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Objective.To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA).Methods.Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks.Results.The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy.Conclusion.TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

A middle-sensitivity scintillating fiber detector (hereafter middle Sci-Fi detector) that works at a deuterium-tritium neutron flux of ~105-107cm−2s−1was utilized to measure secondary deuterium-tritium neutron emission rates with high temporal resolution at a total neutron emission rate of 1013to 1015n/s, where strong magnetohydrodynamic (MHD) instabilities were observed in the large helical device deuterium plasma experiments. The gain and angular characteristics of the middle Sci-Fi detector were evaluated in an accelerator-based deuterium-tritium neutron source in the intense 14 MeV neutron source facility at Osaka University. Observation of 1 MeV triton transport due to MHD instability was performed by a middle Sci-Fi detector whose deuterium-tritium neutron counting rate was approximately 20 times higher than that of the conventional Sci-Fi detector. Fusion-born triton transport due to energetic-particle-driven MHD instability was observed using the middle Sci-Fi detector due to its high detection efficiency and high discrimination ability of deuterium-tritium neutrons from the sea of deuterium-deuterium neutrons.

Abstract: Patients with acute leukemia are at high risk of fungal infection, suggesting that a preventive strategy is required. Fourteen patients receiving intensive chemotherapy for acute leukemia were studied to evaluate antifungal prophylaxis using itraconazole, and the plasma concentration of the drug was measured to determine its relationship to clinical efficacy. The median age of the patients was 50 years (range, 25 to 79 years), and all patients had neutropenia (less than 500 neutrophils/μl) which had lasted a median of 16 days (range, 4 to 30 days). Itraconazole was given orally at a dose of 200 mg (four capsules of 50 mg) once daily for at least 14 days. An H2-receptor antagonist was also given to prevent chemotherapy-induced gastrointestinal toxicity. Trough plasma concentrations of itraconazole and its metabolite, hydroxyitraconazole, were determined by reverse-phase high-performance liquid chromatography. The mean concentrations of itraconazole and hydroxyitraconazole on day 10 were 300 ± 96 ng/ml (range, 131–428 ng/ml) and 776 ± 369 ng/ml (range, 320–1582 ng/ml), respectively. There were marked inter-patient variations in both concentrations. No side effects were observed in the patients, and there was no definite fungal infection episode during this study. Daily oral administration of 200 mg of itraconazole appears to be effective as prophylaxis against fungal infection in neutropenic patients with acute leukemia. However, there were marked individual variations in the itraconazole plasma concentrations, which suggests that the plasma concentration should be monitored in patients with a risk of low absorption of this drug to adjust the dose given to an adequate level.

The molecular dynamics calculations are carried out for molten NaCl and AgI. The radial distribution function and their configurational fluctuation are calculated and the difference between the fluctuation of NaCl and that of AgI is confirmed. The electrical conductivities are also obtained by using the non-equilibrium molecular dynamics method, and these results agree with the experimental conductivities. Furthermore, the deviation from the Nernst–Einstein relation is derived and the relation of the structural fluctuation and the deviation is discussed.

The magnetic susceptibility of molten Ag(Cl1−xIx) was measured as a function of temperature below the liquidus temperature and up to 1050°C. The diamagnetic susceptibility of AgCl increases with increasing temperature after melting, while the susceptibility of molten AgI does not change on melting and its value decreases only slightly with increasing temperature in the liquid state. The temperature coefficients of the susceptibilities in AgCl rich region are rather larger than those in AgI rich region. The susceptibility isotherm of molten Ag(Cl1−xIx) at 700°C is almost linear with composition in each AgCl or AgI rich region. However, there appears a discontinuity in the linear relation around equi-molar fraction. We suggest that there is a difference of the bonding between AgCl and AgI rich region.

Faber-Ziman type partial structure factors in liquid Na-Pb alloys have been derived by using the so-called concentration independent method from the observed total structure factors. A ternary hard-sphere mixture model composed of atoms Na and Pb and Na4Pb molecule is applied to this system.It is shown that the estimated partial structure factors under the assumption of the mixture of hard spheres are in good agreement with the observed ones.

The phase diagrams of binary solutions of C6H14 - CH3OH and C6H12 - CH3OH have been determined. The thermodynamic quantities of mixing, such as concentration-concentration fluctuation in the long wavelength limit, Scc(O, c, T), have been derived by using the treatment of Bhatia and March. The Rayleigh-Brillouin scattering has also been investigated for these solutions. Scc(O, c, T)'s obtained by Rayleigh-Brillouin experiments were in agreement with those obtained by thermodynamical treatment of the phase diagram. The Rayleigh peak intensity of C6H14 - CH3OH system shows a weak position dependence from the interfacial boundary, in the case of the coexistence of two phases, while that of C6H12 - CH3OH does not shown such an unusual behavior. These different behaviors are discussed in terms of the densities of the components.

