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SuperKEKB is an electron–positron asymmetric-energy double-ring collider, which was built in Japan. It has been operated to explore new phenomena in B-meson decays. Hence, extremely higher luminosity is required. A collision scheme of low emittance with a large Piwinski angle called a “nano-beam scheme” has been adopted to achieve higher luminosity by squeezing the vertical beta function at the interaction point to be smaller than the bunch length. A “crab waist collision scheme” proposed by P. Raimondi et al. has also been adopted to improve the luminosity performance. The article presents an overview of the operation of the nano-beam and crab waist collision schemes at SuperKEKB.

Aims To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). Conclusions Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.

AIM The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. METHODS A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. RESULTS SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4

10th International “Hiroshima” Symposium on the Development and Application of Semiconductor Tracking Detectors, HSTD10, Xian, China, 25 Sep 2015 - 29 Sep 2015 ; Nuclear instruments & methods in physics research / A 831, 207 - 212(2016). doi:10.1016/j.nima.2016.04.044, The upgrade to the High-Luminosity LHC foreseen in about ten years represents a great challenge for the ATLAS inner tracker and the silicon strip sensors in the forward region. Several strip sensor designs were developed by the ATLAS collaboration and fabricated by Hamamatsu in order to maintain enough performance in terms of charge collection efficiency and its uniformity throughout the active region. Of particular attention, in the case of a stereo-strip sensor, is the area near the sensor edge where shorter strips were ganged to the complete ones. In this work the electrical and charge collection test results on irradiated miniature sensors with forward geometry are presented. Results from charge collection efficiency measurements show that at the maximum expected fluence, the collected charge is roughly halved with respect to the one obtained prior to irradiation. Laser measurements show a good signal uniformity over the sensor. Ganged strips have a similar efficiency as standard strips., Published by Elsevier, Amsterdam

The ATLAS group has evaluated the charge collection in silicon microstrip sensors irradiated up to a fluence of 1×1016 n eq /cm 2 , exceeding the maximum of 1.6×1015 n eq /cm 2 expected for the strip tracker during the high luminosity LHC (HL-LHC) period including a safety factor of 2. The ATLAS12, n + -on-p type sensor, which is fabricated by Hamamatsu Photonics (HPK) on float zone (FZ) substrates, is the latest barrel sensor prototype. The charge collection from the irradiated 1×1 cm 2 barrel test sensors has been evaluated systematically using penetrating β-rays and an Alibava readout system. The data obtained at different measurement sites are compared with each other and with the results obtained from the previous ATLAS07 design. The results are very consistent, in particular, when the deposit charge is normalized by the sensor's active thickness derived from the edge transient current technique (edge-TCT) measurements. The measurements obtained using β-rays are verified to be consistent with the measurements using an electron beam. The edge-TCT is also effective for evaluating the field profiles across the depth. The differences between the irradiated ATLAS07 and ATLAS12 samples have been examined along with the differences among the samples irradiated with different radiation sources: neutrons, protons, and pions. The studies of the bulk properties of the devices show that the devices can yield a sufficiently large signal for the expected fluence range in the HL-LHC, thereby acting as precision tracking sensors.

A radiation hard n+-in-p micro-strip sensor for the use in the Upgrade of the strip tracker of the ATLAS experiment at the High Luminosity Large Hadron Collider (HL-LHC) has been developed by the “ATLAS ITk Strip Sensor collaboration” and produced by Hamamatsu Photonics. Surface properties of different types of end-cap and barrel miniature sensors of the latest sensor design ATLAS12 have been studied before and after irradiation. The tested barrel sensors vary in “punch-through protection” (PTP) structure, and the end-cap sensors, whose stereo-strips differ in fan geometry, in strip pitch and in edge strip ganging options. Sensors have been irradiated with proton fluences of up to 1×1016 neq/cm2, by reactor neutron fluence of 1×1015 neq/cm2 and by gamma rays from 60Co up to dose of 1 MGy. The main goal of the present study is to characterize the leakage current for micro-discharge breakdown voltage estimation, the inter-strip resistance and capacitance, the bias resistance and the effectiveness of PTP structures as a function of bias voltage and fluence. It has been verified that the ATLAS12 sensors have high breakdown voltage well above the operational voltage which implies that different geometries of sensors do not influence their stability. The inter-strip isolation is a strong function of irradiation fluence, however the sensor performance is acceptable in the expected range for HL-LHC. New gated PTP structure exhibits low PTP onset voltage and sharp cut-off of effective resistance even at the highest tested radiation fluence. The inter-strip capacitance complies with the technical specification required before irradiation and no radiation-induced degradation was observed. A summary of ATLAS12 sensors tests is presented including a comparison of results from different irradiation sites. The measured characteristics are compared with the previous prototype of the sensor design, ATLAS07.

