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Complex relative permeability and permittivity were evaluated simultaneously in the band of 100 MHz–67 GHz using a flexible microstrip line-type probe. In principle, the probe can evaluate the permeability and permittivity of electromagnetic materials regardless of size. The measured permeability and permittivity were obtained from the transmission coefficient (S21). Since S21 under the infinite magnetic field can be estimated by changing the DC magnetic field stepwise, the magnetic and dielectric signals were separated accurately. The complex permeability and permittivity of an NiZn ferrite sheet (10 mm × 10 mm, 0.1 mm thick) and polytetrafluoroethylene (PTFE) (25 mm × 25 mm, 0.79 mm thick) were evaluated accurately.

A highly sensitive microstrip-line-type probe using a flexible substrate was developed to measure thin-film permeability continuously up to the millimeter-wave frequency range (over 30 GHz). The probe enables broad bandwidth and highly sensitive permeability measurements without sample size limitations. The complex permeability of the CoFeB film (45 mm $\times25$ mm and $0.5~\mu \text{m}$ in thickness), CoNbZr film (25 mm $\times25$ mm and 3 nm in thickness), and nickel ferrite film (8 mm $\times5$ mm, and $1.2~\mu \text{m}$ in thickness) were optimized. The measured permeability spectrum and ferromagnetic resonance frequency showed good agreement with the theoretical values based on the Landau–Lifshitz–Gilbert equation and eddy current generation up to 67 GHz.

Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation. Mutations in Rad51 and Rad54 epistatically increased the rates of isochromosome formation and chromosome loss. In sharp contrast, these mutations decreased gene conversion between inverted repeats in the centromere. Remarkably, analysis of recombinant DNAs revealed that rad51 and rad54 increase the proportion of crossovers. In the absence of Rad51, deletion of the structure-specific endonuclease Mus81 decreased both crossovers and isochromosomes, while the cdc27/pol32-D1 mutation, which impairs break-induced replication, did not. We propose that Rad51 and Rad54 promote non-crossover recombination between centromere repeats on the same chromatid, thereby suppressing crossover between non-allelic repeats on sister chromatids that leads to chromosomal rearrangements. Furthermore, we found that Rad51 and Rad54 are required for gene silencing in centromeres, suggesting that HR also plays a role in the structure and function of centromeres.

OBJECTIVES: This study investigated the pharmacokinetic and pharmaco -dynamic profile of tolvaptan, and verified its efficacy and safety in patients with liver cirrhosis-associated ascites, with insufficient response to conventional diuretic treatment. Methods: This multicentre, doubleblind, parallel-group study allocated patients with cirrhosis to receive either 3.75 or 7.5 mg/day tolvaptan orally, once daily, for 7 days. Pharmacokinetic, pharmacodynamic and efficacy variables were measured. Results: Tolvaptan was shown to have high plasma concentrations, and prolonged duration of maximum concentration and half life, in these patients with impaired hepatic function. Tolvaptan resulted in dose-dependent decreases in body weight and ascites volume, and increases in urine output. There were no effects on urinary or serum electrolytes. Tolvaptan was well tolerated, with a good safety profile. Conclusions: Tolvaptan at 3.75 mg/day exerts some effects due to the pharmacokinetic profile in patients with liver cirrhosis. Tolvaptan at 7.5 mg/day is a clinically useful option for treating patients who do not respond well to conventional diuretics.

[Background]: Warm ischemia-reperfusion injury related to donation after cardiac death is a crucial issue in transplantation. Because surfactant function deteriorates in lungs during warm ischemia, we hypothesized pre-recovery surfactant inhalation would mitigate warm ischemia-reperfusion injury. [Methods]: We rendered donor dogs cardiac dead and left them at room temperature. All animals received ventilation for 60 minutes starting at 240 minutes after cardiac arrest. The animals were divided into 2 groups: NS (normal saline, n = 7) group, which received aerosolized normal saline, and SF (surfactant; n = 5), which received aerosolized surfactant. The lungs were flushed and procured, and the left lung was transplanted into recipient dogs. At 45 minutes of reperfusion, the right pulmonary artery was ligated, and the left transplanted lung function was evaluated. [Results]: In the NS group, 2 of 7 dogs died at 75 minutes after reperfusion, whereas all 5 animals in the SF group survived for 240 minutes after reperfusion. The SF group showed significantly better dynamic compliance, oxygenation, and wet-to-dry weight ratio. Furthermore, the SF group had higher levels of high-energy phosphates in the lung tissues and lower levels of interleukin-8, tumor necrosis factor-α, and protein in the bronchoalveolar lavage fluid. Histologically, the lungs in the SF group showed fewer signs of interstitial edema and hemorrhage and significantly less neutrophilic sequestration than those of the NS group. [Conclusions]: Our results indicated pre-recovery surfactant inhalation improved graft function, maintained adenine nucleotide levels, and prevented alveolar–capillary barrier leakage, resulting in the attenuation of warm ischemia-reperfusion injury.

