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Background Methotrexate (MTX) is the anchor drug for treatment of rheumatoid arthritis (RA), but tolerance to MTX is substantially different across ethnics and few studies have assessed efficacy and safety of rapid dose escalation regimen of MTX in Japanese patients with early RA. Objectives To evaluate outcomes of rapid dose escalation regimen of MTX compared with conventional treatment. Methods We implemented a randomized, controlled trial that enrolled patients with RA who fulfilled all of the following criteria: 20 to 70 years-old, disease duration ≤2 years, SDAI ≥11, and without prior use of MTX, tacrolimus (TAC) or biologics. Patients were randomized into rapid escalation (RE) group or conventional treatment (CT) group at 1:1 ratio. In RE group, doses of MTX were escalated up to 0.25 mg/kg/wk within 8 wks after start of MTX and increased maximum tolerable dose or 16 mg/wk until wk 12. If a patient achieved SDAI remission at wk 12, MTX was continued at the same dose. If a patient did not achieve SDAI remission at wk 12 or showed intolerance to MTX, use of TAC or TNF inhibitor (TNFi) were allowed. In CT group, patients were treated with either MTX, TAC, salazosulfapyridine, or bucillamine by the discretion of physicians until wk 12. If a patient achieved SDAI remission at wk 12, same treatment was continued. If a patient did not achieve remission at wk 12, use of TNFi was allowed. Patients were treated by the discretion of physicians at wk 24 and onward. We set two primary endpoints; the percentage of patients achieving SDAI remission and Boolean remission at wk 24. We planned to enroll 120 patients per arm based on expected SDAI remission rates at wk 24, alpha and beta errors and dropout rates. Results Enrollment was terminated prematurely and all patients were followed for 48 wks. Of 115 enrolled patients, 57 were randomly assigned to RE group and 58 to CT group. Baseline demographics were similar between the two groups. The median baseline values (RE vs. CT) were 24.9 and 25.9 for SDAI, 0.88 and 0.69 for HAQ, and 0.64 and 0.61 for EQ-5D, respectively. At wk 24, the percentages of patients achieving remission in RE and CT groups were 42% and 28% by SDAI criteria (p=0.1, χ2 test), and 35% and 17% (p=0.03, χ2 test) by Boolean criteria, respectively. Median values of HAQ at wk 24 in RE and CT groups were 0 and 0.13 (p=0.096, M-W U test), and those of EQ-5D were 0.78 and 0.77 (p=0.12, M-W U test), respectively. At wk 48, these values were not statistically different between the two groups. There were no significant differences between the two groups with incidence of severe adverse events. Conclusions The rapid dose escalation regimen of MTX provided significantly superior Boolean remission rate and tended to provide superior SDAI remission than conventional treatment in patients with early RA in the short term. Disclosure of Interest M. Tsutsumino Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Teijin Pharma Ltd., R. Sakai Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., and Bristol-Meyers Squibb., M. Kihara: None declared, K. Amano Grant/research support from: Pfizer Japan Inc., R. Yoshimi Grant/research support from: Bristol-Myers K.K., M. Inoo: None declared, H. Dobashi: None declared, T. Sugihara Grant/research support from: Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K, Santen Pharmaceutical Co., Ltd., Astellas Pharma Inc., Bristol Myers Squibb K.K., Abbvie Japan Co., Ltd., Takeda Pharmaceutical Co., Ltd, and Astellas Pharma Inc., T. Hidaka: None declared, H. Kohsaka Grant/research support from: Ayumi Pharmaceutical Co., Pfizer Japan Inc., Mitsubishi-Tanabe Pharma Corp., Takeda Pharmaceutical Co. Ltd., AbbVie Japan Co. Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co. Ltd., Bristol-Meyers Squibb, Astellas Pharma Inc., UCB Japan, N. Miyasaka: None declared, M. Harigai Grant/research support from: Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd., Eisai, Pfizer Japan Inc., Sanofi-Aventis KK., Santen Pharmaceutical Co., Ltd and Sekisui Medical Co., Ltd.