We have developed n + -in-p pixel sensors to obtain highly radiation tolerant sensors for extremely high radiation environments such as those found at the high-luminosity LHC. We have designed novel pixel structures to eliminate the sources of efficiency loss under the bias rails after irradiation by removing the bias rail out of the boundary region and routing the bias resistors inside the area of the pixel electrodes. After irradiation by protons with the fluence of approximately 3 × 10 15 n eq / cm 2 , the pixel structure with the polysilicon bias resistor and the bias rails removed far away from the boundary shows an efficiency loss of 0.5 % per pixel at the boundary region, which is as efficient as the pixel structure without a biasing structure. The pixel structure with the bias rails at the boundary and the widened p-stop's underneath the bias rail also exhibits an improved loss of approximately 1% per pixel at the boundary region. We have elucidated the physical mechanisms behind the efficiency loss under the bias rail with TCAD simulations. The efficiency loss is due to the interplay of the bias rail acting as a charge collecting electrode with the region of low electric field in the silicon near the surface at the boundary. The region acts as a “shield” for the electrode. After irradiation, the strong applied electric field nearly eliminates the region. The TCAD simulations have shown that wide p-stop and large Si–SiO 2 interface charge (inversion layer, specifically) act to shield the weighting potential. The pixel sensor of the old design irradiated by γ -rays at 2.4 MGy is confirmed to exhibit only a slight efficiency loss at the boundary.

We have developed flip-chip modules applicable to the pixel detector for the HL-LHC. New radiation-tolerant n+-in-p planar pixel sensors of a size of four FE-I4 application-specific integrated circuits (ASICs) are laid out in a 6-in wafer. Variation in readout connection for the pixels at the boundary of ASICs is implemented in the design of quadsensors. Bump bonding technology is developed for four ASICs onto one quadsensor. Both sensors and ASICs are thinned to 150 μm before bump bonding, and are held flat with vacuum chucks. Using lead-free SnAg solder bumps, we encounter deficiency with large areas of disconnected bumps after thermal stress treatment, including irradiation. Surface oxidation of the solder bumps is identified as a critical source of this deficiency after bump bonding trials, using SnAg bumps with solder flux, indium bumps, and SnAg bumps with a newly-introduced hydrogen-reflow process. With hydrogen-reflow, we establish flux-less bump bonding technology with SnAg bumps, appropriate for mass production of the flip-chip modules with thin sensors and thin ASICs.

Nuclear instruments & methods in physics research / A 831, 167 - 173(2016). doi:10.1016/j.nima.2016.03.042, The “ATLAS ITk Strip Sensor Collaboration” R&D group has developed a second iteration of single-sided n+-in-p type micro-strip sensors for use in the tracker upgrade of the ATLAS experiment at the High-Luminosity (HL) LHC. The full size sensors measure approximately 97×97 mm$^2$ and are designed for tolerance against the 1.1×10$^{15}$n$_{eq}$/cm$^2$ fluence expected at the HL-LHC. Each sensor has 4 columns of 1280 individual 23.9mm long channels, arranged at 74.5μm pitch. Four batches comprising 120 sensors produced by Hamamatsu Photonics were evaluated for their mechanical, and electrical bulk and strip characteristics. Optical microscopy measurements were performed to obtain the sensor surface profile. Leakage current and bulk capacitance properties were measured for each individual sensor. For sample strips across the sensor batches, the inter-strip capacitance and resistance as well as properties of the punch-through protection structure were measured. A multi-channel probecard was used to measure leakage current, coupling capacitance and bias resistance for each individual channel of 100 sensors in three batches. The compiled results for 120 unirradiated sensors are presented in this paper, including summary results for almost 500,000 strips probed. Results on the reverse bias voltage dependence of various parameters and frequency dependence of tested capacitances are included for validation of the experimental methods used. Comparing results with specified values, almost all sensors fall well within specification., Published by North-Holland Publ. Co., Amsterdam

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.

Differential segmental distribution of electrophysiologically distinct myocytes helps to explain the variability of the pulmonary arteries to vasoactive agents. We have studied whether Ca2+ -dependent CI- (CICa) and K+ (KCa) channels are activated differentially in enzymatically dispersed conduit and resistance myocytes. We measured cytosolic [Ca2+] and the changes of membrane current and potential elicited by spontaneous or agonist-induced Ca2+ oscillations. Conduit arteries contained a heterogeneous cell population with a variable mixture of KCa and CICa conductances. Resistance arteries contained a more homogeneous cell population with predominance of CICa channel activation. The relation between KCa and CICa conductances in a given conduit myocyte determines the size of the V(m)change in response to a rise of cytosolic [Ca2+]. Conduit myocytes tend to hyperpolarize towards the K+ equilibrium potential (approximately - 90 m V). In resistance myocytes, release of Ca2+ from stores activates CI Cachannels and brings Vm to a value close to the chloride equilibrium potential (approximately - 20 or - 30 m V) thus favouring opening of Ca2+ channels and Ca2+ influx. In resistance vessels CICachannels contribute to link agonist-induced Ca2+ release from stores and membrane depolarization, thus permitting protracted vasoconstriction.

