Reversal of the Parallel Drift Frequency in Anomalous Transport of Impurity Ions.

It is found that, in the studies of heavy ion transport with gyrokinetic simulations, the ion parallel drift frequency can reverse sign in velocity space when the amplitude variation of the electrostatic potential fluctuation is strong along the magnetic field line. As a result, the particle transport related to the parallel dynamics is strongly enhanced. It is noted that, while parallel gradient of the fluctuation amplitude can be instigated by a large magnetic shear or safety factor in a tokamak, the generic mechanism is independent of its cause, which suggests broader applications to kinetic plasma problems. Some relevant topics are briefly addressed in the end.

Persistence of Ion Temperature Gradient Turbulent Transport at Finite Normalized Pressure.

Plasma ß dependence of electromagnetic turbulent transport is investigated by means of gyrokinetic simulations with self-consistent change of the equilibrium magnetic field. It is found that energy transport due to ion-temperature-gradient (ITG) driven turbulence does not decrease with increasing ß; that is, the ion energy diffusivity does not decrease, and the electron energy diffusivity increases with ß. This is because magnetic fluctuations are significantly influenced by the background magnetic field structure change with ß by the Pfirsch-Schluter current. The magnetic field change weakens the suppression effect of magnetic perturbations on the growth of the ITG mode, and it also suppresses nonlinear zonal flow production. The influence of the magnetic field change is significant as the global magnetic shear increases.

Suppression of Ion-Scale Microtearing Modes by Electron-Scale Turbulence via Cross-Scale Nonlinear Interactions in Tokamak Plasmas.

Gyrokinetic turbulence simulations are applied for the first time to the cross-scale interactions of microtearing modes (MTMs) and electron-temperature-gradient (ETG) modes. The investigation of the fluctuation response in a multiscale simulation including both types of instabilities indicates that MTMs are suppressed by ETG turbulence. A detailed analysis of nonlinear mode coupling reveals that radially localized current-sheet structures of MTMs are strongly distorted by fine-scale E×B flows of ETG turbulence. Consequently, electron heat transport caused by the magnetic flutter of MTMs is significantly reduced and ETG turbulence dominates electron heat transport.

Cross-Scale Interactions between Electron and Ion Scale Turbulence in a Tokamak Plasma.

Multiscale gyrokinetic turbulence simulations with the real ion-to-electron mass ratio and ß value are realized for the first time, where the ß value is given by the ratio of plasma pressure to magnetic pressure and characterizes electromagnetic effects on microinstabilities. Numerical analysis at both the electron scale and the ion scale is used to reveal the mechanism of their cross-scale interactions. Even with the real-mass scale separation, ion-scale turbulence eliminates electron-scale streamers and dominates heat transport, not only of ions but also of electrons. Suppression of electron-scale turbulence by ion-scale eddies, rather than by long-wavelength zonal flows, is also demonstrated by means of direct measurement of nonlinear mode-to-mode coupling. When the ion-scale modes are stabilized by finite-ß effects, the contribution of the electron-scale dynamics to the turbulent transport becomes non-negligible and turns out to enhance ion-scale turbulent transport. Damping of the ion-scale zonal flows by electron-scale turbulence is responsible for the enhancement of ion-scale transport.

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD).