The structure of liquid rare earth metals (So, La, Ce, Pr, Eu, Gd, Tb and Yb) have been systematically examined by X-ray diffraction at temperatures above their melting points. The structure factors of liquid La, Ce, Pr, Eu and Yb were temperature insensitive in the presently available experimental temperature range. In terms of the usual Fourier analysis, the atomic radial distribution functions were obtained from which interatomic distances and coordination numbers were estimated.

Biopsies of 18 patients with lung cancer and cellular specimens of 21 lung cancer patients were analyzed with human monoclonal antibody HB4C5-clone 3 using avidin-biotin-peroxidase techniques. Analyses with the biopsies showed that HB4C5-clone 3 reacted with 16 of 18 biopsy specimens at a high rate of about 90% and reacted with all specimens of five adenocarcinoma tissues, five of six squamous cell carcinomas, two of three large cell carcinomas, both specimens of small cell carcinomas, and both of the other types of carcinomas. In all the reactive cases, the monoclonal antibody was reactive with greater than 50% of cancer cells. With cellular specimens of lung cancer patients, HB4C5-clone 3 reacted with 7 of 13 adenocarcinoma specimens, two of six squamous cell carcinomas, and one of two small cell carcinomas. The immunoreaction with HB4C5-clone 3 was observed in sites of the cytoplasm of cancer cells. From these data, HB4C5-clone 3 is considered to be of potential use in diagnoses of tissues and cellular specimens of lung cancer.

The defect in D-alanine carboxypeptidase IA activity in the dacA11191 mutant of Escherichia coli was correlated with a defect in the release of penicillin G from penicillin-binding protein 5. The results suggest that penicillin-binding protein 5 catalyzes the major D-alanine carboxypeptidase IA activity of the wild type and that the mutation results in a defect in the deacylation step catalyzed by this enzyme.

The microscopic electron theory based on the pseudopotential formalism has been applied to the calculation of the heats of mixing and of activities in liquid Al-Sn alloys. The calculated values for both quantities were found to be in reasonable agreement with the experimental data.

The relationship between liver cirrhosis and the pathogenesis of black pigment stones has not been clarified. We attempted to induce black pigment stone formation in the gallbladders of hamsters. Male golden hamsters were divided into a cirrhosis group and a control group. Liver cirrhosis was induced by administering drinking water containing thioacetamide. The control group was given tap water. Gallstones at 48 weeks after treatment were examined by stereoscopic microscopy and scanning electron microscopy. The copper content of the black pigment stones was analysed by atomic absorption spectrophotometry. Black pigment stones in the gallbladder were detected in 25% of the cirrhosis group. Their surface and cross-section appeared amorphous. Black pigment stones contained copper. We confirmed the formation of gallstones in an animal model of cirrhosis by thioacetamide. Our findings may contribute to the clarification of the relationship between the pathogenesis of black pigment stones and the pathophysiology of liver cirrhosis.

Interfacial reactions of Pd and Pd/Si films on [001]-oriented GaAs substrates have been studied by X-ray photoelectron spectroscopy. In the as-deposited Pd/GaAs system, Pd interacts with Ga and As is isolated. A Pd–Ga–As compound forms under the layer of Pd–Ga and As. Annealing the Pd/GaAs system at 450 °C leads to a large interfacial reaction. In the Pd/Si/GaAs system, Pd diffuses to the GaAs substrate, resulting in the formation of Pd–Ga and Pd–Ga–As compounds. In the 450 °C-annealed Pd/Si/GaAs system, a reaction does not proceed at the interface between the deposited film and GaAs.

Dual enzyme activities for the biosynthesis of peptidoglycan of the cell wall are located in major higher molecular weight penicillin-binding proteins (PBP) of Escherichia coli. Each of these proteins catalyzes the two successive final reactions in the synthesis of cross-linked peptidoglycan from the precursor N-acetylglucosaminyl-N-acetylmuramyl peptide linked to undecaprenol diphosphate; namely, the transglycosylation that extends the glycan chain and the penicillin-sensitive DD-transpeptidation that cross-links the glycan chains through two peptide side chains. Both transglycosylation and transpeptidation catalyzed by PBP-1Bs represent de novo synthesis of cross-linked peptidoglycan. Under appropriate conditions, about 25% cross-linkage was observed during the reaction, the main reaction product supposedly being a regularly cross-linked network of peptidoglycan. The two domains for the transglycosylase and transpeptidase activities were found to be located on a 50-kDa portion of the PBP-1Bs, which are about 90 kDa. Gene recombination experiments indicated that the transglycosylase domain is located upstream, i.e. on the N-terminal side of the transpeptidase domain, suggesting that the gene for these bifunctional peptides may have been formed by fusion of the genes for transglycosylase and transpeptidase that were previously located separately on the chromosome in this order.

