mitogenic stimulation. Analysis of NF-kappa B, CRE, TRE and SRE pathways by luciferase reporter genes did not show a significant influence of HCV core expression on these signal transduction cascades in B-lymphocytes. The effects of HCV core on anti-IgM and anti-FAS-induced apoptosis in B-cell lines was also analysed. In this experimental model, HCV core expression did not significantly modify the apoptotic profile of the B-lymphocyte cell lines tested. These data underline a cell type-specific effect of HCV core expression. In fact, it was not possible to show a significant contribution of the HCV core protein in activation of the major B-cell signal transduction pathways involved in the regulation of proliferation and programmed cell death, which is in contrast with the results reported in hepatoma cell lines.