The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

The effect of the substitution of a rare-earth element for a guest element on the electronic and thermoelectric properties is investigated for clathrates with the nominal composition Ba81xEuxCuySi461y (x = 0, 1, 2; y = 4, 5, 6). The Seebeck coefficient and the electrical conductivity of the rare-earth-substituted Ba81xEuxCuySi461y samples are consistent with n-type conduction and metal-like behavior. The Hall carrier mobility of Ba81xEuxCu6Si40 at room temperature decreases with increasing Eu substitution. The conduction band effective mass of rare-earth-substituted Ba81xEuxCu6Si40 (x = 1, 2) is experimentally estimated to be larger than that of Ba8Cu6Si40. On the basis of ab initio electronic structure calculations for Ba6Eu2Cu6Si40 and Ba8Cu6Si40, it is deduced that the conduction band edges of Ba8Cu6Si40 are modified by the substitution of Eu for the guest atom Ba, resulting in an increase in the density-of-states effective mass, which is consistent with the experimental result. [doi:10.2320/matertrans.E-M2012816]

Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I–II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56+ cells and CD56−CD3+ T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase–polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment. (Cancer Sci 2010; 101: 2333–2340)

Aim: A late evening snack (LES) is recommended for protein-energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched-chain amino acid (BCAA)-enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75-g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non-protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early-stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA-enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.

Centromeres that are essential for faithful segregation of chromosomes consist of unique DNA repeats in many eukaryotes. Although recombination is under-represented around centromeres during meiosis, little is known about recombination between centromere repeats in mitotic cells. Here, we compared spontaneous recombination that occurs between ade6B/ade6X inverted repeats integrated at centromere 1 (cen1) or at a non-centromeric ura4 locus in fission yeast. Remarkably, distinct mechanisms of homologous recombination (HR) were observed in centromere and non-centromere regions. Rad51-dependent HR that requires Rad51, Rad54 and Rad52 was predominant in the centromere, whereas Rad51-independent HR that requires Rad52 also occurred in the arm region. Crossovers between inverted repeats (i.e. inversions) were under-represented in the centromere as compared to the arm region. While heterochromatin was dispensable, Mhf1/CENP-S, Mhf2/CENP-X histone-fold proteins and Fml1/FANCM helicase were required to suppress crossovers. Furthermore, Mhf1 and Fml1 were found to prevent gross chromosomal rearrangements mediated by centromere repeats. These data for the first time uncovered the regulation of mitotic recombination between DNA repeats in centromeres and its physiological role in maintaining genome integrity.

We have determined the isotopic abundance ratio of 7Li/6Li in the interstellar media (ISMs) along lines of sight to HD169454 and HD250290 using the High-Dispersion Spectrograph on the Subaru Telescope. We also observed ζ Oph for comparison with previous data. The observed abundance ratios were 7Li/6Li = 8.1+3.6 –1.8 and 6.3+3.0 –1.7 for HD169454 and HD250290, respectively. These values are in reasonable agreement with those observed previously in the solar neighborhood ISMs within ±2σ error bars and are also consistent with our measurement of 7Li/6Li = 7.1+2.9 –1.6 for a cloud along the line of sight to ζ Oph. This is good evidence for homogeneous mixing and instantaneous recycling of the gas component in the Galactic disk. We also discuss several source compositions of 7Li, Galactic cosmic-ray interactions, stellar nucleosynthesis, and big bang nucleosynthesis.

