Diabetic peripheral neuropathy and prevalence of erectile dysfunction in Japanese patients aged <65 years with type 2 diabetes mellitus: The Dogo Study.

Only limited epidemiological evidence exists regarding the relationship between diabetic neuropathy and erectile dysfunction (ED) among Japanese patients with type 2 diabetes mellitus. To investigate the relationship between diabetic neuropathy and ED among Japanese patients with type 2 diabetes mellitus, a multicenter cross-sectional study was conducted in 287 male Japanese patients with type 2 diabetes mellitus, age (19-65 years). Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms, decreased or disappeared Achilles tendon reflex and/or abnormal vibration perception. ED, moderate to severe ED, and severe ED were defined as present when a subject had a Sexual Health Inventory for Men score <22, <12 and <8, respectively. The prevalence values of diabetic neuropathy and severe ED were 47.0 and 39.0%, respectively. Diabetic neuropathy was independently positively associated with severe ED, but not ED and moderate ED: the adjusted odds ratio was 1.90 (95% confidence interval: 1.08-3.38). No relationships were found between diabetic retinopathy or diabetic nephropathy and ED. Diabetic neuropathy is positively associated with severe erectile dysfunction among Japanese type 2 diabetes mellitus patients aged <65 years.

Depressive symptoms and prevalence of erectile dysfunction in Japanese patients with type 2 diabetes mellitus: the Dogo Study.

In several studies of patients with type 2 diabetes mellitus, a positive association between depressive symptoms and erectile dysfunction (ED) has been reported. No evidence exists, however, regarding the association between depressive symptoms and ED among Japanese patients with type 2 diabetes mellitus. Thus, we examined this issue among Japanese patients with type 2 diabetes mellitus. Study subjects were 469 male Japanese patients with type 2 diabetes mellitus, aged 19 years or over. ED, moderate to severe ED and severe ED were defined as present when a subject had a Sexual Health Inventory for Men score <22, <12 and <8, respectively. Depressive symptoms were defined as present when a subject had a Self-Rating Depression Scale (SDS) score >49. Adjustment was made for age, body mass index, waist, duration of type 2 diabetes, current smoking, current drinking, hypertension, dyslipidemia, coronary artery disease, stroke, glycated hemoglobin and diabetic neuropathy. The prevalence values of depressive symptoms, moderate to severe ED and severe ED were 15.1%, 64.2% and 51.0%, respectively. Depressive symptoms were independently positively associated with moderate to severe ED and severe ED (adjusted odds ratios were 2.23 (95% confidence interval (CI): 1.17-4.43) and 1.86 (95% CI: 1.04-3.41), respectively). In Japanese patients with type 2 diabetes mellitus, depressive symptoms may be associated with ED.

An unusual case of subclinical diffuse glucagonoma coexisting with two nodules in the pancreas: characteristic features on computed tomography.

A lesion was discovered in the tail of the pancreas by ultrasonography performed during a health checkup for a 59-year-old Japanese man. Abdominal contrast-enhanced computed tomography (CE-CT) revealed strong enhancement in a 4-cm tumor in the pancreatic tail and in a 1-cm tumor in the pancreatic body. Serum glucagon levels were elevated to 54,405 pg/mL and a preoperative diagnosis of glucagonoma was made. The pancreatic tail and spleen were resected en bloc, along with a protruding tumor in the pancreatic body. However, histopathological evaluation revealed diffuse glucagonoma throughout the pancreas. When we retrospectively reviewed abdominal CE-CT after the operation, the entire pancreas was seen to be enlarged and diffusely enhanced by strong spots. Immunohistochemical examination using anti-CD31 demonstrated rich microvessels in two solid glucagonomas as well as microglucagonoma throughout the entire pancreas, indicating hypervascularity. Enlarged pancreas and diffuse enhancement of the pancreas by strong spots may be characteristic features of diffuse glucagonoma on abdominal CE-CT.

Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus.

