Time-, spin-, and angle-resolved photoemission spectroscopy with a 1-MHz 10.7-eV pulse laser.

We describe a setup of time-, spin-, and angle-resolved photoemission spectroscopy (tr-SARPES) employing a 10.7 eV (λ = 115.6 nm) pulse laser at a 1 MHz repetition rate as a probe photon source. This equipment effectively combines the technologies of a high-power Yb:fiber laser, ultraviolet-driven harmonic generation in Xe gas, and a SARPES apparatus equipped with very-low-energy-electron-diffraction spin detectors. A high repetition rate (1 MHz) of the probe laser allows experiments with the photoemission space-charge effects significantly reduced, despite a high flux of 1013 photons/s on the sample. The relatively high photon energy (10.7 eV) also brings the capability of observing a wide momentum range that covers the entire Brillouin zone of many materials while ensuring high momentum resolution. The experimental setup overcomes the low efficiency of spin-resolved measurements, which gets even more severe for the pump-probed unoccupied states, and affords the opportunity to investigate ultrafast electron and spin dynamics of modern quantum materials with energy and time resolutions of 25 meV and 360 fs, respectively.

Devil's staircase transition of the electronic structures in CeSb.

Solids with competing interactions often undergo complex phase transitions with a variety of long-periodic modulations. Among such transition, devil's staircase is the most complex phenomenon, and for it, CeSb is the most famous material, where a number of the distinct phases with long-periodic magnetostructures sequentially appear below the Néel temperature. An evolution of the low-energy electronic structure going through the devil's staircase is of special interest, which has, however, been elusive so far despite 40 years of intense research. Here, we use bulk-sensitive angle-resolved photoemission spectroscopy and reveal the devil's staircase transition of the electronic structures. The magnetic reconstruction dramatically alters the band dispersions at each transition. Moreover, we find that the well-defined band picture largely collapses around the Fermi energy under the long-periodic modulation of the transitional phase, while it recovers at the transition into the lowest-temperature ground state. Our data provide the first direct evidence for a significant reorganization of the electronic structures and spectral functions occurring during the devil's staircase.

Hayabusa2 arrives at the carbonaceous asteroid 162173 Ryugu-A spinning top-shaped rubble pile.

The Hayabusa2 spacecraft arrived at the near-Earth carbonaceous asteroid 162173 Ryugu in 2018. We present Hayabusa2 observations of Ryugu's shape, mass, and geomorphology. Ryugu has an oblate "spinning top" shape, with a prominent circular equatorial ridge. Its bulk density, 1.19 ± 0.02 grams per cubic centimeter, indicates a high-porosity (>50%) interior. Large surface boulders suggest a rubble-pile structure. Surface slope analysis shows Ryugu's shape may have been produced from having once spun at twice the current rate. Coupled with the observed global material homogeneity, this suggests that Ryugu was reshaped by centrifugally induced deformation during a period of rapid rotation. From these remote-sensing investigations, we identified a suitable sample collection site on the equatorial ridge.

Experimental Determination of the Topological Phase Diagram in Cerium Monopnictides.

Experimental determinations of bulk band topology in the solid states have been so far restricted to only indirect investigation through the probing of surface states predicted by electronic structure calculations. We here present an alternative approach to determine the band topology by means of bulk-sensitive soft x-ray angle-resolved photoemission spectroscopy. We investigate the bulk electronic structures of the series materials, Ce monopnictides (CeP, CeAs, CeSb, and CeBi). By performing a paradigmatic study of the band structures as a function of their spin-orbit coupling, we draw the topological phase diagram and unambiguously reveal the topological phase transition from a trivial to a nontrivial regime in going from CeP to CeBi induced by the band inversion. The underlying mechanism of the phase transition is elucidated in terms of spin-orbit coupling in concert with their semimetallic band structures. Our comprehensive observations provide a new insight into the band topology hidden in the bulk states.

Evidence for magnetic Weyl fermions in a correlated metal.