Aim: We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- α-2b in patients with advanced HCC. Methods: Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-α-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics. Results: There were no significant differences in the response rate (patients with complete or partial response/all patients; P = 0.736) and survival (P = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child–Pugh score (P = 0.010), α-fetoprotein level (P = 0.0047), and additional therapy (P = 0.002), to be significant prognostic factors. Conclusions: We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-α-2b was not beneficial for advanced HCC.

To evaluate the safety, immune responses, and antitumor responses after the administration of α-galactosylceramide (αGalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs (1 × 109/m2) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-γ-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-γ-producing cells (≥2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = 0.0015). The administration of αGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-γ-producing cells that result from αGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy.

SummaryDevelopment of antibodies (Ab) that either block the function of coagulation factor VIII (FVIII) (inhibitors) or clear it from circulation, seriously complicate the treatment of haemophilia A patients with FVIII products. Autoantibodies which develop in subjects without congenital FVIII defects, cause acquired haemophilia, a rare but life-threatening coagulopathy. Identification of the FVIII epitopes to which inhibitor Abs bind will help understanding the mechanisms of inhibitor activity, and perhaps development of new therapies. Here, we examined the FVIII peptide sequence regions recognised by anti-FVIII Ab in the plasma of six congenital and one acquired haemophilia patients with high inhibitor titers (24.4–2000 BU/ml). We used indirect ELISA and overlapping synthetic peptides, 20 residues long, spanning the sequence of the A and C FVIII domains. None of the plasma samples reacted with A1, A3 or C1 domain peptides. Six plasmas reacted with A2 and/or C2 peptides. Peptides spanning residues A2–521–690 and C2–2251–2332 were recognised most frequently and strongly. They include residues that contribute to the binding sites for activated factor IX and phosphatidyl serine/ von Willebrand factor. These results suggest that anti-FVIII Abs share a pattern of antigen specificity in our panel of patients, and that exposed regions of the FVIII molecule that form functionally important binding sites elicit an intense Ab response.

Several SU UMa-type dwarf novae, in particular, WZ Sge-type stars tend to exhibit rebrightenings after superoutbursts. The rebrightening phenomenon is problematic for the disk instability theory of dwarf novae since it requires a large amount of remnant matter in the disk even after superoutbursts. Here, we report our optical and infrared observations during the first-ever outburst of a new dwarf nova, SDSS J102146.44+234926.3. During the outburst, we detected superhumps with a period of 0.056281 +/- 0.000015 d, which is typical for superhump periods in WZ Sge stars. In conjunction with the appearance of a long-lived rebrightening, we conclude that the object is a new member of WZ Sge stars. Our observations, furthermore, revealed infrared behaviors for the first time in the rebrightening phase of WZ Sge stars. We discovered prominent infrared superhumps. We calculate the color temperature of the infrared superhump source to be 4600-6400 K. These temperatures are too low to be explained with a fully-ionized disk appearing during dwarf nova outbursts. We also found a Ks-band excess over the hot disk component. These unprecedented infrared activities provide evidence for the presence of mass reservoir at the outermost part of the accretion disk. We propose that a moderately high mass-accretion rate at this infrared active region leads to the long-lived rebrightening observed in SDSS J102146.44+234926.3., 11 pages, 10 figures. Accepted for publication in PASJ

In nondestructive evaluation (NDE) using SQUID, the distance between a SQUID and a sample has been used to reduce as much as possible to improve the sensitivity. On the other hand, a remote NDE with a SQUID set several tens mm away from a sample was examined to detect a sample, to which a sensor head could not be close. A through-hole in an aluminum or steel plate was detected by the remote NDE with a SQUID. The signal from the defect up to 50 mm away from the SQUID was detected. This result shows that a remote SQUID-NDE is useful for NDE where a SQUID cannot be close.