Existing mechanical relays have reliability-related issues including unstable contact resistance and limited cycle life. These problems are caused by mechanical fatigue and wearing of the contact surfaces. In the liquid metal micro switch (LiMMS), we employ a liquid-liquid contact to address these issues. The switching operation is achieved by forming a gap in the liquid metal using gas expansion. Our prototype has a microchannel on a glass substrate to hold a tiny amount of mercury, 0.15 mm in width and 0.1 mm in height, and TaN thin-film heaters on a ceramic substrate to expand the operating gas by heating. The substrates are bonded together and the total size of the device is 5/spl times/5/spl times/1.4 mm. We successfully demonstrated 70-m/spl Omega/ on-resistance, 1 ms-switching speed, the ability to handle up to 1 A of dc current and over 1/spl times/10/sup 8/ cycle operation. LiMMS also has good RF performance, better than 1 dB insertion loss, and better than 20 dB isolation up to 18 GHz.

We reported the results of the endovascular treatment using Guglielmi detachable coil (GDC) for wide-necked aneurysms. Fourteen aneurysms were treated with remodeling technique. One aneurysm was performed endovascular treatment followed by partial neck clipping. The other was treated with scaffolding technique. All aneurysms could not be performed by conventional GDC treatment initially because of coil protrusion into the parent artery due to wide neck of these aneurysms. These aneurysms sited at anterior circulation system in 10 cases, and at posterior circulation system in 6 cases. Immediately after the procedure, the obliteration rate could be obtained complete occlusion in 3 cases, > 95% occlusion in 7 cases, > 90% occlusion in 3 cases and < 90% occlusion in 3 cases. In 14 patients follow-up angiography or magnetic resonance image (MRI) was carried out. The angiographic follow-up period is range from 2 to 19 months (mean: 10 months). The results of angiographical follow-up indicated increasing obliteration rate with all aneurysms except for 2 cases. In these 2 cases, the reembolization was needed for recanalization of the aneurysm. The clinical follow-up period is range form one to 26 months (mean: 15 months). There is no evidence of aneurysmal rupture and all cases have been survival without any permanent neurological deficits. The GDC treatment with additional technique (remodeling technique, combined neck-clipping and coiling therapy, scaffolding technique) provides safety and effectiveness, even if there are wide-necked aneurysms.

Although various antimicrobial agents exhibit appreciable microbicidal activity in the early phase (weeks 2 t0 4) of Mycobacterium avium complex (MAC) infection induced in mice, progressive bacterial regrowth subsequently occurs. To clarify the reason for this pattern of changes, we studied changes in the levels of various cytokines in tissue at sites of infection (spleens and lungs) of MAC-infected mice which were or were not given a benzoxazinorifamycin, KRM-1648 (KRM). Levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) in tissues temporarily increased at around weeks 2 to 4 after infection, rapidly decreased thereafter, and returned to normal by week 8. Similar but somewhat delayed changes were noted for levels of interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta), immunosuppressive cytokines with macrophage (M phi)-deactivating activity, in tissue, except that TGF-beta levels in the spleen remained high during weeks 4 to 8. KRM treatment blocked the increase in the levels of all of those cytokines in tissue in the early phase of infection, most strongly at week 4. IL-6 levels were beneath the limit of detection throughout the observation period. Bacterial loads in the visceral organs decreased during the first 2 weeks, and KRM treatment markedly promoted this decrease. However, regrowth of MAC organisms began at weeks 2 to 4 and continued thereafter, even in KRM-treated mice. Splenocytes and splenic M phi s of MAC-infected mice (week 2) produced and/or released into the culture fluid significant amounts of TNF-alpha (in a cell-bound form), IFN-gamma, and IL-10, but not TGF-beta, during 3 days of cultivation. A substantial amount of TGF-beta was produced during 2 weeks of cultivation of peritoneal M phi s. KRM itself did not significantly affect the IL-10- and TGF-beta-producing ability of cultured M phi s. These findings suggest that IL-10 and TGF-beta play important roles in the regrowth of MAC organisms seen during the course of KRM treatment.

Dyskeratosis congenita (DC) is a rare inherited multisystem disorder caused by mutations in seven genes involved in telomere biology, with approximately 20% of cases having pulmonary complications. DKC1 mutations exhibit a severe disease phenotype of DC that develops in early childhood. Here, we report a unique case of DC with pulmonary fibrosis diagnosed at the age of 46. A novel missense mutation(p.Arg65Lys) of DKC1 was detected, and predicted to show a weak mutagenic effect. In spite of the steroid and immunosuppressive treatment, he died of an acute exacerbation seven months after the initial visit. This case suggests that mutation subtypes can cause heterogeneity in DC and pulmonary fibrosis.

The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.