The Gibbs-Bogoliubov formalism in conjunction with the pseudopotential theory is applied to the calculation of the vapour pressure of eight liquid metals from Groups I to IV of the periodic table and of alloys (Na-K). The calculated vapour pressure of the elements and their temperature dependencies, the partial pressures, activities and boiling points of the alloys are all found to be in reasonable agreement with measured data.

A recent derivation of the density of states at the Fermi level of liquid 3d-transition metals has prompted us to present some results for the effect of the d-band on the specific heat and the latent heat of vaporization for these materials.

BACKGROUND & AIMS: In liver cirrhosis, the binding and degradation of hyaluronic acid in the hepatic sinusoidal endothelial cells are considered to be reduced by development of hepatic sinusoidal capillarization, resulting in high serum hyaluronic acid concentration. The aim of this study is to clarify the cause of high blood hyaluronic acid concentration in liver cirrhosis. METHODS: Liver cirrhosis was induced in rats by thioacetamide administration. In vivo observation of sinusoidal capillarization, in vitro immunolocalization of factor VIII- related antigen and CD44, and [14C]hyaluronic acid binding in cultured sinusoidal endothelial cells were determined. RESULTS: Basement membranes were observed on the basal side of sinusoidal endothelial cells. The fenestrae and fluorescent intensity of anti-CD44 bound to the cells decreased with progression of hepatic fibrosis. Immunofluorescent reactive products of factor VIII-related antigen were more abundant in the cirrhotic rats compared with the controls. Amount of [14C]hyaluronic acid binding was significantly decreased in the cirrhotic group compared with the controls. CONCLUSIONS: One reason that the blood hyaluronic acid concentration increases markedly in liver cirrhosis is considered to be the reduction in hyaluronic acid receptors of hepatic sinusoidal endothelial cells and in the amount of hyaluronic acid binding to the cells. (Gastroenterology 1996 Oct;111(4):1049-57)

Penicillin-binding protein (PBP)-2 and the RodA protein are known to function in determining the rod shape of Escherichia coli cells. Peptidoglycan biosynthetic reactions that required these two proteins were demonstrated in the membrane fraction prepared from an E. coli strain that overproduced both of these two proteins and which lacked PBP-1B activity (the major peptidoglycan synthetase activity in the normal E. coli membranes). The cross-linked peptidoglycan was synthesized from UDP-N-acetylmuramylpentapeptide and UDP-N-acetylglucosamine in the presence of a high concentration of cefmetazole that inhibited all of PBPs except PBP-2. The peptidoglycan was synthesized via a lipid intermediate and showed up to 30% cross-linking. The cross-linking reaction was strongly inhibited by the amidinopenicillin, mecillinam, and by other beta-lactam antibiotics that have a high affinity for PBP-2, but not by beta-lactams that had very low affinity for PBP-2. The formation of peptidoglycan required the presence of high levels of both PBP-2 and the RodA protein in the membranes, but it is unclear which of the two proteins was primarily responsible for the extension of the glycan chains (transglycosylation). However, the sensitivity of the cross-linking reaction to specific beta-lactam antibiotics strongly suggested that it was catalyzed by PBP-2. The transglycosylase activity of the membranes was sensitive to enramycin and vancomycin and was unusual in being stimulated greatly by a high concentration of a chelating agent.

Background: We examined the relationships among vitronectin (VN), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor β1 (TGF-β) in liver diseases to evaluate the presence of plasmin cascade in human hepatic fibrosis. Methods: Blood and liver tissues were obtained from 57 patients with liver disease. Plasma VN, PAI-1 antigen, and PAI-1 activity levels were evaluated. Biopsied liver specimens were observed by light and electron microscopy after immunohistochemical staining. Morphometric analysis was performed on these specimens. Results: Plasma VN and PAI-1 activity levels decreased significantly with the progression of hepatic fibrosis and were particularly marked in the liver cirrhosis group. Plasma PAI-1 antigen level increased significantly. The immunolocalization of the active form of TFG-β became more intense with the progression of hepatic fibrosis, whereas that of the dual-stained positive areas of PAI-1 and VN (PAI-1-VN) decreased. There was a positive correlation between TGF-β and PAI-1, whereas there was a negative correlation between TGF-β and PAI-1VN. Immunoelectron microscopy showed the localization of PAI-1 VN in the extracellular space around the sinusoidal cells or surface of aggregating platelets, TGF-β mainly in Ito cells, and VN in hepatocytes near the focal necrotic area or fibrous septa. Conclusions: These findings suggest that VN and PAI-1 are related to the active form of TGF-β and that it is possible that the plasmin cascade is present in the human liver.