It has been previously reported that the non-structural region 5A (NS5A) of the hepatitis C virus (HCV) includes an interferon sensitivity determining region (ISDR) and that amino acid substitutions in this region are closely associated with the response to interferon (IFN) treatment. We assessed the clinical significance of serial changes of amino acid sequences in the ISDR during repeated IFN treatment in patients with chronic hepatitis C (genotype 1b), related to serum HCV RNA load. During treatment, additional amino acid substitutions in the ISDR were observed in four of eight patients (50% 2/5 of complete responders (CR); 2/3 of non-responders (NR). However, comparing these amino acid substitutions to wild-type ISDR, the number of amino acid mutations was limited to only one amino acid identified in two CRs. The virus load changed regardless of the amino acid substitutions in the ISDR during treatment, and the wild-type and intermediate type (with less than three amino acid substitutions) showed wide variations in virus load. These data indicate that amino acid mutations in the ISDR, which indicate the switch to mutant-type do not occur easily even during repeated IFN treatment, and the additional amino acid substitutions in the ISDR are not a sensitive marker during repeated IFN treatment. In cases where virus load is used as a marker of response to repeated UN treatment, serial examinations are necessary to determine the precise virus load levels.

血液ガス分析試料の経時安定性を求めるために、牛の動脈血液と静脈血液を血液ガス専用シリンジ(PII)およびディスポーザブルシリンジ(PS)にそれぞれ各10本ずつ分取し、0、0.5、1、2、3、4、8、12、18および24時間目にpH、炭酸ガス分圧(PCO2)および酸素分圧(PO2)を経時的に測定した。動脈血液におけるこれら3項目の測定値の推移は、PIIではpHが4時間目以降に有意(p＜0.05)に低下し(7.400±0.012→7.374±0.015)、PO2値は24時間目に有意に上昇した。PCO2値は経過とともに上昇したが、有意な変化は認められなかった。一方、PSではpH値が24時間目に有意の低下、PO2値は3時間目以降有意に上昇(89.0±9.3mmHg)した。PCO2値は徐々に上昇したが24時間目まで有意な変化は認められなかった。静脈血液ではPIIにおいてpH値が12時間目に有意に低下(7.361±0.017→7.321±0.024)したが、PCO2およびPO2値は上昇がみられたものの24時間目まで有意な変化は認められなかった。これに対してPSではpH値が下降、PCO2およびPO2値は上昇したが24時間目まで有意な変化は認められなかった。これらの成績から、PIIを用いた場合、動脈血液は3時間、静脈血液は8時間まで、PSでは動脈血液が2時間まで、静脈血液では少なくとも24時間は安定であることが確認された。

The immunopathogenesis of autoimmune hepatitis (AIH), and the role of T cells in the onset and maintenance of this disease, are still unclear. Since T cells expand clonally after stimulation by an antigen, it is important to analyze the behavior of T cells at a clonal level. We have established recently a novel system, using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP) that allows the identification of clonal accumulation of T cells in a lymphocyte population. Using this system, we demonstrated that oligoclonal T cells were accumulated in the liver of patients with AIH, and that identical T-cell clonotypes were detected in two different regions of the liver, although these features were also observed in cases with viral hepatitis. Only in cases with AIH, however, nearly all identical T cells were found to belong to CD8+ subset and there were very few CD4+ T cells in this population. Our results suggest that common antigens presented to CD8+ T cells in the context of HLA class I molecule are distributed diffusely in the liver of AIH. These findings also suggest that antigens recognized by CD4+ T cells may be relatively heterogeneous in the liver with AIH.

Summary. Recombinant interferon-α2a (IFN-α2a) in a total dose of 702 MU was given to 31 patients: nine with wild-type hepatitis B virus (HBV) and hepatitis B e antigen (HBeAg) (A); four with HBeAg and a mixed infection with wild-type HBV and precore mutants (B); 11 with antibody to HBeAg (HBeAb) and a mixed infection (C); and seven with HBeAb and precore mutants alone (D). HBV DNA was not cleared in any patient in groups A and B. By contrast, in patients with HBeAb, HBV DNA was ultimately lost in four patients in group C, as well as in 10 patients in group D. Thus, patients with HBeAb and infected with precore mutants alone (D) lost serum HBV DNA more often than those with HBeAg and wild-type HBV (A). Patients with low pre-treatment levels of HBV DNA cleared virus more frequently, and the response of precore mutant to IFN was comparable with that of wild-type HBV in patients who had a mixed infection. Based on these results, precore mutants do respond to IFN, and therefore, IFN is indicated in patients with HBeAb, especially those with low serum HBV DNA levels.