Context. Red giants are evolved stars that exhibit solar-like oscillations. Although a multitude of stars have been observed with space telescopes, only a handful of red giant stars were targets of spectroscopic asteroseismic observing projects. Aims: We search for solar-like oscillations in the two bright red giant stars γ Psc and θ1 Tau from a time series of ground-based spectroscopy and determine the frequency of the excess of oscillation power νmax and the mean large frequency separation ∆ν for both stars. Seismic constraints on the stellar mass and radius will provide robust input for stellar modelling. Methods: The radial velocities of γ Psc and θ1 Tau were monitored for 120 and 190 days, respectively. Nearly 9000 spectra were obtained. To reach accurate radial velocities, we used simultaneous thorium-argon and iodine-cell calibration of our optical spectra. In addition to the spectroscopy, we acquired interferometric observations of γ Psc for an independent estimate of the radius. We also analysed 22 days of observations of θ1 Tau with the MOST satellite. Results: The frequency analysis of the radial velocity data of γ Psc revealed an excess of oscillation power around 32 μHz and a large frequency separation of 4.1 ± 0.1 μHz. θ1 Tau exhibits oscillation power around 90 μHz, with a large frequency separation of 6.9 ± 0.2 μHz. Scaling relations indicate that γ Psc is a star of about 1 M☉ and 10 R☉. The object θ1 Tau appears to be a massive star of about 2.7 M☉ and 10 R☉. The radial velocities of both stars were found to be modulated on timescales much longer than the oscillation periods. Conclusions: The estimated radii from seismology are in agreement with interferometric observations and also with estimates based on photometric data. While the mass of θ1 Tau is in agreement with results from dynamical parallaxes, we find a lower mass for γ Psc than is found in the literature. The long periodic variability agrees with the expected timescales of rotational modulation. Based on observations made with the HERMES spectrograph mounted on the 1.2 m Mercator Telescope at the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofsica de Canarias; the CORALIE spectrograph mounted on the 1.2 m Swiss telescope at La Silla Observatory, the HIDES spectrograph, mounted on the 1.9 m telescope at Okayama Astrophysical Observatory, NAOJ, the MOST space telescope, and and observations made with ESO Telescopes at the La Silla Paranal Observatory under program ID 086.D-0101.

目的:裂肛に対する用手肛門拡張術(AD)について検討した.対象:2003年1月から2005年9月の問にADを行った98例(男性52例,女性46例).方法:ジャックナイフ位,仙骨硬膜外麻酔下で肛門に左右の示指を挿入して輪状の肛門内括約筋を触知しながら前後左右に少しずつ慎重に拡張した.結果:排便痛は術前83/98例(85%)に認められたが,術後3カ月後には7/51例(14%)に減少した.出血も73/98例(75%)から5/51例(10%)に減少した.術後の肛門管最大静止圧(MRP)は平均17.2mmHgの有意な低下が認められた.術後1カ月後の肛門超音波検査では,内外肛門括約筋に異常は認められなかった.1例で術後1カ月時点において下痢時の軽度便失禁を認めたが便失禁症状は数日で消失した.結論:ADの合併症は極めて少ないことが示されたため保存療法に抵抗する裂肛に対するスタンダードな治療となりうる.

Severe hemophilia A patients treated with factor (F)VIII may develop antibodies (Ab) that block FVIII function (inhibitors). Autoimmune inhibitors may develop in subjects without congenital hemophilia, and cause acquired hemophilia. Hemophiliacs without inhibitors and healthy subjects may also have small amounts of antiFVIII Ab. FVIII-specific CD4(+) T cells induce antiFVIII Ab synthesis. Here, we have examined their epitope repertoire in hemophilia patients and healthy subjects. We used overlapping synthetic peptides, spanning the sequence of the FVIII A3 domain, to challenge blood CD4(+) T cells in proliferation assays. The epitopes recognized in hemophilia A patients with or without inhibitors, acquired hemophilia patients, or healthy subjects overlapped, yet had characteristic differences. Most members of one or more study groups recognized the sequence regions 1691-1710, 1801-1820, 1831-1850, and 1941-60. In the proposed three-dimensional structure of the A3 domain, these sequences are largely exposed to the solvent and flanked by flexible sequence loops: these are structural features characteristic of 'universal' CD4(+) T epitopes. Hemophilia A patients with inhibitors recognized prominently only the sequence 1801-1820, which overlaps a known inhibitor binding site. This is consistent with the possibility that CD4(+) T cells recognizing epitopes within residues 1801-1820 have a role in inducing inhibitor synthesis. In contrast, CD4(+) T cells sensitized to sequences 1691-1710 and 1941-60, which are recognized by healthy subjects and hemophilia A patients without inhibitors, might curb inhibitor synthesis.