Weyl fermions have been observed as three-dimensional, gapless topological excitations in weakly correlated, inversion-symmetry-breaking semimetals. However, their realization in spontaneously time-reversal-symmetry-breaking phases of strongly correlated materials has so far remained hypothetical. Here, we report experimental evidence for magnetic Weyl fermions in Mn3Sn, a non-collinear antiferromagnet that exhibits a large anomalous Hall effect, even at room temperature. Detailed comparison between angle-resolved photoemission spectroscopy (ARPES) measurements and density functional theory (DFT) calculations reveals significant bandwidth renormalization and damping effects due to the strong correlation among Mn 3d electrons. Magnetotransport measurements provide strong evidence for the chiral anomaly of Weyl fermions-namely, the emergence of positive magnetoconductance only in the presence of parallel electric and magnetic fields. Since weak magnetic fields (approximately 10 mT) are adequate to control the distribution of Weyl points and the large fictitious fields (equivalent to approximately a few hundred T) produced by them in momentum space, our discovery lays the foundation for a new field of science and technology involving the magnetic Weyl excitations of strongly correlated electron systems such as Mn3Sn.

Gastric adenocarcinoma of fundic gland type (chief cell predominant type) with unique endoscopic appearance curatively treated by endoscopic submucosal resection.

Gastric adenocarcinoma of fundic gland type [chief cell predominant type; (GA-FD-CCP)] is a rare gastric cancer variant arising from non-atrophic mucosa without Helicobacter pylori infection in the upper third portion of the stomach. GA-FD-CCP originates deep in the mucosal layer; hence, endoscopic lesion detection is often difficult at an early stage because of a minimal change in the mucosal surface. Here we present a 66-year-old man with an early stage of GA-FD-CCP showing characteristic endoscopic features. Esophagogastroduodenoscopy demonstrated a flat, slightly reddish area with black pigment dispersion and irregular micro-surface structure at the gastric fornix. The tumor was resected by endoscopic submucosal dissection and was pathologically diagnosed as GA-FD-CCP. Prussian blue staining revealed that the black pigment was a hemosiderin deposition. We reported a rare case of successfully treated GA-FD-CCP with black pigmentation that aided in early lesion detection.

Possible involvement of angiogenesis in chronic liver diseases: interaction among renin-angiotensin-aldosterone system, insulin resistance and oxidative stress.

Angiogenesis plays a pivotal role in many pathological processes including chronic liver diseases. Various factors, such as renin-angiotensin-aldosterone system (RAAS), insulin resistance (IR), and reactive oxygen species (ROS) contribute reciprocally to promote angiogenesis. Blockade of RAAS by angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II (AngII) receptor blocker (ARB) markedly attenuates liver fibrosis and hepatocellular carcinoma (HCC) along with suppression of angiogenesis, IR, and ROS. Aldosterone (Ald), a downstream component of AngII, is also involved in these processes, and a selective Ald blocker (SAB) significantly suppressed the progression of chronic liver diseases. The IR status itself has shown to directly accelerate the progression of chronic liver diseases whereas inhibition of ROS by iron chelator suppressed it through augmentation and inhibition of neovascularization. The combination therapy of ACE-I/ARB/SAB with other clinically used agents, such as interferon, imatinib mesylate, vitamin K, iron chelator, and branched-chain amino acids (BCAA) exerted more potent inhibitory effects on the development of liver fibrosis and HCC than the treatment using a single agent alone. Collectively, the anti-angiogenic treatment targeting RAAS, IR, ROS with clinically available agents may become a new therapeutic strategy against the progression of chronic liver diseases.

[Anomalous origin of the right coronary artery from the ascending aorta].

The patient was a 77-year-old man. In June 2008, he underwent off-pump coronary artery bypass (OPCAB) for unstable angina Intraoperative epiaortic echo showed an anomalous origin of theright coronary artery from the ascending aorta 4 cm above the sinotubular junction (STJ). The right coronary artery traveled through the planned proximal anastomotic site of the saphenous vein graft (SVG). If diagnosis of the anomalous origin of the right coronary artery had not been made, there would have been a high likelihood that the right coronary artery could have been injured. Thus, the usefulness of epiaortic echo was reaffirmed. An anomalous origin of the coronary artery is a rare congenital anomaly and its incidence is approximately 1%. An anomalous origin of the right coronary artery is very rare from the ascending aorta 4 cm above the STJ and only a few cases have been reported. An anomalous origin of the coronary artery can cause serious complications affecting the prognosis after open heart surgery. Thus, such an anomalous origin needs to be considered in preoperative evaluation.

Effects of trans and conjugated LC N-3 polyunsaturated fatty acids on lipid composition and abdominal fat weight in rats.

