Differential tumor surveillance by natural killer (NK) and NKT cells

Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12. does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12, A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor J alpha 281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.

Magnetic resonance imaging (MRI) and diseases of the liver and biliary tract. Part 1. Basic principles, MRI in the assessment of diffuse and focal hepatic disease

Magnetic resonance imaging (MRI) relies on the physical properties of unpaired protons in tissues to generate images. Unpaired protons behave like tiny bar magnets and will align themselves in a magnetic field. Radiofrequency pulses will excite these aligned protons to higher energy states. As they return to their original state, they will release this energy as radio waves. The frequency of the radio waves depends on the local magnetic field and by varying this over a subject, it is possible to build the images we are familiar with. In general, MRI has not been sufficiently sensitive or specific in the assessment of diffuse liver disease for clinical use. However, because of the specific characteristics of fat and iron, it may be useful in the assessment of hepatic steatosis and iron overload. Magnetic resonance imaging is useful in the assessment of focal liver disease, particularly in conjunction with contrast agents. Haemangiomas have a characteristic bright appearance on T-2 weighted images because of the slow flowing blood in dilated sinusoids. Focal nodular hyperplasia (FNH) has a homogenous appearance, and enhances early in the arterial phase after gadolinium injection, while the central scar typically enhances late. Hepatic adenomas have a more heterogenous appearance and also enhance in the arterial phase, but less briskly than FNH. Hepatocellular carcinoma is similar to an adenoma, but typically occurs in a cirrhotic liver and has earlier washout of contrast. The appearance of metastases depends on the underlying primary malignancy. Overall, MRI appears more sensitive and specific than computed tomography with contrast for the detection and evaluation of malignant lesions. (C) 2000 Blackwell Science Asia Pty Ltd.

Magnetic resonance imaging and diseases of the liver and biliary tract. Part 2. Magnetic resonance cholangiography and angiography and conclusions

Magnetic resonance cholangiography (MRC) relies on the strong T-2 signal from stationary liquids, in this case bile, to generate images. No contrast agents are required, and the failure rate and risk of serious complications is lower than with endoscopic retrograde cholangiopancreatography (ERCP). Data from MRC can be summated to produce an image much like the cholangiogram obtained by using ERCP. In addition, MRC and conventional MRI can provide information about the biliary and other anatomy above and below a biliary obstruction. This provides information for therapeutic intervention that is probably most useful for hilar and intrahepatic biliary obstruction. Magnetic resonance cholangiography appears to be similar to ERCP with respect to sensitivity and specificity in detecting lesions causing biliary obstruction, and in the diagnosis of choledocholithiasis. It is also suited to the assessment of biliary anatomy (including the assessment of surgical bile-duct injuries) and intrahepatic biliary pathology. However, ERCP can be therapeutic as well as diagnostic, and MRC should be limited to situations where intervention is unlikely, where intrahepatic or hilar pathology is suspected, to delineate the biliary anatomy prior to other interventions, or after failed or inadequate ERCP. Magnetic resonance angiography (MRA) relies on the properties of flowing liquids to generate images. It is particularly suited to assessment of the hepatic vasculature and appears as good as conventional angiography. It has been shown to be useful in delineating vascular anatomy prior to liver transplantation or insertion of a transjugular intrahepatic portasystemic shunt. Magnetic resonance angiography may also be useful in predicting subsequent variceal haemorrhage in patients with oesophageal varices. (C) 2000 Blackwell Science Asia Pty Ltd.

Characterization of peroxisome proliferator-activated receptor alpha in normal rat mammary gland and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mammary gland tumors from rats fed high and low fat diets

Normal Sprague-Dau ley rat mammary gland epithelial cells and mammary gland carcinomas induced by 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine, a carcinogen found in the diet, were examined for the expression of peroxisome proliferator-activated receptor alpha (PPAR alpha). PPAR alpha mRNA and protein was detected in normal and tumor tissue by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. By quantitative RT-PCR, carcinomas had a 12-fold higher expression than control mammary glands, a statistically significant difference. PPAR alpha expression was examined in carcinomas and normal tissues from rats on high fat (23.5/% corn oil) and low fat (5% corn oil) diets. Although neither carcinomas, nor control tissues showed statistically significant differences between the two diet groups, PPAR alpha expression was the highest in carcinomas from rats on the high fat diet. The expression of PPAR alpha in normal mammary gland and its significant elevation in mammary gland carcinomas raises the possibility of its involvement in mammary gland physiology and pathophysiology. (C) 2000 Published by Elsevier Science Ireland Ltd. All rights reserved.