BACKGROUND: Liver fibrosis is the main predictor of the progression of nonalcoholic fatty liver disease. Transient elastography (FibroScan), which measures liver stiffness, is a novel, noninvasive method to assess liver fibrosis. AIM: We investigated the usefulness of liver stiffness measurement in the evaluation of liver fibrosis in nonalcoholic fatty liver disease patients. STUDY POPULATION: A total of 97 nonalcoholic fatty liver disease patients. METHODS: Transient elastography was performed for liver stiffness measurement in 97 nonalcoholic fatty liver disease patients. And the relationship between histological parameters and liver stiffness measurement was studied by multivariate analysis. Moreover, we investigated the relationship between liver stiffness measurement and the serum levels of hyaluronic acid and type IV collagen 7s domain. RESULTS: The liver stiffness was well correlated with the stage of liver fibrosis (Kruskal-Wallis test p < 0.0001). The areas under the receiver-operating characteristic curves were 0.927 for > or = F1, 0.865 for > or = F2, 0.904 for > or = F3, 0.991 for > or = F4. Only fibrosis stage was correlated significantly with liver stiffness measurement by multiple regression analysis. Liver stiffness was also strongly correlated with the serum levels of type IV collagen 7s domain (r = 0.525, p < 0.0001) and hyaluronic acid (r = 0.457, p < 0.0001). CONCLUSIONS: Our results show a significant correlation between liver stiffness measurement and fibrosis stage in nonalcoholic fatty liver disease patients, as confirmed by the results of liver biopsy, which remains the gold standard for evaluation of the severity of liver fibrosis in patients with nonalcoholic steatohepatitis.

A clinicopathological study of acute hepatitis in heavy drinkers, unrelated to hepatitis A, B, or C viruses.

BACKGROUND: There are six histological classifications of alcoholic liver disease (ALD) in Japan. However, it is unclear whether all cases of the disease conform to these criteria. This study investigated the clinicopathological features of eight histologically unusual cases of ALD. METHODS: The characteristic features of alcohol drinking behavior, subjective and objective symptoms, laboratory data on admission, and progress after admission were analyzed for eight patients with acute-onset hepatitis. RESULT: The eight patients showed histologically acute hepatitis, with much spotty necrosis that contained granular ceroid pigment by Kupffer cells, which indicated acute parenchymal damage of the liver, but with no Mallory bodies and unremarkable intrasinusoidal neutrophilic infiltration. The only etiological factor for all the cases was habitual alcohol consumption, with increased consumption just before the onset of symptoms. In five cases that were tested, the patients were negative for hepatic viral markers, which included hepatitis G virus RNA and TT virus DNA. CONCLUSION: Some cases of ALD may not conform to the current histological classifications in either Japan or Western countries. It seems natural to consider that these cases are developed by other, unknown causes that overlap with ALD rather than as a result of damage from alcoholic overload.

Mechanisms of alcoholic liver disease: cytokines.

This article represents the proceedings of a workshop at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Manuela G. Neuman. The presentations were (1) New aspects of hepatic fibrosis, by D. A. Brenner; (2) Cellular immune response in hepatitis C models, by B. Rehermann; (3) The role of interleukin-10 in acute alcoholic hepatitis, by J. Taieb, S. Chollet-Martin, M. Cohard, J. J. Garaud, and T. Poynard; (4) Cytokine-mediated apoptosis in vitro, by M. G. Neuman; (5) Signaling for apoptosis and repair in vitro, by G. G. Katz, R. G. Cameron, N. H. Shear, and M. G. Neuman; (6) Interferons activate the P42/44 mitogen-activated protein kinase and Janus Kinase signal transducers and activation of transcription (JAK-STAT) signaling pathways in hepatocytes: Differential regulation by acute ethanol via a protein kinase C-dependent mechanism, by B. Gao; (7) Genetic polymorphisms of interleukin-1 in association with the development of Japanese alcoholic liver disease, by M. Takamatsu, M. Yamauchi, M. Ohata, S. Saito, S. Maeyama, T. Uchikoshi, and G. Toda; and (8) Increased levels of macrophage migration inhibitory factor in sera from patients with alcoholic liver diseases, by T. Kumagi, S. M. F. Akbar, M. Abe, K. Michitaka, N. Horiike, and M. Onji.

Congenital hepatic fibrosis with fatal cholestatic liver damage.