Trans and conjugated fatty acids may exhibit either beneficial or detrimental bioactive effects depending on their metabolic properties. This study was conducted to elucidate if isomerization and conjugation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) demonstrate more favorable bioactivity on lipid metabolism compared to unmodified EPA and DHA. The effects of dietary intake of trans and conjugated forms of EPA and DHA on lipid metabolism were evaluated in animal trials and compared to a control group fed soybean oil. None of the experimental diets showed significant differences from the control in terms of body weight; however, the white adipose tissue weight of rodents fed trans DHA, conjugated EPA (CEPA), and conjugated DHA (CDHA) was significantly lower than the control. Triacylglycerol levels in plasma were significantly decreased in groups fed trans DHA (17.2 mg/dL) and CDHA (31.9 mg/dL) relative to the control (51.3 mg/dL). The total cholesterol concentrations were significantly lower than the control (68.0 mg/dL) in all experimental groups (47.3 to 53.7 mg/dL) except CEPA (58.3 mg/dL). Fatty acid compositions of lipids extracted from rodent livers were influenced by the dietary fatty acid profiles, with all groups showing higher concentrations of stearic acid and lower levels of linoleic acid compared to the control. Rodents fed trans DHA did not have detectable levels of these fatty acid isomers in their livers, suggesting either quick metabolism or a difficulty with bio-absorption.

Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice.

BACKGROUND: Orchestration of two major classes of angiogenic factors-namely, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2)-has been shown to play a pivotal role in tumour angiogenesis, including hepatocellular carcinoma (HCC). However, few studies have focused on the direct interaction of these factors on in vivo tumour development and angiogenesis. AIM: To examine the interaction between both factors in murine HCC. METHODS: We examined the combination effect of VEGF and Ang-2 overexpression by means of a combination of a retroviral tetracycline (tet) regulated gene manipulating system in vivo, by providing tet in the drinking water, and a conventional plasmid gene expression system. RESULTS: Neither Ang-2 nor VEGF overexpression induced proliferation of HCC cells in vitro. In vivo, although overexpression of Ang-2 did not increase tumour development, simultaneous expression of Ang-2 and VEGF synergistically augmented tumour growth and angiogenesis in murine HCC. Ang-2 plus VEGF induced tumour development was markedly attenuated by treatment with neutralising monoclonal antibodies against VEGF receptors. Ang-2 plus VEGF overexpression significantly increased the activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the tumour. Suppression of intratumoral VEGF almost completely abolished this augmentation of MMPs. CONCLUSIONS: These results suggest that Ang-2 synergistically augments VEGF mediated HCC development and angiogenesis. This proangiogenic activity was exerted only in the presence of VEGF, at least partly mediated via induction of MMP-2 and MMP-9 in the tumour.

Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.

BACKGROUND: It has been shown that expression of the potent angiogenic factor, vascular endothelial growth factor (VEGF), and its receptors, flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), increased during the development of liver fibrosis. AIMS: To elucidate the in vivo role of interaction between VEGF and its receptors in liver fibrogenesis. METHODS: A model of CCl(4) induced hepatic fibrosis was used to assess the role of VEGFR-1 and VEGFR-2 by means of specific neutralising monoclonal antibodies (R-1mAb and R-2mAb, respectively). R-1mAb and R-2mAb were administered after two weeks of treatment with CCl(4), and indices of fibrosis were assessed at eight weeks. RESULTS: Hepatic VEGF mRNA expression significantly increased during the development of liver fibrosis. Both R-1mAb and R-2mAb treatments significantly attenuated the development of fibrosis associated with suppression of neovascularisation in the liver. Hepatic hydroxyproline and serum fibrosis markers were also suppressed. Furthermore, the number of alpha-smooth muscle actin positive cells and alpha1(I)-procollagen mRNA expression were significantly suppressed by R-1mAb and R-2mAb treatment. The inhibitory effect of R-2mAb was more potent than that of R-1mAb, and combination treatment with both mAbs almost completely attenuated fibrosis development. Our in vitro study showed that VEGF treatment significantly stimulated proliferation of both activated hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). VEGF also significantly increased alpha1(I)-procollagen mRNA expression in activated HSC. CONCLUSIONS: These results suggest that the interaction of VEGF and its receptor, which reflected the combined effects of both on HSC and SEC, was a prerequisite for liver fibrosis development.

The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

Dietary effects of bitter gourd oil on blood and liver lipids of rats.