The immunosuppressive state of tumour-bearing hosts is attributable, at least in part, to myeloid-derived suppressor cells (MDSC). However, the role of MDSC in physiological conditions and diseases other than cancer has not been addressed. As the liver is a tolerogenic organ, the present study attempted to localize and assess functions of hepatic MDSC in a normal liver and in a murine model of chronic hepatitis B virus (HBV) infection. MDSC was identified in the liver of normal mice and HBV transgenic mice (TM) as CD11b(+) Gr1(+) cells by dual-colour flow cytometry. Highly purified populations of MDSC and their subtypes were isolated by fluorescence-activated cell sorting. The functions of MDSC and their subtypes were evaluated in allogenic mixed lymphocyte reaction (MLR) and hepatitis B surface antigen (HBsAg)-specific T cell proliferation assays. Normal mice-derived liver MDSC, but not other myeloid cells (CD11b(+) Gr1(-) ), suppressed T cell proliferation in allogenic MLR in a dose-dependent manner. Alteration of T cell antigens and impaired interferon-γ production seems to be related to MDSC-induced immunosuppression. In HBV TM, the frequencies of liver MDSC were about twice those of normal mice liver (13·6±3·2% versus 6·05±1·21%, n=5, P<0·05). Liver-derived MDSC from HBV TM also suppressed proliferative capacities of allogenic T cells and HBsAg-specific lymphocytes. Liver MDSC may have a critical role in maintaining homeostasis during physiological conditions. As liver MDSC had immunosuppressive functions in HBV TM, they may be a target of immune therapy in chronic HBV infection.

Mechanism of restoration of immune responses of patients with chronic hepatitis B during lamivudine therapy: increased antigen processing and presentation by dendritic cells.

Restoration of host immunity has been reported in patients with chronic hepatitis B (CHB) after treatment with lamivudine; however, the underlying mechanisms of this treatment have not been determined. This study examined the role of antigen-presenting dendritic cells (DC) in restoration of host immunity. Circulating DC were isolated from peripheral blood of 23 patients with CHB before and 1, 3, and 12 months after starting lamivudine therapy. The non-antigen-specific proliferation of DC was assessed in allogenic mixed leucocyte reaction. Dendritic cells were cultured with hepatitis B surface antigen (HBsAg) to prepare HBsAg-pulsed DC. Proliferative capacity and production of interleukin (IL)-12 and interferon (IFN)-γ of HBsAg-pulsed DC were evaluated. Circulating unpulsed DC and HBsAg-pulsed DC showed significantly higher levels of T-cell proliferation capacities 1 month after lamivudine therapy compared to proliferation levels before therapy (P<0.05). HBsAg-pulsed DC also produced significantly higher levels of IL-12 and IFN-γ with lamivudine therapy compared to levels before therapy (P<0.05). HBsAg-pulsed DC from lamivudine-treated patients induced proliferation of T cells of patients with CHB in an antigen-specific manner (P<0.05). However, T-cell stimulatory capacity of DC did not increase significantly 3 and 12 months after lamivudine therapy compared to 1 month after lamivudine therapy. Immune restoration as a result of lamivudine therapy is regulated at least in part by activation of DC. However, progressive activation of DC was not seen as treatment duration progressed, indicating the limitations of this mechanism of viral clearance.

Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B.

The immune modulator capacity of antigen-pulsed dendritic cells (DC) has been documented in patients with cancers and in animal models of chronic viral infections. Cancer antigen-pulsed DC are now used for treating patients with cancer. But viral antigen-pulsed DC are not used in chronic viral-infected patients because safety of antigen-pulsed DC has not been evaluated in these patients. DC were isolated from human peripheral blood mononuclear cells by culturing with human-grade granulocyte-macrophage colony stimulating factor and interleukin-4. Human blood DC were cultured with hepatitis B surface antigen (HBsAg) for 8h to prepare HBsAg-pulsed DC. After immunogenicity assessment of HBsAg-pulsed DC in vitro, five million HBsAg-pulsed DC were administered intradermally to five patients with chronic hepatitis B (CHB) 1-3 times. HBsAg-pulsed DC were immunogenic in nature because they produced significantly higher levels of interleukin-12 and interferon-γ compared to unpulsed DC (P<0.05). Also, HBsAg-pulsed DC induced proliferation of HBsAg-specific T lymphocytes in vitro. CHB patients injected with HBsAg-pulsed DC did not exhibit generalized inflammation, exacerbation of liver damage, abnormal kidney function, or features of autoimmunity. Administration of HBsAg-pulsed DC induced anti-HBs in two patients and HBsAg-specific cellular immunity in 1 patient. This is the first study about preparation of antigen-pulsed DC using human consumable materials for treating patients with CHB. Because HBsAg-pulsed DC were safe for all patients with CHB and had immune modulation capacity in some patients, phase I and phase II clinical trials with antigen-pulsed DC in CHB and other chronic infections are warranted.

