AIM： To investigate the effects of long-term albumin administration on survival, recurrence of ascites and onset of other complications.
METHODS： One hundred consecutive patients admitted for ...first-onset ascites were randomized to receive diuretics plus human albumin 25 g/wk in the first year and 25 g every two wk thereafter （group 1） or diuretics alone （group 2）. The primary endpoint was survival without liver transplantation. Secondary endpoints were recurrence of ascites and occurrence of other complications.
RESULTS： Median follow-up was 84 （2-120） mo. Albu- min-treated patients had significantly greater cumulative survival rate （Breslow test= 7.05, P= 0.0078） and lower probability of ascites recurrence （51% versus 94%, P〈0.0001）. Chronic albumin infusion resulted in a mean increase in survival of 16 mo.
CONCLUSION： Long-term albumin administration after first-onset ascites significantly improves patients＇ survival and decreases the risk of ascites recurrence.
Following liver injury, hepatic stellate cells (HSC) undergo proliferation and migrate into damaged areas in response to chemotactic factors. HSC have been shown to regulate leukocyte trafficking by ...secreting monocyte chemotactic protein‐1 (MCP‐1), a chemokine that recruits monocytes and lymphocytes. In this study, we explored whether MCP‐1 exerts biological actions on HSC. HSC were isolated from normal human livers, cultured on plastic, and studied in their myofibroblast‐like phenotype, and three different cells lines were used. Chemotaxis was measured in modified Boyden chambers. Phosphatidylinositol 3‐kinase (PI 3‐K) was assayed on phosphotyrosine immunoprecipitates. Exposure of HSC to MCP‐1 stimulated migration of HSC in a dose‐dependent fashion. Maximal stimulation was obtained with 250 ng/mL MCP‐1, which resulted in a 3‐ to 4‐fold stimulation of cell migration. Checkerboard analysis showed that the increase in cell migration was almost completely a result of chemotaxis rather than chemokinesis. In contrast, in quiescent HSC, MCP‐1 did not exert any effect on cell migration. In leukocytes, MCP‐1 activates the pertussis toxin‐sensitive CCR2 receptor. However, transcripts for CCR2 could not be shown in HSC, and pertussis toxin only modestly inhibited MCP‐1‐induced migration. Exposure of HSC to MCP‐1 was associated with an increase in cytosolic calcium concentration, PI 3‐K activity, protein tyrosine phosphorylation. Blocking calcium influx or pretreatment of HSC with the PI 3‐K inhibitor wortmannin markedly reduced cell migration. This study shows, for the first time, a potential direct profibrogenic action of MCP‐1 via HSC chemotaxis. MCP‐1–dependent signals in these cells are not transduced by CCR2 and may be mediated by alternative chemokine receptors.
Background/Aims
: Little is known about the role of fractalkine (CX3CL1) in the liver. The aim of this study was to investigate the expression patterns of fractalkine and its receptor CX3CR1 in ...normal human liver and in conditions of injury.
Methods
: Distribution and expression of fractalkine and its receptor were investigated using immunohistochemistry, in situ hybridization, flow cytometry and reverse transcriptase–polymerase chain reaction. In vitro experiments were conducted in HepG2 cells.
Results
: Both fractalkine and CX3CR1 were up-regulated during chronic injury, in areas of portal and lobular inflammation. In severe acute hepatitis, fractalkine and CX3CR1 were expressed at high levels not only in areas of inflammation but also in regenerating epithelial cells within bile duct-like structures, which showed co-expression of fractalkine and cytokeratin-7 or CX3CR1. The human hepatocarcinoma cell line HepG2 expressed fractalkine at the gene and protein level, and HepG2-conditioned medium was chemotactic for cells overexpressing CX3CR1. Transcripts for CX3CR1 were detected in HepG2, and exposure of these cells to recombinant fractalkine induced cell migration.
Conclusions
: This study shows that the fractalkine system is up-regulated during liver damage, and suggests that fractalkine may play a role in the recruitment and adhesion of inflammatory cells and in the biology of liver epithelial cells.
Uveitis in autoimmune hepatitis： A case report Romanelli, Roberto Giulio; La Villa, Giorgio; Almerigogna, Fabio ...