Bitter gourd is widely used as an edible plant in Asia. In this study, we evaluated the effects of bitter gourd oil (BGO) on the blood and liver lipids of rats. Three groups of rats were given a basal diet (AIN-93G) containing 7% fat by weight. The dietary fat consisted of soybean oil (control), soybean oil + BGO (6.5:0.5, w/w; 0.5% BGO), or soybean oil + BGO (5:2, w/w; 2.0% BGO). This fat treatment gave 3.4 and 15.4% of cis(c)9,trans(t)11,t13-18:3 in the dietary fat of 0.5 and 2.0% BGO, respectively. Fatty acid analysis showed the occurrence of c9,t11-18:2 in the liver of rats fed BGO diets, whereas this conjugated linoleic acid (CLA) isomer was not detected in the liver of rats fed the control diet. Furthermore, dietary BGO decreased the concentration of 18:2n-6 and increased the concentration of 22:6n-3. The formation of the CLA isomer in the liver lipids of rats fed BGO diets could be explained by either of the following two metabolic pathways, namely, enzymatic biohydrogenation of c9,t11,t13-18:3 or enzymatic isomerization of c9,c12-18:2. The BGO diets had significantly reduced free cholesterol levels with a trend toward an increase in HDL cholesterol, but there was no significant change in the total cholesterol. The dietary BGO also affected the level of plasma hydroperoxides. A slight but significant increase in hydroperoxides was found in the rats fed 2.0% BGO. This may be attributed to the lower oxidative stability of c9,t11,t13-18:3 in BGO.

Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats.

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II) has been suggested to play an important role in liver fibrogenesis. It induces hepatic stellate cell (HSC) proliferation and up-regulates the transforming growth factor beta(1) (TGF-beta(1)) expression via AT-II type 1 receptor (AT(1)-R) in vitro. The aim of the present study was to examine the in vivo effect of candesartan (CA), a clinically used AT(1)-R blocker (ARB), and perindopril (PE), an angiotensin-converting enzyme (ACE) inhibitor (ACE-I), on pig serum-induced liver fibrosis development in rats. The clinically available comparable doses of CA and PE significantly attenuated the fibrosis development. These inhibitory effects of PE and CA were also found in the on-going liver fibrosis model. The hepatic hydroxyproline and serum fibrosis markers were significantly suppressed by CA and PE treatment. Furthermore, the alpha smooth muscle actin (alpha-SMA) positive cells in number were markedly suppressed by CA and PE treatment. Similarly, the hepatic TGF-beta(1) protein and messenger RNA (mRNA) levels were significantly suppressed. Our in vitro study showed that AT-II increased the TGF-beta(1) mRNA expression in the activated HSCs, and this effect was totally blocked by CA. These results suggested that the RAS, especially AT-II and AT(1)-R interaction plays a pivotal role in liver fibrosis development through HSC activation. Because both CA and PE are widely used in clinical practice without serious side effects, these drugs may provide an effective new strategy for anti-liver fibrosis therapy.

Cytotoxic effect of conjugated trienoic fatty acids on mouse tumor and human monocytic leukemia cells.

The cytotoxicity of fatty acids from seed oils containing conjugated linolenic acids (CLN) was studied. Fatty acids from pomegranate, tung, and catalpa were cytotoxic to human monocytic leukemia cells at concentrations exceeding 5 microM for pomegranate and tung and 10 microM for catalpa, but fatty acids from pot marigold oil had no effect at concentrations ranging up to 163 microM. The main conjugated fatty acids of pomegranate, tung, catalpa, and pot marigold were cis(c)9,trans(t)11,c13-CLN (71.7%), c9,t11,t13-CLN (70.1%), t9,t11,c13-CLN (31.3%), and t8,t10,c12-CLN (33.4%), respectively. Therefore, the cytotoxicities of fatty acids from pomegranate, tung, and catalpa were supposed to be due to 9,11,13-CLN isomers. To elucidate the cytotoxicity of these CLN, we separated each CLN isomer from the fatty acid mixtures by high-performance liquid chromatography and analyzed its cytotoxicity. The cytotoxicities of c9,t11,c13-CLN, c9,t11,t13-CLN, and t9,t11,c13-CLN were much stronger than that of t8,t10,c12-CLN. Therefore, the higher cytotoxicity of fatty acids from pomegranate, tung, and catalpa than those from pot marigold would be derived from the different activities of 9,11,13-CLN and 8,10,12-CLN. Since there was little difference in the cytotoxicities of c9,t11,c13-CLN,c9,t11,t13-CLN, and t9,t11,c13-CLN, it is suggested that the cis/trans configuration of 9,11,13-CLN isomers had little effect on their cytotoxic effects. The mechanism of the cytotoxicity of the four fatty acids above may involve lipid peroxidation, because the order of toxicity of the fatty acids was consistent with their susceptibility to peroxidation in aqueous phase. This was supported by the decrease in the cytotoxicity of the fatty acids by addition of butylated hydroxytoluene.