Impaired dendritic cell functions because of depletion of natural killer cells disrupt antigen-specific immune responses in mice: restoration of adaptive immunity in natural killer-depleted mice by antigen-pulsed dendritic cell.

The primary aim of this study was to evaluate the role of natural killer (NK) cells on antigen-specific adaptive immune responses. After analysing the mechanism of impaired adaptive immune responses of NK-depleted mice, an immune interventional approach was developed to restore adaptive immunity in NK-depleted mice. NK cells were depleted from mice by administration of anti-asialo GM1 antibody (100 mul/mouse), twice, at an interval of 48 h. Hepatitis B surface antigen (HBsAg) was administered intraperitoneally to normal C57BL/6 mice (control mice) and NK-depleted mice. The levels of antibody to HBsAg (anti-HBs) in the sera and HBsAg-specific lymphocytes in the spleen were assessed. The functions of T lymphocytes, B lymphocytes and dendritic cells (DCs) were evaluated in vitro. HBsAg-pulsed DCs were prepared by culturing spleen DCs with HBsAg for 48 h and administered once to NK-depleted mice. The levels of anti-HBs in the sera and HBsAg-specific lymphocytes were significantly lower in NK-depleted mice compared with control mice (P < 0.05). The functions of T and B lymphocytes were similar between control mice and NK-depleted mice. However, the functions of spleen DC and liver DC were significantly lower in NK-depleted mice compared with control mice (P < 0.05). Administration of HBsAg-pulsed DCs, but not HBsAg, induced HBsAg-specific humoral and cellular immune responses in NK-depleted mice. Our study suggests that cross-talk between NK cells and DCs regulates the magnitude of adaptive immunity. In addition, antigen-pulsed immunogenic DCs represent potent immune modulator even if subjects with diminished innate immunity.

Impaired functional capacities of liver dendritic cells from murine hepatitis B virus (HBV) carriers: relevance to low HBV-specific immune responses.

The chronic hepatitis B virus (HBV) carrier exhibits ongoing replication of HBV and expresses abundant amounts of HBV-related antigens in the liver. However, HBV-specific immune responses are either absent or narrowly focused in these subjects. With the postulation that impaired functional abilities of liver dendritic cells (DCs) might be responsible for this, we assessed the functions of liver DCs in HBV transgenic mice (HBV-TM), an animal model of the HBV carrier state. Liver DCs were isolated from normal C57BL/6 mice and HBV-TM without the use of cytokines or growth factors. Lymphoproliferative assays were conducted to evaluate the ability of liver DCs to induce the proliferation of allogenic T lymphocytes and hepatitis B surface antigen (HBsAg)-enriched T lymphocytes. Liver DCs were stimulated with viral and bacterial products to assess their cytokine-producing capacities. In comparison to liver DCs from normal C57BL/6 mice, liver DCs from HBV-TM exhibited significantly decreased T cell proliferation-inducing capacities in allogenic mixed leucocyte reaction (P <0.05) and HBsAg-enriched T lymphocytes proliferation assays (P <0.05). Liver DCs from HBV-TM produced significantly lower levels of interleukin-12p70, tumour necrosis factor-alpha, interferon-gamma, and interleukin-6 (P <0.05) compared to liver DCs from normal C57BL/6 mice. This study provides evidence that liver DCs from HBV-TM had impaired ability to induce both innate and adaptive immune responses. This might account for a weak and almost undetectable HBV-specific immune response in chronic HBV carriers. This inspires hope that up-regulation of the functions of liver DCs in situ may have therapeutic implications in chronic HBV carriers.

Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C.

Patients with chronic hepatitis C (CHC) are unable to prime and maintain vigorous T cell responses that are initiated during the acute phase of hepatitis C virus (HCV) infection. As dendritic cells (DCs) induce and regulate both innate and adaptive immune responses, the aim of this study was to analyse two critical functions of DCs: firstly, production of interferon (IFN)-alpha and, secondly, polarization of T helper 1 lymphocytes. The frequencies of plasmacytoid DC (PDC) and myeloid DC (MDC) were estimated in 63 patients with CHC and 34 normal controls using four-colour flow cytometry. Circulating DCs were isolated from peripheral blood of CHC patients (n = 10) and normal controls (n = 10). These DCs were cultured with herpes simplex virus-1 to evaluate their capacity to produce IFN-alpha. The capacity of DCs to induce polarization of autologous naive CD4(+) T lymphocytes to IFN-gamma-producing effector T lymphocytes was also assessed. The frequencies of PDCs producing intracellular IFN-alpha (P < 0.01) and the levels of IFN-alpha in culture supernatant of PDCs (P < 0.01) were significantly lower in patients with CHC compared to those of normal controls. The numbers of MDC were significantly lower in patients with CHC (8.2 (6.0)/ micro l, median (interquartile range), n = 63) compared to normal control (11.7 (7.8)/ micro l, n = 34) (P < 0.01). Moreover, DCs from patients with CHC induced significantly lower numbers of IFN-gamma-producing effector T lymphocytes compared to that of controls (P < 0.01). This study indicates that the low IFN-alpha-producing capacity and impaired T helper 1 polarization ability of DCs from patients with CHC might be responsible for the typical low anti-HCV immune responses in these patients.

Isolation and functional analysis of circulating dendritic cells from hepatitis C virus (HCV) RNA-positive and HCV RNA-negative patients with chronic hepatitis C: role of antiviral therapy.

Hepatitis C virus (HCV) RNA has been localized in antigen-presenting dendritic cells (DCs) from patients with chronic hepatitis C (CHC). DCs from patients with CHC also exhibit impaired functional capacities. However, HCV RNA in DCs and functional impairment of DCs in CHC might be independent or interrelated events. Moreover, the impact of antiviral therapy on the functions of DCs in CHC is not well documented. In order to address these issues, we took advantage of antiviral therapy in these patients. Ten patients with CHC, expressing HCV RNA in circulating DCs, became negative for HCV RNA in circulating DCs after therapy with interferon-alpha and ribavirin for 4 weeks. The functions of DCs from HCV RNA+ patients (isolated before antiviral therapy) and HCV RNA- patients (isolated 4 weeks after antiviral therapy) were compared in allogenic mixed leucocyte reactions. In comparison to circulating DCs from normal control subjects, DCs from HCV RNA+ patients had a significantly decreased capacity to stimulate allogenic T lymphocytes (P < 0.01) and produce interleukin-12 (P < 0.05). However, the allostimulatory capacity of circulating DCs from HCV RNA- patients was several-fold higher compared to that of HCV RNA+ DCs from the same patient. DC from HCV RNA- patients also produced significantly higher levels of interleukin-12 compared to HCV RNA+ DCs from the same patient (P < 0.01). Taken together, this study is the first to provide experimental evidence regarding the impact of HCV RNA and antiviral therapy on the function of DCs in patients with CHC.

A novel and effective approach of developing aggressive experimental autoimmune gastritis in neonatal thymectomized BALB/c mouse by polyinosinic:polycytidylic acid.