SummaryFormation of inhibitor antibodies to factor VIII (FVIII) is a major complication of FVIII replacement therapy for hemophilia A patients, and it occurs through a T-cell dependent process. The C2 domain of FVIII contains epitopes that are recognized by antibody inhibitors. We have examined regions of the C2 domain that form epitopes for T cells in mice congenitally deficient in FVIII. We obtained CD4+ T cells from mice immunized by intravenous infusion of therapeutic doses of recombinant human FVIII (rFVIII), or by subcutaneous injections of rFVIII or recombinant human C2 domain in adjuvant. In all cases, the T cells recognized most strongly and consistently two overlapping peptides that spanned residues 2191 to 2220 of the C2 domain. Analysis of the crystal structure of human factor VIII C2 bound to a human monoclonal antibody, BO2C11, showed these residues also constitute part of a human alloimmune B-cell epitope (Spiegel et al., Blood 2001; 98: 13-19).This region includes one of the “hydrophobic spike” protrusions, consisting of M2199 and F2200, as well as the basic residues R2215 and R2220. These residues contribute to membrane binding and to association with von Willebrand factor (vWF).These findings suggest that a major T-cell epitope in the C2 domain recognized by hemophilic mice is located within the same region that binds to inhibitors, vWF, and activated membranes.

平成10年4月より平成14年3月まで,4年間に当院で2カ所以上の結紮切除術を施行した内痔核症例2,045例のうち,術後出血のため再手術を必要とした30例(1.5%)について検討した.男性15例,女性15例で,平均年齢は49.8歳であった.出血は早期出血(術当日から術後1日)と晩期出血(術後6日から術後16日)に分け検討した.2例に複数回出血が認められた.早期出血のrisk factorとしては術者要因が挙げられ,経験症例数300例以下は早期出血率1.49%,301例以上は0.60%であった.晩期出血については術者要因に関連が無く,risk factorとして排便障害との関連が示唆された(p

We utilized HLA transgenic mice to identify the dominant epitopes on the human (H)-AChR alpha subunit. The cytoplasmic H-AChR peptide alpha320-337 was the dominant T cell epitope for DQ8, DR3, and DQ8xDQ6 F1 mice. The H-AChR-immunized HLA-DQ8, DR3, DQ8xDR3 F1 and DQ8xDQ6 F1 mice developed clinical EAMG, whereas HLA-DQ6 mice were less susceptible.

(2003). Friction welding of dissimilar metals. Welding International: Vol. 17, No. 4, pp. 271-275.

Myasthenia gravis (MG) is a T cell-dependent, Ab-mediated autoimmune disease. Ab against muscle acetylcholine receptor (AChR) cause the muscular weakness that characterizes MG and its animal model, experimental MG (EMG). EMG is induced in C57BL6 (B6) mice by three injections of Torpedo AChR (TAChR) in adjuvant. B6 mice develop anti-TAChR Ab that cross-react with mouse muscle AChR, but their CD4+ T cells do not cross-react with mouse AChR sequences. Moreover, murine EMG is not self-maintaining as is human MG, and it has limited duration. Several studies suggest that IL-4 has a protecting function in EMG. Here we show that B6 mice genetically deficient in IL-4 (IL-4−/−) develop long-lasting muscle weakness after a single immunization with TAChR. They develop chronic self-reactive Ab, and their CD4+ T cells respond not only to the TAChR and TAChR α subunit peptides, but also to several mouse AChR α subunit peptides. These results suggest that in B6 mice, regulatory mechanisms that involve IL-4 contribute to preventing the development of a chronic Ab-mediated autoimmune response to the AChR.

MgB 2 thin films on nontextured Al tape substrates were fabricated by electron beam evaporation. MgB 2 thin film with a boron buffer layer of about 3 nm thickness was also prepared. The thickness of MgB 2 thin films is 250 nm. The obtained MgB 2 thin films on Al tape substrates were boron rich in composition and c -axis oriented. The self-field J c of the MgB 2 thin film with a boron buffer layer at 10 K and 20 K are 9.45 × 10 10 A/m 2 and 4.85 × 10 10 A/m 2 , respectively. The magnetic field reduction of J c in MgB 2 thin films on Al tape substrates is smaller compared with MgB 2 wires fabricated by a powder-in-tube method and MgB 2 thin films fabricated by a hybrid physical chemical vapor deposition method. The field angular dependences of J c of MgB 2 thin films on Al tape substrates are similar to that of the MgB 2 thin film on Si, which was reported previously. This result indicates that grain boundaries act as a dominant pinning center in MgB 2 thin films on Al tape substrates.