X-ray diffraction experiments for stage-2 potassium-intercalated graphite C24K and stage-1 C8K have been carried out. Disordered profiles have been observed for both samples. The measured structure factor S(Q) for the disordered potassium in C8K shows a characteristic subpeak in the small angle region below the first peak, which suggests that there exists a short-range order in the potassium layers. The phases of the pair distribution function g(r) and S(Q) for the potassium layers in C8K disagree with those in C24K. To check the influence of the carbon layers, the profiles of g(r)s of C8K and C24K are compared with that of normal liquid potassium.

A thermosensitive mutant of Escherichia coli K-12 was isolated in which the membrane fractions were deficient both in penicillin-binding protein-1Bs, the major components of protein 1 [Spratt, B.G. & Pardee, A.B. (1975) Nature 254, 516-517] and in activity for in vitro peptidoglycan synthesis. The mutant was also supersensitive to many kinds of beta-lactam antibiotics. All these phenotypic changes were found to be caused by a single mutation (mrc). Genetic mapping studies show that the mrc mutation was located at about 3.3 min on the E. coli chromosome linkage map [Bachmann, B.J., Low, K.B. & Taylor, A.L. (1976) Bacteriol. Rev. 40, 116-167]. Penicillin-binding protein-1Bs seemed to be identical to one of the essential enzymes involved in crosslinking of peptidoglycan and the target of cell-lytic action of penicillins. Possible functions of some other penicillin-binding proteins in compensating for lack of protein-1Bs were also proposed.

A mutant of Escherichia coli that is deficient in D-alanine carboxypeptidase IA has been isolated. The enzyme is membrane bound and moderately sensitive to penicillin. It catalyzes in vitro both D-alanine carboxypeptidase and transpeptidase reactions. Being able to synthesize crosslinked peptidoglycan both in vivo and in vitro despite the absence of enzyme activity, the newly isolated mutant grew normally under a wide range of growth conditions. Therefore, this enzyme, like D-alanine carboxypeptidase IB, is not required for normal peptidoglycan synthesis in E. coli. The defect in the activity of D-alanine carboxypeptidase IA in the mutant however was not associated with disappearance of penicillin-binding proteins 5 and 6 (which have been shown to be D-alanine carboxypeptidase IA) or any of the other protein bands that bind [14C]penicillin G. Genetic mapping studies showed that the mutation (dacA) is located close to leuS(13.7 min) on the E. coli chromosome map. Double mutants (dacA dacB) that are deficient in both D-alanine carboxypeptidases IA and IB were obtained. These double mutants also were found to grow normally and to catalyze normal formation of crosslinked peptidoglycan.

Recent X-ray diffraction data for liquid sodium under pressure have been analyzed for the purpose of studying the triplet correlation function by means of the method proposed by Egelstaff, Page and Heard. Besides, the pair correlation function and pair potential have been calculated from these diffraction data at various pressures using the common Fourier Analysis and the Born-Green equation. The relation between the pair, triplet correlation functions and the pair potential and the various changes of the structure factor by pressure was investigated.

The atomic structure of liquid In—Te and Tl—Te alloys have been investigated as a function of composition and temperature by means of X-ray diffraction. The following features emerge from this experiment. The structure of liquid In—Te alloys is similar to that of pure Te in the range of composition from 35 to 100 at % Te. This implies that the structure of pure Te plays a significant role in these alloys. At the composition of In2Te3, the second peak near the region ofQ=3.2Å-1 disappears with the increase of temperature. This corresponds to the breakdown of the electron localization based on the measurement of magnetic susceptibility. On the other hand, there is no substantial change in the structure of liquid Tl—Te alloys as the delocalization temperature of the electrons is approached.

The curve of the electrical resistivity of liquid Na-Pb alloys has a large maximum around the composition of Na4Pb corresponding to a minimum value of the concentration-concentration fluctuation in the long wavelength limit, Scc(0). The maximum in the resistivity curve is interpreted in terms of a resonance scattering of the conduction electrons by the short range ordered 'complex', based on the t-matrix formulation and with the help of thermodynamic data of these alloys.

New measurements of the free energy and entropy of mixing and association thermodynamic properties of liquid Na-TI alloys at three temlperatures are reported. A thermodynamic model is developed and fitted to these with success but the failure of the model to fit the properties of Na-Ga is reported. The problems involved in fitting thermodynamic models are discussed.