Neonatal thymectomy induces autoimmune gastritis (AIG) in 40-70% of BALB/c mice. We presumed that induction of autoimmunity by polyinosinic:polycytidylic acid (poly I:C) might allow development of a more aggressive model of AIG. A group of BALB/c mice were thymectomized on day 3 after birth. Neonatal thymectomized mice were either injected with poly I:C or phosphate-buffered saline (PBS). Non thymectomized neonatal BALB/c mice were injected with only poly I:C. All neonatal thymectomized mice injected with poly I:C developed 3 cardinal features of AIG: (1) moderate to severe degree gastritis (2) presence of autoantibody to H(+)/K(+) ATPase and (3) loss of parietal cells. However, only 70% of the PBS-treated neonatal thymectomized BALB/c mice developed some, but not, all features of AIG. A mild degree of AIG was seen in 12 of 31 nonthymectomized BALB/c mice administered with only poly I:C. Administration of poly I:C in neonatal thymectomized BALB/c mice in the first and second week appeared to be the most effective for induction of aggressive AIG. The levels of interleukin (IL)-6, IL-12p70, interferon-gamma and tumour necrosis factor-alpha were significantly higher in poly I:C-injected thymectomized mice compared to PBS-injected neonatal thymectomized mice (P < 0.05). The frequencies of CD4(+)CD25(+) regulatory T cells in the spleen were significantly decreased in neonatal thymectomized mice administered with poly I:C compared to PBS-treated neonatal thymectomized mice (P < 0.01). Taken together, these results suggest that induction of inflammatory cytokines and reduction of regulatory T cells by poly I:C might contribute to the development of an aggressive model of AIG in neonatal thymectomized BALB/c mice.

Primary carcinoid tumor of the liver: report of two cases with an emphasis on US findings.

Primary carcinoid tumor of the liver is rare, and its sonographic (US) findings have rarely been reported. We present two histologically proven cases. Both patients were asymptomatic and huge masses, found incidentally by US, were echogenic with many cystic areas. Lesions were markedly hypervascular on color Doppler US and angiography. Thus, primary carcinoid tumor of the liver should be considered when US detects this type of mass in asymptomatic patients.

Macrophage migration inhibitory factor activates antigen-presenting dendritic cells and induces inflammatory cytokines in ulcerative colitis.

The level of macrophage migration inhibitory factor (MIF) and the functions of dendritic cells (DC) are up-regulated in the peripheral blood, and the numbers of MIF-expressing cells and mature DC are increased at the colonic mucosa from patients with ulcerative colitis (UC). However, a functional relationship between MIF and DC, and the role of MIF in the pathogenesis of UC, are not clear. In this study, we showed that a pure population of peripheral blood DC is a new and still unknown source of MIF. DC from UC patients produced significantly higher levels of MIF (17 x 5 +/- 9 x 8 ng/ml, n = 10) compared with patients with Crohns disease (CD) (4 x 6 +/- 2 x 5 ng/ml, n = 5, P< 0 x 01) and control subjects (5 x 0 +/- 2 x 6 ng/ml, n = 10, P< 0 x 01). A double immunofluorescence study revealed the expression of MIF by CD83-positive mature DC at the colonic mucosa from UC patients. Blood DC treated with high amounts of MIF (500 ng/ml) showed a significantly higher stimulatory capacity (43287 +/- 5998 CPM, n = 5) in an allogenic mixed leucocyte reaction compared with untreated DC (27528 +/- 8823 CPM, n = 5, P< 0 x 05). Study of intracellular cytokine expression showed that MIF induced significant levels of interleukin (IL)-1 and IL-8 in monocytes and DC from UC and CD patients. These results showing the capacity of MIF to induce increased functional capacity of DC, and to produce IL-1 and IL-8 from monocytes and DC, indicate a role of MIF in the induction and/or perpetuation of the inflammatory environment in UC.

Changes in gastrointestinal lymph and blood vessels in patients with cirrhotic portal hypertension.

BACKGROUND: The aim of this study was to characterize the lymph vessels in different parts of the gastrointestinal tract and also to evaluate morphometric changes in these vessels during cirrhotic portal hypertension. METHODS: Sixteen patients with cirrhotic portal hypertension and 18 control subjects without portal hypertension were enrolled in the study. Tissue specimens were collected at autopsy or surgery, and were stained enzyme histochemically, using 5'-nucleotidase and alkaline phosphatase to distinguish lymph vessels and blood vessels, respectively. The numbers of vessels and their luminal areas were estimated using computer graphics software (National Institutes of Health [NIH] image program). RESULTS: The numbers and luminal areas of the lymph vessels varied considerably among the different organs of the gastrointestinal tract, both in controls and in the patients with cirrhotic portal hypertension. There was no significant difference in the numbers of lymph vessels between controls and patients with cirrhotic portal hypertension. However, the luminal area of the lymph vessels in the esophagus and stomach was significantly greater in the patients with cirrhotic portal hypertension than in the controls. These differences in lymph vessels were not seen in the small intestine and colon. CONCLUSIONS: These data indicate that dilatation of lymph vessels may be related to the absorption of excess interstitial fluid, resulting from congestion, in cirrhotic portal hypertension.