we investigated the clinical efficacy of intra-arterial administration of fasudil hydrochloride for cerebral vasospasm.we reviewed 90 cases treated with intra-arterial administration of fasudil hydrochloride between August 1998 and April 2009 and investigated the clinical efficacy for cerebral vasospasm.angiographic improvement of vasospasm was noted in all procedures. Eight had ischemic lesion on CT at discharge in Group A, which included 39 patients who presented angiographic and symptomatic vasospasm. However, 4 (50%) of these eight were recovered with a condition of GR. No patients showed ischemic lesion on CT in Group B, which included 51 patients who presented angiographic vasospasm without symptoms. Two (3.3%) of 59 patients who presented angiographic vasospasm without symptoms at the initial follow-up angiography had ischemic lesion on CT at discharge. The 1-year follow-up showed 78.9% of GR. No patient showed any adverse effects resulting from intra-arterial administration of fasudil hydrochloride.intra-arterial administration of fasudil hydrochloride was an effective and safe management technique for vasospasm.

A new expression for the band-to-band tunneling in the presence of a nonuniform electric field is derived, with emphasis on the importance of the exact evaluation of integrals over wave vectors of a tunneling electron. Nonuniformity of the electric field is taken into account in calculating the interband matrix element, although it is neglected in the electronic wave functions. Nonuniformity of the electric field tends to decrease the tunneling rate. The new expression shows a different electric field dependence from E.O. Kane's (1959, 1961) tunneling rate especially in high electric fields. The appropriate evaluation of wave-vector integrations and the consideration of the spatial dependence of the electric field are indispensable to obtaining a correct electric-field dependence of the tunneling rate. >

Background and Objective: A study was conducted to evaluate the effects of low-intensity pulsed ultrasound on wound healing in periodontal tissues after mucoperiosteal flap surgery. Material and Methods: Bony defects were surgically produced bilaterally at the mesial roots of the mandibular fourth premolars in four beagle dogs. The flaps were repositioned to cover the defects and sutured after scaling and planing of the root surface to remove cementum. The affected area in the experimental group was exposed to low-intensity pulsed ultrasound, daily for 20 min, for a period of 4 wk from postoperative day 1 using a probe, 13 mm in diameter. On the control side, no ultrasound was emitted from the probe placed contralaterally. After the experiment, tissue samples were dissected out and fixed in 10% formalin for histological and immunohistochemical analyses. Results: The experimental group showed that the processes in regeneration of both cementum and mandibular bone were accelerated by low-intensity pulsed ultrasound compared with the control group. In addition, the expression level of heat shock protein 70 was higher in the gingival epithelial cells of the low-intensity pulsed ultrasound-treated tooth. Conclusion: Our results suggest that osteoblasts, as well as cells in periodontal ligament and gingival epithelium, respond to mechanical stress loaded by low-intensity pulsed ultrasound, and that ultrasound accelerates periodontal wound healing and bone repair.

To elucidate precisely the prevalence and significance of cryoglobulinemia in hepatitis C, we examined the prevalence of serum cryoglobulin (CG) among 232 consecutive hepatitis C virus carriers (23 asymptomatic carriers, 164 with chronic hepatitis, 45 with cirrhosis), 30 consecutive hepatitis B virus carriers and 100 age- and sex-matched healthy volunteers. We used a gel-diffusion procedure that detects CG with greater sensitivity and specificity than the conventional precipitation method. Among the 232 patients, 166 were tested for the presence or absence of CG by the precipitation method also, which showed 60 (36.1%) patients to be positive for CG. On the other hand, 164 of the 232 patients (70.7%) were positive for CG using the diffusion method. 5 (16.7%) of the 30 HBV carriers and 2 (2%) of the healthy volunteers also were positive for CG using the gel-diffusion procedure. CG was detected more frequently among the patients with chronic hepatitis or cirrhosis than the asymptomatic carriers. In spite of the high prevalence of CG positivity, only one patient had symptoms related to cryoglobulinemia. Positivity for CG was not related to viral serogroup, viral load or the presence of antinuclear antibody, but it was related closely to CH50: 58 of 63 (92.1%) patients with lower levels of CH50 were positive for serum CG. In conclusion, cryoglobulinemia is a very common feature of chronic hepatitis C.