A 23-year-old male with congenital hepatic fibrosis died because of progressive cholestatic liver damage. Pathologically, marked extension of fine fibers along the sinusoids in addition to fibrosis in Glisson's sheath, miniaturization and pseudo-glandular formation of hepatocytes as parenchymal damage, and nodular regenerative hyperplasia were considered as the cause of rapid aggravation of liver damage or portal hypertension.

Hepatic veno-occlusive lesions and other histopathological changes of the liver in severe alcoholic hepatitis--a comparative clinicohistopathological study of autopsy cases.

BACKGROUND: The clinicopathological features of veno-occlusive lesions (VOL) in the liver were studied in 18 autopsy cases of severe alcoholic hepatitis (sALH). All the cases were heavy drinkers and died of liver failure or variceal rupture. METHODS: We performed histological evaluation by examining stained sections of liver blocks from each case. The severity of VOL was compared with the clinical findings and histopathological changes of alcoholic liver diseases (ALD). RESULTS: Clinically, as the severity of VOL increased, the amount of ascites observed during autopsy increased significantly (p = 0.001) and the time from hospitalization to death was significantly longer (p < 0.05). The peripheral leukocyte count tended to increase and the serum bilirubin level increased significantly (p < 0.05) with increased VOL severity, after we excluded one case that was complicated by acute respiratory distress syndrome and bacterial endocarditis. Histopathologically, the appearance of Mallory bodies increased significantly as VOL became more severe (p < 0.05), but the VOL severity did not correlate with sinusoidal neutrophil infiltration. Fatty degeneration tended to be milder as VOL increased in severity although the difference was not significant, whereas bile retention tended to be more marked. CONCLUSIONS: We conclude that investigation of VOL is clinicopathologically important when assessing the pathophysiology and severity of sALH.

Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients.

OBJECTIVE: Cytokine interleukin-1beta plays a central role in the inflammation process. Serum levels of IL-1beta are elevated in patients with alcoholic liver disease (ALD), especially in those with cirrhosis and alcoholic hepatitis. Recently, the presence of genetic polymorphisms of this cytokine was confirmed. The aim of this study was to determine whether IL-1beta polymorphisms are associated with the development of ALD. METHODS: We examined the frequency of two polymorphisms in the IL-1beta gene located in promoter -511 and exon 5 +3953 locus by restriction fragment length polymorphisms in 142 male patients with ALD, 30 heavy drinkers without ALD, and 218 healthy controls. RESULTS: The carriers of -511 IL-1beta allele 2 were present significantly more often in patients with alcoholic cirrhosis than in those with noncirrhotic ALD (p = 0.026), heavy drinkers without ALD (p = 0.001), and healthy controls (p = 0.032). The frequencies of allele 2 and heterozygotes of +3953 polymorphism were both significantly higher in heavy drinkers without ALD than in patients with ALD (allele, p = 0.030; genotype, p = 0.027) and healthy controls (allele, p = 0.047; genotype, p = 0.043). The haplotype, IL-1beta -511 allele 2/+3953 allele 1 was associated with the development of alcoholic cirrhosis (p < 0.05). CONCLUSIONS: These results suggest that IL-1beta polymorphisms may be related to the development of ALD in Japanese alcoholics.

[Disappearance of Mallory bodies in the liver of autopsy cases with a history of heavy drinking].

Mallory bodies, the intra-cytoplasmic inclusions in hepatocytes, are thought to be a pathognomonic feature of alcoholic liver disease, particularly of alcoholic hepatitis. The presence of Mallory bodies is considered as a reflection of serious illness in alcoholic liver disease. Mallory bodies are thought to disappear relatively rapidly with the use of therapeutic agents after giving up alcohol drinking. However, histological vicissitudes of Mallory bodies have not been studied extensively. In the present study, 19 autopsied cases with a history of heavy drinking were clinicopathologically evaluated. All patients were admitted to our hospital, and stopped alcohol drinking. These period of non-drinking ranged from one day to 150 days (group A: 1-7 days, group B: 8-30 days, group C: 31-150 days). Histological evaluation was performed by hematoxylin and eosin staining, Luxol Fast blue staining and chromotrope aniline blue staining of formalin-fixed paraffin-embedded liver sections. Hepatocytes including Mallory bodies were counted. The incidence of Mallory body formation was as follows: Group A (50%), group B (100%), and group C (100%) respectively. Average count of Mallory bodies: Group A (12.3/10 fields), group B (141.4/10 fields), and group C (188.3/10 fields). Fatty change was more significant in group A than in group B or C, and bile stasis was more significant in group B or C than in group A. These findings suggest that Mallory bodies may remain for several months after giving up drinking.