Immunobiology of liver dendritic cells

Dendritic cells (DC) are rare, bone marrow-derived antigen-presenting cells that play a critical role in the induction and regulation of immune reactivity. In this article, we review the identification and characterization of liver DC, their ontogenic development, in vivo mobilization and population dynamics. In addition, we discuss the functions of DC isolated from liver tissue or celiac lymph, or propagated in vitro from liver-resident haemopoietic stem/progenitor cells. Evidence concerning the role of DC in viral hepatitis. liver tumours, autoimmune liver diseases, granulomatous inflammation and the outcome of liver transplantation is also discussed.

Modulation of cytochrome P450 monooxygenase by cadmium chloride in the mouse liver: Involvement of transcription factor Nrf2.

Modulation of the cytochrome P450 (CYP) monooxygenase system and haem oxygenase by cadmium was investigated in male, adult DBA/2J mice treated with a single dose (16 Amol/kg body weight, i.p.) of cadmium chloride (CdCl2), at various time points. Total CYP content of liver microsomes decreased significantly (P < 0.05) at 12, 18, and 24 hours (22%, 47%, and 56%, respectively) after treatment. In contrast, progressive increases of hepatic coumarin 7-hydroxylase (COH) activity (indicative of CYP2A5 activity) were observed at 8 hrs (2-fold), 12 hrs (3-fold), and 7-fold at 18 and 24 hrs. Simultaneously, haem oxygenase activity increased significantly at 4 hours and continued to increase progressively to more than 50-fold compared to control. Liver CYP2A5 mRNA levels increased maximally 12 hours after treatment and decreased to almost half 6 hours later, while western blot analysis showed 2- and 3- fold increase in CYP2A5 apoprotein at 12 and 24 hours. The CYP2A5 mRNA levels in the liver increased after Cd treatment in Nrf2 +/+ but not in Nrf2 / mouse. This study demonstrates that hepatic haem oxygenase and CYP2A5 are upregulated by cadmium. The upregulation of haem oxygenase precedes that of CYP2A5. The strong upregulation of the CYP2A5 both at mRNA and enzyme activity levels, with a simultaneous decrease in the total CYP concentration suggest an unusual mode of regulation of CYP2A5 in response to cadmium exposure, amongst the CYP enzymes. The observed increase in the mRNA but not in protein levels after maximal induction may suggest involvement of post-transcriptional mechanisms in the regulation. Upregulation of CYP2A5 by cadmium in the Nrf2 +/+ mice but not in the Nrf2 / mice indicates a role for this transcription factor in the regulation.

Photodynamic therapy with aluminum-chloro-phtalocyanine induces necrosis and vascular damage in mice tongue tumors

In this paper we describe the efficacy of the liposomal-AlClPc (aluminum-chloro-phthalocyanine) formulation in PDT study against Ehrlich tumor cells proliferation in immunocompetent swiss mice tongue. Experiments were conduced in sixteen tumor induced mice that were divided in three control groups: (1) tumor without treatment; (2) tumor with 100 J/cm(2) laser (670 nm) irradiation; and (3) tumor with AlClPc peritumoral injection; and a PDT experimental group when tumors received AlClPc injection followed by tumor irradiation. Control groups present similar macroscopically and histological patterns after treatments, while PDT treatment induced 90% of Ehrlich tumor necrosis after 24 h of one single showing the efficacy of liposome-AlClPc (aluminum-chloro-phthalocyanine) mediated PDT application, on the treatment of oral cancer. (C) 2008 Elsevier B.V. All rights reserved.

Presence of the metabolic syndrome is associated with reduced adiponectin levels and liver dysfunction in patients with type 2 diabetes

No abstract.