World journal of gastroenterology : WJG,
03/2006, Letnik:
12, Številka:
10
Journal Article
Odprti dostop
In this case report we describe for the first time an association between autoimmune hepatitis （AIH） and uveitis, without any doubts about other possible etiologies, such as HCV, since all the old ...reports describe the association of AIH with iridocyclitis before tests for HCV-related hepatitis could be available. A 38-year-old businessman with abnormal liver function tests and hyperemia of the bulbar conjunctiva was admitted to the hospital. Six years before admission, the patient presented with persistent fever, arthralgias, conjunctival hyperemia, leukocytosis and increased ESR, referred to acute rheumatic fever. The presence of systemic diseases, most commonly associated with uveitis, was investigated without results and the patient was then treated with topical corticosteroids. His symptoms resolved. A test for anti-nuclear antibodies was positive, at a titre of 1：320, with a speckled and nucleolar staining pattern. Liver ultrasound showed mild hepatomegaly with an increased echostructure of the liver. Percutaneous liver biopsy was performed under ultrasound assistance. Histological examination showed necroinflammation over the portal, periportal and Iobular areas, fibrotic portal tracts, with periportal fibrosis and occasional portal-to-portal bridgings, but intact hepatic architecture. Some hepatocytes showed barely discernible granules of hemosiderin in the Iobular area. Bile ductules had not any significant morphological alterations. METAVIR score was A2-F3, according to the modified HAI grading/fibrosis staging. The patient was diagnosed to have AIH with mild activity and fibrosis and was discharged on 25 mg prednisone, entering clinical and biochemical remission, further confirming diagnosis. After discharge the patient continued to have treatment with corticosteroids as an outpatient at a dose of 5 mg. On January 2002 the patient was readmitted to the hospital. A test for anti-nuclear antibodies was positive, at a titre of 1：320, with a speckled and nucleolar staining pattern. Anti-smooth muscle antibody test was also positive （1：160）, while anti-LKM antibodies were negative. Ophthalmologic examination revealed inflammatory cells and proteinaceous flare in the anterior chamber of the left eye, and a stromal lesion in the cornea. He was maintained on immunosuppressive therapy （5 mg prednisone plus topical antibiotic therapy for two weeks） and then discharged. A complete remission of the symptoms was registered on follow-up. At present （July 2005）, the patient is on prednisone （5 rag） and has no symptoms. Liver function tests are also within the normal range.
We investigated the infection of peripheral blood mononuclear cells (PBMNC) by hepatitis C virus (HCV) in 5 patients with HCV-related chronic hepatitis. The presence of HCV-RNA-positive and -negative ...strands was tested with the polymerase chain reaction (PCR) method. In all subjects, HCV-RNA was shown in PBMNC. In 3 cases, HCV-RNA was shown in the T- and B-cell populations, with viral RNA also present in the monocyte-macrophage fraction of two of these. HCV-RNA-negative stranded molecules, indicative of the viral multiplication, were significantly increased in cells maintained in cultures with PHA/PMA stimulation. The results indicate that HCV infect blood mononuclear cells, thus suggesting that this cellular tropism may play a role in HCV infection.
A proof-theoretic analysis and new
arithmetical semantics are proposed for some paraconsistent
C-systems, which are a relevant sub-class of
Logics of Formal Inconsistency (
LFIs) introduced by W.A. ...Carnielli et al. (2002, 2005)
8,9. The sequent versions
BC,
CI,
CIL of the systems
bC,
Ci,
Cil presented in Carnielli et al. (2002, 2005)
8,9 are introduced and examined.
BC,
CI,
CIL admit the cut-elimination property and, in general, a weakened sub-formula property. Moreover, a formal notion of
constructive paraconsistent system is given, and the constructivity of
CI is proven. Further possible developments of proof theory and provability logic of
CI-based arithmetical systems are sketched, and a possible weakened Hilbertʼs program is discussed. As to the semantical aspects,
arithmetical semantics interprets
C-system formulas into Provability Logic sentences of classical Arithmetic
PA (Artemov and Beklemishev (2004)
2, Japaridze and de Jongh (1998)
19, Gentilini (1999)
15, Smorynski (1991)
22): thus, it links the notion of
truth to the notion of
provability inside a
classical environment. It makes true infinitely many contradictions
B
∧
¬
B
and falsifies many arbitrarily complex instances of non-contradiction principle
¬
(
A
∧
¬
A
)
. Moreover,
arithmetical models falsify both classical logic
LK and intuitionistic logic
LJ, so that a kind of metalogical completeness property of
LFI-paraconsistent logic w.r.t.
arithmetical semantics is proven. As a work in progress, the possibility to interpret
CI-based paraconsistent Arithmetic
PACI into Provability Logic of classical Arithmetic
PA is discussed, showing the role that
PACI
arithmetical models could have in establishing new meta-mathematical properties, e.g. in breaking classical equivalences between consistency statements and reflection principles.