Balloon catheter-assisted endoscopic sclerotherapy for gastric fundal varices using alpha-cyanoacrylate monomer.

We present two patients with bleeding episodes from gastric fundal varices. The gastric fundal varices were treated by balloon catheter-assisted endoscopic sclerotherapy using alpha-cyanoacrylate monomer. The varices were successfully obliterated with no complications or hemodynamic changes to the gastrorenal shunts. This procedure may be considered a novel, feasible approach to the treatment of gastric fundal varices in the future.

The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model.

The vascular endothelial growth factor-A (VEGF-A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF-A are mediated through flt-1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than those of VEGF-A nAb. The autophosphorylation of KDR/ Flk-1 in the peritoneal wall was almost completely abolished by KDR/ Flk-1 nAb, whereas a certain level of activation was still shown by VEGF-A nAb treatment. Another VEGF-family, VEGF-C, which also binds KDR/Flk-1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk-1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF-A, VEGF-C may also be involved in the malignant ascites formation via KDR/ Flk-1 activation.

The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor.

Angiotensin-I converting enzyme (ACE) inhibitor is used widely as an antihypertensive agent, and it has been suggested recently that it decreases the risk of cancer (A. F. Lever et al., Lancet, 352: 179-184, 1998). In this study, we examined the effect of several ACE inhibitors and angiotensin-II type 1 receptor (AT(1)-R) antagonists on tumor development and angiogenesis in a murine hepatocellular carcinoma model. Among ACE inhibitors, perindopril appeared to be a potent inhibitor of tumor development and angiogenesis, whereas AT(1)-R antagonists did not exert such an inhibitory effect. The inhibitory effect of perindopril was achieved even on established tumors. The level of the potent angiogenic factor, vascular endothelial growth factor (VEGF), in the tumor was significantly suppressed by perindopril. In vitro studies showed that perindopril-derived active form, perindoprilat, suppressed the endothelial cell tubule formation. Perindoprilat treatment also significantly inhibited VEGF mRNA expression in BNL-HCC cells in vitro. These results showed that the ACE inhibitor perindopril inhibited tumor development and angiogenesis independent from AT(1)-R blockage, and that VEGF alternation may be involved in the mechanism of this inhibitory effect. Because perindopril is widely used in clinical practice, it may represent an effective new strategy for anticancer therapy.

Magnetic resonance angiography for monitoring prophylactic endoscopic treatment of high risk esophageal varices.

BACKGROUND AND STUDY AIMS: Endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) are used worldwide as the treatment for esophageal varices. We evaluated portal hemodynamics using magnetic resonance angiography (MRA) in these two forms of treatment. PATIENTS AND METHODS: The study was carried out in 50 cirrhotic patients. MRA was performed to identify the hepatofugal supply vein selectively for esophageal varices. Those who showed a positive MR angiogram for the supply vein were randomly allocated to one of two groups, using the sealed envelope method, and underwent either EIS or EVL. On the other hand, those with a negative angiogram received only EVL. EIS was done to embolize esophageal varices as well as their feeders by intravariceal injection of sclerosant under fluoroscopic guidance. RESULTS: A positive MR angiogram of the hepatofugal left gastric vein as the supply vein was observed in 41 patients. Nine patients showed negative MRA results. Among those with positive angiograms, the rate of eradication of the left gastric vein was higher in the EIS-treated group than in the EVL treated group (50% vs. 8.6%). After either treatment, the recurrence-free rate for high risk esophageal varices was higher in patients with complete eradication of the left gastric vein than in those without (88% vs. 35%). In patients with negative angiogram results, who only underwent EVL, high risk esophageal varices did not reappear over a long period. CONCLUSION: MRA is useful for evaluating portal hemodynamics. With the aim of avoiding recurrence of esophageal varices, EIS was suitable for patients who had a hepatofugal supply vein for the varices because recurrence could be prevented by embolization of the supply vein. EVL may be expected to be efficacious in patients where no image of a hepatofugal supply vein is found on MRA.

Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.