We present spectropolarimetry of the Type Ic supernova SN 2002ap and give a preliminary analysis: the data were taken at two epochs, close to and one month later than the visual maximum (2002 February 8). In addition we present June 9 spectropolarimetry without analysis. The data show the development of linear polarization. Distinct polarization profiles were seen only in the O I \lambda 7773 multiplet/Ca II IR triplet absorption trough at maximum light and in the Ca II IR triplet absorption trough a month later, with the latter showing a peak polarization as high as ~2 %. The intrinsic polarization shows three clear position angles: 80 degs for the February continuum, 120 degs for the February line feature, and 150 degs for the March data. We conclude that there are multiple asymmetric components in the ejecta. We suggest that the supernova has a bulk asymmetry with an axial ratio projected on the sky that is different from 1 by of order 10 %. Furthermore, we suggest very speculatively that a high velocity ejecta component moving faster than ~0.115c (e.g., a jet) contributes to polarization in the February epoch.

We have obtained a high resolution (R~90,000) spectrum of the carbon- and s-process-element-rich, very metal-poor ([Fe/H]=-2.7) subgiant LP625-44, as well as that of HD140283 (a metal-poor subgiant with normal abundance ratio) for comparison, with the High Dispersion Spectrograph (HDS) for the Subaru Telescope for detailed abundance study. The oxygen abundance derived from the O I triplet around 7770A is uncertain, but the excess of oxygen in LP625-44 seems remarkable (perhaps by nearly a factor 10), in comparison with that of HD140283 derived from the same lines. The Na enhancement in LP625-44 is by about a factor 50, suggesting hydrogen burning in the 22Ne-rich layer in an asymptotic giant branch star which produces the abundance pattern of this object. In our new spectrum of LP625-44, the Pb I lambda 3683A line has been detected, as well as the Pb I lambda 4057A line which has already been studied, confirming the Pb abundance (log epsilon(Pb)~1.9) derived by the previous work. The abundance ratio of s-process elements at the second peak (e.g., La, Ce and Nd) to that at the third peak (Pb) in LP 625-44 is significantly higher (by a factor 5) than that in other three s-process element-rich objects recently studied by van Eck et al.. Recent theoretical works have modeled the s-process nucleosynthesis in the radiative layer of asymptotic giant branch stars in the inter-pulse phase, and the above results means that these processes produced a large scatter in the abundance ratios. Another possiblity is that different processes (e.g., s-process nucleosynthesis during thermal pulses) have contributed to heavy elements in the early Galaxy., 65 pages, 11 figures, to appear in PASJ

Susceptibility to myasthenia gravis (MG) is positively linked to expression of HLA-DQ8 and DR3 molecules and negatively linked to expression of the DQ6 molecule. To elucidate the molecular basis of this association, we have induced experimental autoimmune MG (EAMG) in mice transgenic for HLA-DQ8, DQ6, and DR3, and in DQ8xDQ6 and DQ8xDR3 F(1) transgenic mice, by immunization with human acetylcholine receptor (H-AChR) in CFA. Mice expressing transgenes for one or both of the HLA class II molecules positively associated with MG (DQ8 and DR3) developed EAMG. T cells from DQ8 transgenic mice responded well to three cytoplasmic peptide sequences of H-AChR (alpha320-337, alpha304-322, and alpha419-437), of which the response to alpha320-337 was the most intense. DR3 transgenic mice also responded to this sequence very strongly. H-AChR- and alpha320-337 peptide-specific lymphocyte responses were restricted by HLA class II molecules. Disease resistance in DQ6 transgenic mice was associated with reduced synthesis of anti-AChR IgG, IgG(2b), and IgG(2c) Ab's and reduced IL-2 and IFN-gamma secretion by H-AChR- and peptide alpha320-337-specific lymphocytes. Finally, we show that DQ8 imparts susceptibility to EAMG and responsiveness to an epitope within the sequence alpha320-337 as a dominant trait.