The authors propose a novel model for band-to-band tunneling caused by a nonuniform electric field, which is expressed in terms of the local field and its spatial variation rate and gives tunneling probabilities in magnitude and electric field dependence that are different from those given by conventional models. The proposed model can be incorporated into device simulators, and the results show the reasonable coincidence with experimental findings without any fitting parameter. >

To compare the effect of exposure time from a blue(460 nm) light emitting diode(LED) on the morphology of the outer retina and determine conditions where damage occurs.Young adult rhesus monkeys were anesthetized, and received blue LED exposure from a modified slit-lamp. A 3 mm beam of 0.85 mW was imaged onto the retina through a lens positioned before the cornea and exposure damage was determined at time intervals for 12 to 90 min. Fundus photography, fluorescein angiography(FAG), retinal tomography(HRT), and s-cone electororetinogram(S-ERG) were recorded at baseline, 2, and 30 days.Two days after 40 min exposure, there was a grey, discolored region, which was over-fluorescent in FAG, and an incresse in HRT and S-ERG corresponding to the site which was exposed to LED light. In histological examination at 30 days, the LED had caused produced a marked disruption of the disks of photoreceptor cells, damaged retinal pigment epithelium(RPE) apical villi, and a loss of RPE melanin after 90 min exposure.A threshold level was found around 40 min. This morphological damage may impair function and continuous exposure to blue light is potentially dangerous to vision.

For beneficial Interferon therapy to patients with chronic hepatitis C, we assess the change of serum HCV RNA levels during the early phase of IFN therapy, comparing the schedule of IFN beta 3 MU x 2 times per day and daily administration of IFN alpha 2b 10 MU once per day. During first 2 weeks, decrease in serum HCV RNA levels was significantly faster in IFN beta 2 times per day than alpha 2b. We concluded that the administration of IFN beta 2 times per day for 2 weeks followed by IFN alpha 10 MU will be suitable for IFN induction therapy.

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.

The amino acid mutations in a part of the non-structural region 5A (NS5A) of the hepatitis C virus (HCV) genome, called the interferon sensitivity determining region (ISDR), can affect the response to interferon (IFN) treatment. We analyzed the serial changes of the amino acid substitutions in the ISDR during the natural course of patients with sustained long-term normal alanine aminotransferase (ALT) levels in relation to the changes in virus load, and assessed the clinical significance of ISDR in the natural course and IFN treatment. The subjects were nine patients infected with HCV (genotype 1b) who had been examined for serum ALT levels every month for more than 1 year and had well-sustained normal levels. The amino acid sequence of the ISDR was determined by the direct sequencing method, and the number of amino acid mutations was evaluated in comparison with the prototype (HCV-J). Quantitation of serum HCV RNA levels was conducted by the Amplicor-monitor method (Nihon Roche). On the initial analysis of the ISDR, six patients were determined to have no mutations, and three patients had one or two mutations. However, an increased number in amino acid mutations compared with the wild type during the follow-up period was confirmed in only one patient, and that increase was limited to within two amino acids. Virus load changed regardless of the changes in amino acid substitutions in the ISDR. The ISDR was therefore inferred to be a stable region unrelated to the virus load in patients with well-sustained normal ALT levels. Additional changes of amino acid sequence in this region were not a sensitive marker for determining whether IFN treatment is indicated.

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.

Medial medullary infarction is characterized by ipsilateral hypoglossal nerve palsy with contralateral hemiparesis and disturbance of deep and discriminative sensory perception. We examined the extent and distribution of disturbances in deep sensation and compared the findings with the lesion location in the medial lemniscus detected by MRI in 3 patients with medial medullary infarction. We classified the lesion location into 2 groups; type I and type II. Type I was ventral to the middle medial lesion of the medial lemniscus, and type II was ventral to the dorsal medial lesion. In our series, type I (Case 1) impairment of the three kinds of deep sensations was more severe in the lower extremities than in the up-per extremities. In type II (Cases 2, 3) the severity or impairment in the upper extremities was moderate or severe and nearly equal to that in the lower extremities. There was no difference in the severity of impairment for the four kinds of discriminative sensations. In the literature, type I (8 patients) impairment of position sense in deep sensation was found in 1 of 7 patients in the upper extremities and 5 of 7 patients in the lower extremities. Impairment of vibration sense was found in 1 of 7 patients in the upper extremities and in all patients in the lower extremities. In type II (14 patients) severe impairment of position and vibration sense in deep sensation was found in 3 patients in the upper extremities equal to that in the lower extremities. There was no tendency in the severity of impairment of four kinds of discriminative sensations. Including our 3 cases and 22 in the literature, impairment of deep sensation was more severe in the lower extremities than in the upper extremities in type I (9 patients) and the extent was none (7), mild or moderate (2) in the upper extremities, mild (2), moderate (1), severe (2), obscure (4) in the lower extremities, while in type II (16 patients) the severity in the upper extremities was nearly equal to that in the lower extremities and the extent was none (1), mild or moderate (1), severe (5), obscure (9) in the upper extremities, none (2), mild or moderate (1), severe (6), obscure (7) in the lower extremities. It is concluded that hemiparesis appeared with lesions located in the pyramidal tract of the medulla, hemiparesis and disturbance of deep sensation in the upper and lower extremities, predominantly in the lower extremities with the lesion of the pyramidal tract to the middle of medial lemniscus in the medulla, hemiparesis and disturbance of the upper and lower extremities deep sensation with lesions of the pyramidal tract to the whole of the medial lemniscus in the medulla. Evaluating deep sensation of the upper and lower extremities is useful for speculation of the lesion location in the medial lemniscus in medial medullary infarction.