Hepatic veno-occlusive lesions in severe alcoholic hepatitis and alcoholic liver cirrhosis: a comparative histopathological study in autopsy cases.

Clinicopathological features of veno-occlusive lesions in hepatic veins were studied in autopsy cases of severe alcoholic hepatitis (15 cases) and alcoholic liver cirrhosis (15 cases). All the cases were heavy drinkers and died of liver failure or variceal rupture. The frequency and degree of veno-occlusive lesions, and the diameter and number of hepatic veins were studied from stained sections of liver blocks from each case. The hepatic veins observed ranged from 60 to 3000 microm in diameter. The veno-occlusive lesions were found in hepatic veins mainly 60 to 1200 microm in diameter. These findings were recognized in the majority of severe alcoholic hepatitis cases and alcoholic liver cirrhosis cases. Furthermore, more severe veno-occlusive lesions were noted in severe alcoholic hepatitis, compared with alcoholic liver cirrhosis. In the cases with obstruction in hepatic veins of >400 microm, a decrease in the number of hepatic veins and zonal necrosis were noted. In addition, some of the veno-occlusive lesions were recognized focally in the same cases. Clinical findings also indicated that ascites increased with the progression of the veno-occlusive lesions. We conclude that investigation of veno-occlusive lesions in severe alcoholic liver disease has clinicopathological significance.

Increased serum levels and sinusoidal expression of thrombomodulin in acute liver damage.

Thrombomodulin (TM) is a surface glycoprotein of endothelial cells involved in both anticoagulation and antifibrinolysis. In this study, we assessed the clinical significance of TM in acute liver damage by using a rat model induced by intraperitoneal injection of D-galactosamine (Gal-N). Serum TM levels were measured with enzyme immunoassay utilizing rabbit anti-rat TM antibody. Simultaneously, immunohistochemical examination was performed using the same antibody. Serum TM levels increased significantly after the injection of Gal-N compared with preinjection levels, peaking from 48 to 72 hours after injection and normalizing by 168 hours. Changes in parenchymal damage were synchronized with changes of TM, and changes of TM levels mirrored changes of liver weight. In immunohistochemical examination, TM immunoreactivity was observed only on the endothelial surfaces of both the artery and portal vein within Glisson's sheath in controls. After injection of Gal-N, TM immunoreactivity was gradually intensified, especially around the necrotic area and the central veins. These findings disappeared with improvement of parenchymal damage. Both the increase of serum TM levels and intensified TM immunoreactivity in the liver were synchronized with acute liver parenchymal damage induced by Gal-N. These findings on TM are related to endothelial damage with parenchymal necrosis and liver regeneration interacting with both homeostasis of microcirculation and healing of parenchymal damage.

Recent performance of the Photon Factory gratingcrystal monochromator station BL-1A in the soft X-ray region.

This paper describes the recent performance of the Photon Factory beamline 1A with InSb(111) crystals used as the diffracting elements of the grating/crystal monochromator for monochromatizing soft X-rays. Pt-coated collimating and focusing mirrors located upstream and downstream of the monochromator have recently been replaced with Ni-coated mirrors in order to remove absorption structures at the Pt M-edges from output spectra in the soft X-ray region. Output spectra without the absorption structures and with higher intensity in the range 2000-3400 eV were obtained by using the Ni-coated collimating and focusing mirrors.