Effect of the immunosuppressants on hepatocyte proliferation and apoptosis in a young animal model of liver regeneration: An immunohistochemical study using tissue microarrays

Hepatocyte proliferation and apoptosis (programmed cell death) occur during the liver parenchyma regeneration and the liver size modeling is mainly controlled by hepatocyte apoptosis. The purpose of the present study was to verify the influence of immunosuppressant drugs on these phenomena by utilizing tissue microarray techniques. Thirty-six weaning rats (age 21-23 days, weight 30-50 g) were divided into six groups: control, sham, hepatectomy, hepatectomy plus solumedrol, hepatectomy plus CsA, and hepatectomy plus Tac. The animals were killed one day after hepatectomy, and the remnant livers were weighed and harvested for tissue microarray sections. Liver cell proliferation was evaluated by staining for PCNA and apoptosis was detected by the TUNEL method. It was verified that CsA promoted a decrease in the liver weight, Tac and CsA decreased the proliferation index of hepatocytes, and glucocorticoid had no significant effects. The apoptosis index was not altered by hepatectomy or immunosuppressants. Our data indicate that, in the growing rat, CsA and Tac have negative effects on hepatocyte proliferation and have no effect on the hepatocyte apoptosis.

Expression of the iron regulatory peptide hepcidin is reduced in patients with chronic liver disease

Disturbances in iron metabolism often accompany liver disease in humans and hepatic iron deposition is a frequent finding. Since the peptide hepcidin, a major regulator of body iron homeostasis, is synthesised in the liver, alterations in hepcidin expression could be responsible for these effects. To investigate this possibility, we studied hepcidin expression in liver biopsies from patients with hepatitis C virus (HCV) infection, non-alcoholic fatty liver disease (NAFLD) and hemochromatosis (HC). Total RNA was extracted from the liver tissue of 24 HCV, 17 NASH and 5 HC patients, and 17 liver transplant donors (controls). The levels of mRNA for hepcidin and several other molecules involved in iron metabolism (DMT1, Dcytb, hephaestin, ferroportin, TfR1, TfR2, HFE and HJV) were examined by ribonuclease protection assay and expressed relative to the housekeeping gene GAPDH. The expression of hepcidin was significantly decreased in HCV and NASH patients relative to control liver (109±16 and 200±44 versus 325±26 respectively; P=0.008 and 0.02). We have previously reported similar findings in patients with HC, and this was confirmed in the current analysis (176±21; P=0.003). In both HCV and NAFLD patients the expression of the iron reductase Dcytb and the transferrin binding regulatory molecule TfR2 was also decreased, while the cellular iron exporter ferroportin showed a significant increase. Levels of the mRNA for the iron oxidase hephaestin were lower in HCV patients alone, while expression of the major transferrin binding molecule TfR1 was decreased only in NAFLD patients. Of particular interest was the finding that the expression of HJV (which is mutated in patients with juvenile HC) was significantly increased in NAFLD patients. No changes were seen in the expression of the iron importer DMT1 or the regulatory molecule HFE. Decreased expression of hepcidin in patients with HCV and NAFLD provides an explanation why iron homeostasis could be perturbed in these disorders. Reduced hepcidin levels would increase intestinal iron absorption and iron release from macrophages, which could contribute to hepatic iron accumulation. This in turn could lead to alterations in the expression of various proteins involved in iron transport and its regulation. Indeed most of the changes in the expression of such molecules observed in this study are consistent with this. However, the mechanisms leading to changes in the expression of hepcidin in these diseases remain to be elucidated.

Bradycardia in the Early Postoperative Period of Liver Transplantation in Children

The aim of this investigation was to describe the occurrence of bradycardia during the early postoperative period of liver transplantation in children. We retrospectively analyzed a cohort of 79 children with end-stage liver diseases who underwent liver transplantation. All children experienced >= 1 episode of a cardiac rate below the 2nd percentile of a 1-hour minimum duration, which was considered to be bradycardia. Patients <24 months were compared with older ones. The overall incidence of bradycardia was 37% (n = 31), including 25 patients who displayed bradycardia until postoperative day 3. In all cases, the electrocardiogram was normal, showing sinus rhythm. A comparison of the groups demonstrated an increased incidence of bradycardia among patients <24 months of age (P = .03). In all patients, there were no hemodynamic consequences; the cardiac rate returned to normal uneventfully. The explanations for bradycardia could not be applied to these patients because none of them had any volume change or electrolyte disturbances; liver function tests were not seriously altered. The mechanisms of this postoperative complications are unclear.