Antigen-presenting cells at the liver tissue in patients with chronic viral liver diseases: CD83-positive mature dendritic cells at the vicinity of focal and confluent necrosis.

Although defective functions of peripheral blood or splenic antigen-presenting cells (APCs) are implicated in the pathogenesis of persistent infection in murine and human hepatitis B virus (HBV) and hepatitis C virus (HCV)-carriers, little is known regarding liver-infiltrating APCs in patients with chronic liver diseases. Using immunohistochemical methodology and antigen retrieval technique, we have detected APCs such as HLA DR-positive cells, interdigitating cells (IDCs) and CD83-positive mature and activated dendritic cells (DCs) at the liver specimens from 39 patients with chronic hepatitis (CH) and 10 patients with liver cirrhosis (LC). All 3 types of APCs were detected at the portal areas in both CH and LC, the most abundant being the HLA DR-positive APCs. CD83-positive, mature and activated DCs were detected in patients with CH around the areas of focal and confluent necrosis at the liver parenchyma in close association with T cells. The localization of CD83-positive mature and activated DCs at the liver tissues from patients with CH warrants further study about the role of these DCs in the induction of hepatocellular damage. This may also help to design DC-based therapy for patients with chronic liver diseases.

Glucagon attenuates the action of insulin on glucose output in the liver of the Goto-Kakizaki rat perfused in situ.

The effects of glucagon and insulin on glucose production were explored directly using the isolated perfused liver of the Goto-Kakizaki (GK) rat, an animal model of type-2 diabetes. In the perfused liver of control rats, infusion of glucagon (0.06-1.0 nM) into the portal vein dose-dependently increased glucose output. In the GK rat liver, in which the intracellular distribution of glycogen was heterogeneous, basal glucose output during perfusion was significantly higher than in control, whereas the effect of glucagon on the maximum glucose output was not different. Infusion of insulin inhibited the glucagon-induced hepatic glucose output by 30-40% in control livers, but had no effect on that from the GK rat liver. The increase in hepatic cAMP content after glucagon infusion was antagonized by insulin in control livers, but not in the livers of GK rats. These results indicate that the antagonistic effect of insulin on glucagon-induced hepatic glucose production was attenuated in the isolated liver of the GK rat and suggest that this insulin resistance appeared in the signal transduction process of glucagon upstream from cAMP production.

Apoptosis of rat gastric mucosa and of primary cultures of gastric epithelial cells by indomethacin: role of inducible nitric oxide synthase and interleukin-8.

In order to gain insights into indomethacin-induced gastric injury, rats were fed with indomethacin (20 mg/kg), or alternatively, the primary cultures of rat gastric epithelial cells were cultured with different doses of indomethacin (1-1000 microM). Light microscopy, electron microscopy, fluorescence microscopy, TdT-mediated dUTP-biotin nick end labelling staining, ssDNA staining and DNA fragmentation assay were employed to evaluate the levels of gastric injury and apoptosis. Cells expressing inducible nitric oxide synthase (iNOS) and interleukin (IL)-8 were localized at the rat gastric mucosa by immunohistochemistry. Administration of indomethacin to rats caused apoptosis and injury of the gastric mucosal epithelial cells. Indomethacin also induced apoptosis of primary cultures of gastric epithelial cells in a dose-dependent manner. Cells expressing iNOS and IL-8 were detected at and around the sites of gastric injury in the indomethacin-fed rats, but not in the control rats. The induction of apoptosis by indomethacin in the primary cultures of gastric epithelial cells suggests that the direct apoptotic capacity of indomethacin. iNOS and IL-8 may be involved in this process.