To compare effects of i.v. infusion of a small volume (5 ml/kg of body weight) of hypertonic saline (7.2% NaCl) solution (HSS) and i.v. infusion of an equivalent volume of isotonic saline (0.9% NaCl) solution (ISS) on arterial blood gases in conscious heifers with hypoxemia caused by endotoxin infusion.9 Holstein heifers.All heifers received 2.0 microg of endotoxin/kg, i.v., during a 5-minute period. Twenty-five minutes after endotoxin infusion, 3 heifers received ISS, 3 received HSS, and the remaining 3 did not receive fluids (control). Heifers were monitored for 150 minutes after initiation of fluid replacement. Arterial blood gases, blood pressure, and serum electrolyte concentrations were measured.Endotoxin administration had a profound effect on pulmonary function, causing severe hypoxemia accompanied by a significant decrease in the partial pressure of oxygen (PaO2) and a significant increase in the arterial-alveolar O2 gradient (P[A-a]O2). Cattle in the HSS group had progressive and significant increases in PaO2 and O2 saturation, compared with the other groups. The P(A-a)O2 values for the control and ISS groups were slightly decreased until 150 minutes after initiation of fluid replacement; however, HSS infusion induced a progressive and significant decrease in P(A-a)O2 for the remainder of the experimental period.Rapid infusion of HSS can successfully resuscitate conscious cattle with induced pulmonary dysfunction. Infusion of HSS may be beneficial for initial resuscitation of cattle with naturally developing bovine respiratory disease complex.

A 65-years-old woman admitted to the hospital in order to treat of the mediastinal tumor, but she suffered from palpitation, slight fever, sweating, uneasiness, sleeplessness and weightloss. On the physical examination, she was experiencing tachycardia, fevering (37.2 approximately 37.6 degrees C). Skin was moist but had no exophtalmos or neck tumor. Chest X-ray showed an abnormal shadow in the upper mediastinum. On chest CT, a tumor mass (9 x 5 x 4 cm) with cystic regions and scattered calcifications occupied from anterior to posterior mediastinum. The tumor compressed trachea to the left and right brachiocephalic vein and SVC to the right. Lower portion of the tumor intruded into behind of the trachea. Lymph node swelling of mediastinum was also detected. Results of general laboratory examination were within normal limits. Thyroid function test revealed hyperthyroidism; T3U 58%, free T3 24.4 pg/ml, free T4 6.0 ng/dl and thyroglobulin 967 mg/dl, but TSH was0.01 microIU/ml. After daily administration of methimazole (300 mg/day) for 4 weeks, thyroid function became to normal level and symptoms of hyperthyroidism was disappeared. The tumor was completely extirpated with right hemithyroidectomy and lymph node dissection under neck colla incision and median sternotomy. Pathological finding of the tumor showed follicular-fetal adenoma of thyroid with hyaloid degeneration and cystic change. There was no finding suspected of Graves' disease. She is well without any complications for 8 months after operation. Some discussion of the literature was mentioned.

The association between the actual status of cryoglobulins (CGs) expression in hepatitis C-related chronic liver disease (C-CLD) and different types of liver pathology, HCV-RNA titers and genotypes was investigated. Sixteen out of 1340 ordinary clinical specimens were CGs-positive (1%), and in 8 of them (50%) the patients blood was HCV-RNA positive. CGs was detected in 63% of C-CLD patients as a whole, but when compared with the histological findings in the liver, it was 88% in F3, and 92% in A3, and thus high percentages were detected in patients with progression of liver fibrosis and patients with strong activity. Serum IgG, IgM, transaminase and gamma-GTP levels were significantly higher in the patients with CGs, and their RA test and C3dCIC levels tended to be higher, but the differences were not significant, and no association was found with the anti-nuclear antibody positive level, or the HCV-RNA titers or genotypes. Based on the above, there was a clear involvement of HCV infection, especially the activity and histological progression of hepatitis in CGs formation in Japan as well, but there were few extrahepatic manifestations, suggesting differences in CGS levels and immune response to CGs from cases in Western countries.