In cirrhotic patients, portal hypertension is often associated with a hyperdynamic circulatory syndrome, with high cardiac output and reduced systemic vascular resistance and arterial pressure. The ...hyperdynamic circulatory syndrome is due to arterial vasodilation that mainly occurs in the splanchnic circulation, while vascular resistance in the other circulatory districts is normal or increased, accordingly with the degree of portal hypertension, liver impairment and activation of the renin-aldosterone and sympathetic nervous system. The mechanism(s) leading to splanchnic vasodilation is unclear. A favored hypothesis translocation of intestinal bacteria and/or some their products, such as endotoxin, into the interstitial space in the splanchnic organs results in the local release of vasodilating factors such as nitric oxide, carbon monoxide and others.
Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological ...response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO was associated with a dose-dependent increase in cell migration and chemoinvasion through Matrigel-coated filters. A checkerboard analysis showed that the effects of TPO on cell migration were dependent on both chemotaxis and chemokinesis. Exposure of HepG2 cells to TPO resulted in the activation of different members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated with increased activation of nuclear factor-kappaB. With the use of specific inhibitors, tyrosine phosphorylation and activation of PI3K were found to be required for the induction of migration in response to TPO. We conclude that TPO exerts biological actions on cultured hepatoblastoma cells via activation of c-Mpl and its downstream signaling.
Thrombin is generated during tissue damage in several organs, including the liver, and participates in the process of tissue repair through proteolytic activation of a specific thrombin ...receptor(TR).The aim of this study was to investigate TR expression in human liver by immunohistochemistry and in situ hybridization. In normal liver, immunostaining for TR was present in the endothelial lining of the hepatic sinusoids. During chronic hepatitis, several cells expressing the TR were detected in the inflammatory infiltrate of portal tracts. In cirrhosis with chronic active hepatitis, expression of the TR was also present in mesenchymal cells of fibrous septa. TR expression was markedly up‐regulated during fulminant hepatitis, with the highest expression in mesenchymal cells in areas of regeneration. Up‐regulation of TR expression was associated with increased levels of TR messenger RNA (mRNA), as assessed byin situ hybridization and RNAse protection assay of liver RNA. Immunostaining of serial sections using specific cellular markers showed that different nonparenchymal cells contribute to TR expression during liver injury. TR expression was also shown in cultured human hepatic stellate cells, with increasing signal comparing activated versus quiescent cells. Because thrombin is rapidly generated after tissue damage, regulated TR expression may be involved in tissue remodeling and/or scarring during liver damage.
Background & Aims:
Because aldosterone-dependent sodium and water retention contribute to portal hypertension, the safety and effect of an antialdosteronic drug (Kcanrenoate) have been evaluated on ...the occurrence of de novo appearance of ascites and the development of esophageal varices or the progression of small varices.
Methods:
Inclusion criteria were as follows: Child–Pugh A viral pre-ascitic cirrhosis, with either F1 esophageal varices or no varices, but endoscopic and/or ultrasound evidence of portal hypertension. Thirteen Italian Liver Units prospectively enrolled 120 patients randomized to receive double-blind either Kcanrenoate (100 mg/day; 66 patients) or placebo (54 patients). Endoscopy and sonography were performed at entry and at 52 weeks unless the patient developed ascites earlier, whereas laboratory examinations were performed at entry and every 3 months thereafter. An intention-to-treat analysis was performed, with each end point assessed by the Fisher exact test; the cumulative risk for the appearance of any end point was analyzed by the adjusted log-rank test (Tarone–Ware), with censoring for drop-outs.
Results:
The progression of variceal status or appearance of ascites, analyzed independently, was not significantly more frequent on placebo (24.1% and 9.2%, respectively) than on Kcanrenoate (12.1% and 1.5%, respectively), whereas the cumulative occurrence of end points was decreased on Kcanrenoate (17.6% vs 38.3% with placebo;
P < .05, Tarone–Ware test). The incidence of adverse events was negligible and did not differ between groups.
Conclusions:
This preliminary study shows that 100 mg/day of Kcanrenoate is well tolerated and does not reduce the individual incidence of ascites and/or the appearance or progression of esophageal varices in preascitc cirrhosis, but may decrease their 1-year cumulative occurrence.
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