Macrophage migration inhibitory factor in hepatocellular carcinoma and liver cirrhosis; relevance to pathogenesis.

The levels of macrophage migration inhibitory factor (MIF), a proinflammatory and carcinogenic cytokine, were significantly higher in the sera from patients with hepatocellular carcinoma (HCC; 25.6+/-15.3 ng/ml, n=55) and liver cirrhosis (LC; 18.9+/-10.7 ng/ml, n=26) compared with sera from patients with gastrointestinal cancer (6.8+/-7.5 ng/ml, n=29) and normal controls (5.6+/-1.2 ng/ml, n=45; P<0.01). Hepatocytes from patients with LC and HCC, but not from chronic hepatitis, expressed very high levels of MIF. A possible association between overexpression of MIF and hepatocarcinogenesis is suggested.

Dendritic cells and chronic hepatitis virus carriers.

Many individuals infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) are unable to clear these viruses following an acute infection and become chronically infected. There are more than 400 million HBV and HCV carriers in the world and a considerable number of these patients would eventually develop more severe complications like liver cirrhosis and hepatocellular carcinoma. It is not clearly known how an individual develops a chronic hepatitis virus carrier state; however, a defective immune response of the host is thought to play a critical role in the underlying pathogenetic mechanism. On the other hand, dendritic cells (DCs), the most potent antigen-presenting cells, are widely distributed in both lymphoid and nonlymphoid tissues. Recognition of the microbes or microbial antigens by DCs is one of critical events for the initiation of an immune response. DCs also play a cardinal role during the progression and termination of an immune response. The aim of this overview is to provide information regarding the role of DCs in the pathogenesis of chronic hepatitis due to HBV and HCV in humans and in animal models of HBV and HCV carrier states. First, we summarize our current understanding of the pathogenesis of hepatitis virus carrier states and also of general properties of DCs. Next, we discuss the data on the phenotypes and functions of DCs in both human and murine HBV and HCV carriers. We also discuss vaccine therapy in murine HBV carriers because activation of DCs due to vaccination-initiated HBsAg-specific immune responses in HBV transgenic mice (HBV-Tg), which in turn resulted in complete clearance of hepatitis B surface antigen and hepatitis B e antigen and decreased levels of HBV DNA in some HBV-Tg. Finally, we discuss the extracted questions and future research directions.

Characterization of antigen-presenting dendritic cells in the peripheral blood and colonic mucosa of patients with ulcerative colitis.

OBJECTIVE: Increased lymphocyte activation and production of inflammatory cytokines are implicated in the pathogenesis of ulcerative colitis. Because antigen-presenting dendritic cells play a cardinal role in the activation and survival of activated lymphocytes, the aim of the present study was to characterize dendritic cells in ulcerative colitis. DESIGN: This study was designed to compare the phenotypes and functions of peripheral blood dendritic cells among healthy normal volunteers and patients with ulcerative colitis or Crohn's disease. Activated dendritic cells were also localized at the colonic mucosa. METHODS: Peripheral blood dendritic cells were generated from 15 patients with ulcerative colitis, 10 patients with Crohn's disease and 15 healthy control volunteers. The stimulatory capacities of dendritic cells were analysed in an allogenic mixed lymphocyte reaction. Nitric oxide was detected by the Griess method. Single- and dual-colour flow cytometry was employed to study the levels of maturation of dendritic cells. Activated dendritic cells were localized immunohistochemically in the colonic mucosa. RESULTS: In comparison to normal controls, peripheral blood dendritic cells from patients with ulcerative colitis showed significantly increased stimulatory capacities (P < 0.05) and produced significantly higher levels of nitric oxide (P < 0.05). The numbers of activated dendritic cells were also significantly higher in ulcerative colitis (P < 0.05). Mature and activated dendritic cells expressing the CD83 antigen were detected at the inflamed colonic mucosa in patients with ulcerative colitis and Crohn's disease. CONCLUSIONS: Activated and mature dendritic cells may have a role in the induction of an exacerbated immune response in ulcerative colitis. This study provides the scientific and logical basis for blocking the maturation and activation of dendritic cells in ulcerative colitis as a new therapeutic intervention.