We evaluated the outcome of 71 Japanese patients with chronic hepatitis C who exhibited a sustained normal level of serum ALT for one to five years after the cessation of interferon (IFN) therapy. Patients were classified into two groups: 9 (13%) cases with a sustained positive for serum HCV-RNA (incomplete responders: ICR) and 62 (87%) cases with a sustained negative for serum HCV-RNA (complete responders: CR). The anti-C100-3 titer was similarly decreased in both groups especially up to one year after cessation of IFN becoming negative in 50% of each group over a 4-year period. The anti-C-22 titer was also decreased in the CR group and stabilized at about 100U (RIA). The titer of anti-C-22 was either increased or maintained at pretreatment levels in most cases of ICR. Monitoring of anti-C-22 may be useful in distinguishing the presence of HCV viremia from a previous HCV infection. According to the backgrounds between both groups, ICR cases were significantly older and more often of genotype 1b (67%) than CR cases (1b; 32%), however there were no significant differences in sex, liver histology or pretreatment levels of HCV-RNA. Serum levels of HCV-RNA in ICR cases after IFN therapy either increase or remained similar to pretreatment levels however most patients with ICR showed an improvement in liver histology. Thus if the serum ALT level remained normal in case of ICR the objective of administering IFN to treat chronic hepatitis C was considered to have been achieved despite the persistence of HCV viremia.

Mutations in the precore region are not always detected in hepatitis B virus (HBV) from patients with chronic hepatitis B who respond to interferon and lose hepatitis B e antigen (HBeAg) from serum. The other mutations may also be responsible for the loss of HBeAg and response.Forty six consecutive patients with HBeAg-positive chronic hepatitis B received recombinant-alpha 2 a interferon (total dose: 702 MU). The mutation for stop codon 28 in the precore region was determined by restriction fragment length polymorphism, and mutations in the core promoter were searched for in five HBV DNA clones propagated from each patient.HBeAg was cleared at 6 months after interferon in 11 (61%) of 18 patients with the precore mutation and in 12 (43%) of 28 without it. Of these 28 patients, 19 with mutations in the core promoter in all five HBV DNA clones lost HBeAg more frequently than the remaining nine who had at least one clone among the five that lacked such mutations (58 vs 11%, p0.05).HBeAg-positive patients infected with HBV variants having mutations for an HBeAg-negative phenotype would respond better to interferon by clearing HBeAg from serum. Such mutations may not necessarily be in the precore region but also in the core promoter, which would interfere with the synthesis and secretion of HBeAg either at the translation or transcription level.

Decerebrate spasm is a generalized muscular spasm produced by some stimuli on decerebrate posture. Such spasm are called "tonic fit" or "decerebrate extensor spasm". We reported a 50-year-old man with periodic decerebrate spasm after cerebral hemorrhage. On admission, the patient was comatose. The pupils were round but anisocoric and did not react to light. Corneal reflexes were absent. The face, arms, and legs did not move voluntarily. Two weeks after admission, he was found in decerebrate rigidity. Periodic decerebrate spasms were also observed and were accompanied by ocular dipping. Cheyne-Stokes respiration, and hypersympathetic activity (transiently dilated pupils, hypertension, tachycardia). These symptoms persisted for two months and were induced by painful or sonic stimuli and suppressed by sleep, sedative or antiedematous drugs. The cycle was 0.6 approximately 0.7 per minute in accord with that of Cheyne-Stokes respiration. Magnetic resonance imaging revealed an area of low signal intensity in the midbrain to the bottom of the pons caused by the tentorial herniation on T1-weighted images. From the the clinical features and results of MRI studies, we considered that dysfunction of the midbrain to the pons in addition to diffuse cerebral dysfunction played some role in the manifestation of periodic decerebrate spasm with ocular dipping.

Case 1, a 9-year-old woman, was admitted to our hospital because of nausea, vomiting, and epigastralgia. Diagnosis of Bochdalek hernia was made by the unusual course of naso-gastric tube. At surgery through the left posterorateral thoracotomy, the herniation of the stomach, small intestine, and colon to the thoracic cavity through the dorsolateral defect of the diaphragm were revealed. Case 2, a 35-year-old man, was admitted to our hospital because of dyspnea. Similar diagnosis was made by the examination of upper G1 series and barium enema, which demonstrated the presence of multiple loops of the small intestine and colon in the left thoracic cavity. Their postoperative courses were uneventful. Most of Bochdalek hernia is observed in infancy, and adolescent or adult case is is rarely reported (approximately 10% of all cases). Since this often misdiagnosed as pleuritis or pulmonary tuberculosis, a cautious examination is necessary for the establishment of the correct diagnosis.