Nasal administration of synthetic CD4(+) epitopes of the acetylcholine receptor (AChR) prevents experimental myasthenia gravis (EMG) in C57Bl/6 mice, but not in IL4-deficient C57Bl/6 (IL4(-/-)) mice. Here we verify that nasal tolerance requires IL4, by showing that CD4(+) cells from C57Bl/6 mice treated nasally with a pool of AChR CD4(+) epitopes protected IL4(-/-) mice from EMG and caused a reduced production of anti-AChR antibody. CD4(+) cells from C57Bl/6 mice treated with unrelated peptides or sham-treated did not induce protection. CD4(+) cells from C57Bl/6 mice treated with just one AChR peptide protected IL4(-/-) mice from EMG without affecting antibody synthesis.

In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies. Copyright © 2014, Mary Ann Liebert, Inc.

A detailed abundance analysis has been carried out for the Hg-Mn star 46 Aql using high-resolution spectra in the visual region (5100–6400 u A) obtained with the High Dispersion Spectrograph of the Subaru Telescope. Our attention has been mainly focused on those elements which have not been analyzed previously. He, C, N, and O are underabundant, while Na shows the solar abundance. We have confirmed previously reported underabundances of Mg, Al, and Si, and have found an overabundances of P (+1.5dex) and Ti (+1.0dex) and a significant underabundance of S (−1.8dex). Fe is overabundant by +0.8 ±0.1dex and a microturbulent velocity of 0.3kms −1 was found from an analysis of the Fe II lines. Among a few hundred unidentified absorption lines, we identified lines of AsII and Xe II and a very large (+4.0dex) overabundance of Xe is obtained. We have confirmed emission lines of Mn II and Ti II near 6100 u A, while those of Cr II cannot have been seen.

SummaryMice genetically deficient in factor VIII (fVIII) are a model of hemophilia A. As a first step to reproduce in this mouse model what occurs over time in hemophilia A patients treated with human fVIII (hfVIII), we have investigated the time course and the characteristics of their immune response to hfVIII, after multiple intravenous injections. Anti-hfVIII antibodies appeared after four to five injections. They were IgG1 and to a lesser extent IgG2, indicating that they were induced by both Th2 and Th1 cells. Inhibitors appeared after six injections. CD4+ enriched splenocytes from hfVIII-treated mice proliferated in response to fVIII and secreted IL-10: in a few mice they secreted also IFN-γ and in one mouse IL-4, but never IL-2. A hfVIII-specific T cell line derived from hfVIII-treated mice secreted both IL-4 and IFN-γ, suggesting that it included both Th1 and Th2 cells. CD4+ enriched splenocytes of hfVIII-treated mice recognized all hfVIII domains. Thus, hemophilic mice develop an immune response to hfVIII administered intravenously similar to that of hemophilia A patients. Their anti-hfVIII antibodies can be inhibitors and belong to IgG subclasses homologous to those of inhibitors in hemophilic patients; their anti-hfVIII CD4+ cells recognize a complex repertoire and both Th1 and Th2 cytokines, and especially IL-10, may drive the antibody synthesis. Abbreviations used: antibodies, Ab; antigen presenting cells, APC; Arbitrary Units, AU; enzyme-linked immunosorbant assay, ELISA; factor VIII, fVIII; human factor VIII, hf VIII; intravenous, i.v.; optical density, OD; polymerase chain reaction, PCR; phosphate buffered saline solution, PBS; PBS containing 3% bovine serum albumin, PBS/BSA; PBS containing 0.05% polyoxyethylene sorbitan monolaurate, PBS/Tween-20; phytohemoagglutinin, PHA; stimulation index, SI

We examined the proliferative response of blood CD4(+) cells to muscle acetylcholine receptor (AChR) subunits and the epitope repertoire of the epsilon and gamma subunits, in ocular myasthenia gravis (oMG) patients and healthy subjects. oMG patients seldom recognized all subunits. The frequency and intensity of recognition was the same for all subunits, irrespective of the disease duration. The responses in oMG were lower than in generalized myasthenia gravis. Healthy subjects had frequent, low responses to one or more subunits. oMG patients recognized several epitopes on the gamma and epsilon subunits, that partially overlapped those recognized in gMG. The subunits and epitopes recognized by individual oMG patients changed over time. Thus, oMG patients have minimal and unstable sensitization of anti-AChR CD4(+) cells, in agreement with their low and inconsistent synthesis of anti-AChR antibody.