An ultrahigh-vacuum goniometer for in situ soft X-ray standing-wave analysis of semiconductor surfaces.

An ultrahigh-vacuum goniometer was developed for in situ X-ray standing-wave (XSW) analysis of semiconductor surfaces prepared by molecular-beam epitaxy (MBE). Although two ultrahigh-vacuum motors for chi and phi rotating axes are inside the analysis chamber, low-energy photoelectrons can still be collected as the magnetic field is sufficiently suppressed by using metal shields. Furthermore, the sample can be annealed at temperatures higher than 870 K on the goniometer in the analysis chamber. This goniometer is used at beamline 1A (BL-1A) at the Photon Factory, where both monochromated soft X-rays and UV radiation are available. This analysis system was shown to be suitable not only for in situ soft-XSW and X-ray absorption near-edge structure (XANES) studies but also for synchrotron radiation photoelectron spectroscopy (SRPES) studies. The annealing effects on an S-adsorbed GaAs(001) surface could be studied by SRPES, XANES and XSW using this new goniometer.

Indication of chemoembolization therapy without gelatin sponge for hepatocellular carcinoma.

This study evaluated the effect of chemoembolization (C-LIP) consisting of ethiodized oil (Lipiodol Ultra Fluid; André Guerbet, Aulnay-sous-Bois, France) and epirubicin, without gelatin sponge on hepatocellular carcinoma (HCC), administered by hepatic arterial infusion. We analyzed the cases from two points of view: the local recurrence rate for hypervascular solitary small HCC (tumor size: < or =3 cm in diameter) and the cumulative survival rate for advanced HCC (stage VI according to the criteria of Liver Cancer Group of Japan) following C-LIP therapy. The C-LIP also was compared with transcather arterial embolization (TAE; C-LIP followed by gelatin sponge) and percutaneous ethanol injection therapy (PEIT). In the small HCC cases, the recurrence rate at 1 year after C-LIP was 77% (10 of 13 patients), while the local recurrence rate was 46% (six of 13 patients) at 6 months and 61% (eight of 13 patients) at 1 year. The local recurrence rate at 1 year was 29% (four of 14 patients) after TAE and 20% (three of 15 patients) after PEIT. These results showed that the effect of local anticancer therapy by C-LIP was not as potent as that of TAE or PEIT. In advanced HCC cases, the cumulative survival rate for 13 patients treated by C-LIP was 72% at 6 months, 36% at 1 year, and 14% at 2 years. However, the survival rates for 13 patients at 6 months, 1 year, and 2 years after TAE were 46%, 23%, and 8%, respectively. There was no difference between the C-LIP patients and TAE patients with regard to the pretreatment liver function. Three patients died within 2 months after the initial TAE. These deaths were mainly due to damage to the noncancerous liver parenchyma. Therapy with C-LIP alone was not appropriate for hypervascular solitary small HCCs, and additional treatment was necessary. We think C-LIP therapy should be selected instead of TAE for advanced HCCs to avoid severe parenchymal damage.

Immunologic reaction and genetic factors in biliary atresia.

The characteristic histopathological features seen in the livers of patients with biliary atresia (BA) are very similar to those of primary biliary cirrhosis, which is an autoimmune disease. To clarify whether BA liver possess an immunological response similar to that in primary biliary cirrhosis, we studied HLA-DR expression in liver tissue of BA patients, using a HLA-DR staining method, and determined the frequency of HLA types in BA patients and their families. HLA-DR was expressed by the bile duct epithelium in 11 of 16 liver specimens obtained from 13 BA patients. By contrast, HLA-DR was not expressed in liver specimens from 6 patients with congenital biliary dilatation. Among the HLA types seen in BA patients and their families, HLA-A33, -B44 and -DR6 were frequently expressed in blood. These results suggest that certain immunological factors and disease-susceptible genes might be involved in the etiology of BA.