We evaluated 39 cases where sequential anastomoses had been performed using arterial graft (AG) in coronary artery bypass grafting (CABG). Fourty three AGs were used, and anastomosed to 87 coronary arterial branches. The details of these anastomoses were: 25 right gastroepiploic arteries (RGEA) to 51 branches; 10 left internal thoracic arteries (LITA) to 20 branches; 8 right internal thoracic arteries (RITA) to 16 branches. The interrupted suture was employed for all anastomoses. The proxymal site was initially anastomosed in the parallel way to a native coronary artery, and then, the distal anastomosis was done. In CABG using RGEA, the number of cases receiving anastomoses to RCA and LCX was the largest as in 13 cases, and the patent rate was favorable. There were also 8 cases of anastomoses to LAD and Dx and these GEA'S grafts were all patent. But, in the 2 cases of astomoses to RCA and LAD, the GEA's grafts between RCA and LAD were occluded. Therefore, this combination was thought to be inadequate for sequential hypass. On the other hand, in the 10 cases using LITA, these grafts were all anastomosed to LCA system, and were all patent. In the 8 cases using RITA, 4 in-situ grafts and 4 free grafts were employed. There were 3 anastomoses to LAD and D1 in the former, and 2 cases each of anastomoses to LAD and D1, and LCx (segment 12) in the latter. The patency was excellent, 100%. Although there were 1 case of post-operative early death (renal failure) and 1 case of remote death (cerebral infarction), they were found not due to arterial sequential bypass. In the 37 cases of post-operative angiography, patency was recognized in 40 AGs out of the 41 (97.6%) and 78 anastomosed branches out of the 83 (94.0%). These satisfactory findings indicate that it is possible and effective to perform sequential bypass in multivessel GABG using AG.

It would be a great contribution in coronary artery bypass grafting (CAGB) using arterial graft (AG) if right gastroepiploic artery (GEA) could be grafted onto left anterior descending artery (LAD) in situ. In this study, we discussed 22 cases where anastomosis of GEA to LAD was made in situ. The subjects were limited to high stenotic cases of90% stenosis or more75% stenoses recognized in the proximal segment of coronary artery from the anastomosed site. The sex ratio of 18 (male): 4 (female) and the age varied from 40 to 78 years (the mean age: 58 years). The details were 2 cases of single CABG, 6 cases of double CABG, 11 cases of triple CABG and 3 cases of quadruple CABG and 22 GEA's were anastomosed onto 32 vessels. There was no operative death. Postoperative angiography performed on the 21 cases showed the patency of 95.2% (20/21). These finding indicate that the use of GEA is effective for multivessel CABGs in LAD.

To determine the effects of interferon (IFN) treatment for chronic hepatitis C on vascular endothelium, we measured the concentrations of tissue plasminogen activator (t-PA) and its inhibitor (PAI-1) in the plasma from patients before and after IFN treatment for 14 consecutive days. The plasma t-PA and PAI-1 levels were measured before and after treatment. The plasma t-PA level was significantly increased after IFN treatment (p0.01) but no significant difference in plasma PAI-1 level was observed before and after treatment. The ratio of t-PA/PAI-1 was significantly increased after IFN treatment (p0.05). These changes may be caused by the effect of IFN on endothelium, leading to an activation of the endothelium derived fibrinolysis factors. Increase in plasma t-PA concentration may induce hyperfibrinolysis which may be one of the causes of suborbital hemorrhage. Further study on the fibrinolysis pathway in the blood is necessary to elucidate the mechanisms of the many side effects observed during IFN treatment.

Reports of adrenal teratomas in adults are rare, and all of adrenal teratomas which were reported in the literature were found in unilateral adrenal gland. This is the first reported case of CA19-9 producing huge teratomas found in bilateral adrenal gland. Twenty-two year-old woman was hospitalized for an episode of abdominal growing mass and an abnormality of high CA19-9 serum level. Operatively, bilateral adrenal tumors were removed, and the weights of right one and left one were 3976g and 618g, respectively. Histological diagnosis of both tumors was mature teratoma. Immunohistochemical findings revealed CA19-9 was produced from intestinal epithelium in teratoma.

Serum HCV-RNA levels were determined by newly developed branched DNA probe (bDNA) assay in 87 patients with hepatocellular carcinoma (HCC), compared with 73 patients with chronic hepatitis active and 30 patients with liver cirrhosis. Patients with decompensated liver cirrhosis (LC-d) had a significant lower viremia (mean 3.2Meg.eq./ml, bDNA positive rate; 40%) than chronic hepatitis active (18.0; 64%) and compensated LC (LC-c, 17.9; 80%) (p0.05). Those data indicates that HCV replication may decrease as progression of LC. In contrast, there was no difference between the levels of HCC with LC-c (8.2; 85%) and LC-d (6.1; 89%), and their positive rate of bDNA assay were significantly higher than LC-d without HCC (p0.01). Therefore, patients undergoing LC in whom serum HCV-RNA sustained high level may correspond to the high risk group of HCC. In HCC of heavy drinker, serum HCV-RNA levels (11.3; 91%) were significantly higher than the levels (4.6; 79%) of HCC without heavy drink (p0.05). The result indicates that heavy drink may induced an increase in HCV replication.