SummaryAntibodies (Ab) that inhibit factor VIII (fVIII) may develop in patients with hemophilia A and rarely in individuals without congenital fVIII deficiency (acquired hemophilia). Synthesis of fVIII inhibitors requires CD4+ T cells. We investigated the proliferative response of blood CD4+ cells from 11 patients with congenital or acquired hemophilia and 12 healthy subjects, to recombinant human fVIII, and to pools of overlapping synthetic peptides spanning the sequences of individual fVIII domains. All patients had CD4+ cells that responded to fVIII. The intensity of the responses fluctuated over time: several patients had brief periods when they did not respond to fVIII. All healthy subjects had transient CD4+ responses to fVIII, that were significantly lower than those of hemophilia patients. Also, healthy subjects responded to fVIII less frequently and for shorter periods than hemophilia patients. All patients and healthy subjects recognized several fVIII domains: the A3 domain was recognized most strongly and frequently. The transient sensitization of CD4+ cells to fVIII in healthy subjects suggests that inadequate tolerization of CD4+ cells to fVIII, due to lack of endogenous fVIII, is an important factor in the development of clinically significant anti-fVIII antibodies in hemophilia A.

Immunization with acetylcholine receptor (AChR) causes experimental myasthenia gravis (EMG). We investigated EMG in interleukin (IL)-4 knock out B6 (KO) mice, that lack Th2 cells. EMG was more frequent in KO than in wild type B6 mice. KO and B6 mice developed similar amounts of anti-AChR antibodies. They were IgG2a and IgG2b in KO mice, IgG1 and IgG2b in B6 mice. CD4+ cells from KO and B6 mice recognized the same AChR epitopes. Nasal administration of synthetic AChR CD4+ epitopes reduced antibody synthesis and prevented EMG in B6, not in KO mice. Thus, Th2 cells may have protective functions in EMG.

IntroductionIn spite of the significant advances in the treatment of hemophilia over the last 30 years, the development of antibodies that neutralize the procoagulant activity of factor VIII (factor VIII inhibitors) remains a serious complication of treatment with factor VIII products. Recent prospective studies of previously untreated patients with severe hemophilia have reported the incidence of inhibitor development to be approximately 20% to 25%.1-11 Factor VIII inhibitors may also develop in individuals without congenital factor VIII deficiency. Acquired autoimmune hemophilia occurs with an incidence of 0.2 to 1.0 per 1,000,000 per year in the general population.12,13 In both congenital and acquired hemophilia, anti-factor VIII antibody inhibitors are significant contributors to the morbidity and mortality of those affected. As such, these cases present difficult therapeutic challenges.Much work over the last decade has focused on defining the epitopes on factor VIII to which inhibitor antibodies bind. While this work has clarified some of the mechanisms by which inhibitors neutralize the procoagulant function of factor VIII, our knowledge of the factor VIII-specific CD4+ T helper cells, whose activation is crucial for the synthesis of factor VIII inhibitors, remains quite limited. This review will, first, discuss how a better understanding of the cellular mechanisms involved in the immune response to factor VIII may lead to improved methods of long-term inhibitor suppression and, perhaps, even prevention of inhibitor development. Lastly, this review will describe the work in our laboratory that has begun to characterize the CD4+ T cell response to factor VIII in patients with hemophilia and in normal subjects.

セルフケアが容易で, 合併症のないストーマを造設することは患者のQOL上極めて重要である.ストーマの形態としては, 高齢者のオストメイトの増加を考慮し, 洗腸療法, 自然排便法の双方に対応できる突出型のストーマを造設しておくのが良い.それでも皮膚切開の大きさや, 挙上腸管の長さ, 縫合法などにより術後のストーマの形状はさまざまである.著者らは過去7年間, 20例の単孔式結腸ストーマ造設に際し, 皮膚切開の大きさ, 挙上腸管の長さを測定し, その結果としてのストーマの最大径, 高さを計測してきた.種々の検討の結果, 皮膚切開は2.5×1.5cm (縦×横), 挙上腸管の長さを3.0～3.5cmとすると, ストーマの最大径は2.5cm, 高さ1cm程度の円形のストーマが造設され満足しうる結果を得た.