On 1992 we started the study of 500kg-class satellite mainly for technology demonstration mission which contributes to mitigate the project risk. It goes without saying that this class of satellite is characterized by low cost and fast turn-around-time, but are different from the same class satellites which we'd developed in the '80s. In this paper, we present the outline of this class of satellites, and focusing to Space Environments and Effects Observation Satellite(SEES) under pre-phase A. A lot of failures which have happened on orbit are caused by space environments. So it is necessary to understand in detail the behavior, and to develop technology to endure them.

The in vitro and in vivo activities of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium tuberculosis were studied. The MIC at which 50% of the isolates are inhibited (MIC50) and the MIC90 of KRM for 30 fresh isolates of M. tuberculosis measured by the BACTEC 460 TB System were 0.016 and 2 micrograms/ml, respectively. These values were much lower than those for rifampin (RMP), which were 4 and >128 micrograms/ml, respectively, and considerably lower than those for rifabutin (RBT), which were 0.125 and 8 micrograms/ml, respectively. A correlational analysis of the MICs of these drugs for the clinical isolates revealed the presence of cross-resistance of the organisms to KRM and either RMP or RBT although the MICs of KRM were distributed over a much lower range than were those of the other two drugs. KRM and RMP at concentrations of 1 to 10 micrograms/ml almost completely inhibited the bacterial growth of RMP-sensitive strains (H37Rv, Kurono, and Fujii) of M. tuberculosis phagocytosed in macrophage-derived J774.1 cells. KRM was more active than RMP in inhibiting the growth of the RMP-resistant (MIC = 8 micrograms/ml) Kurata strain but failed to show such an effect against the RMP-resistant (MIC >128 micrograms/ml) Watanabe stain. When KRM was given to M. tuberculosis-infected mice at dosages of 5 to 20 mg/kg of body weight by gavage, one daily six times per week from day 1 after infection, it was much more efficacious than RMP against infections induced in mice by the RMP-sensitive Kurono strain, as measured by a reduction of rates of mortality, a reduction of the frequency and extent of gross lung lesions, histopathological changes in lung tissues, and a decrease in the bacterial loads in the lungs and spleens of infected mice. KRM also displayed significant therapeutic efficacy against infection induced by the RMP-resistant Kurata strain, while neither KRM nor RMP was efficacious against infection by the RMP-resistant Watanabe strain. In the case of infection with the Kurono strain, the efficacy of the drugs in prolonging the time of survival was in the order KRM, RBT, RMP. KRM was much more efficacious than RMP, when given at 1- to 4-week intervals. These findings suggest that KRM may be useful for the clinical treatment of tuberculosis contracted through RMP-sensitive strains, even when it is administered at long intervals.

Preparation and magnetic properties of Sm2Fe17Nxα-Fe composite magnets obtained by HDDR method have been investigated. Sm-Fe alloys prepared by arc melting were rapidly quenched at a surface velocity of Vs=50 m/s. These as-quenched ribbons, containing 6∼8 at%Sm, possessed a Sm-Fe phase of TbCu7-type. After HDDR treatment, a Th2Zn17-type Sm-Fe phase and an α-Fe phase were observed. Sm2Fe17Nx+α-Fe composite magnets were obtained by subsequent nitrogenation. Nitrogenated Sm8Zr2Fe90 powders exhibited high magnetic properties with σm=115 emu/g and HcJ=12.4 kOe, after applying magnetization field of 50 kOe. These powders showed σr/σm ratio of 0.63 without demagnetization correction.

We have fabricated 77 K deep-submicron MOSFETs on the basis of the temperature-dimension combination scaling theory (CST). The 77 K MOSFETs with 1-V supply voltage are designed from a 300 K MOSFET with 4-V supply voltage. The fabricated 77 K 0.18 /spl mu/m device has exhibited fully scaled characteristics. The subthreshold swing (S) and the threshold voltage (V/sub th/) of the 77 K device are found to be 1/4/spl ap/77 K/300 K of those of the 300 K device. Furthermore, S and V/sub th/ are achieved to be 27 mV/dec and 0.21 V without short-channel effect degradation. >

Japanese pressurised thermal shock (PTS) integrity study has been carried out to obtain public acceptance of reactor pressure vessels integrity against PTS events and to provide the data base for their life extension. This paper introduces a research plan and results.

Effects of carperitide (alpha-human atrial natriuretic peptide) on hemodynamics and renal function in dogs with congestive heart failure (CHF) produced by volume expansion and ligation of the left anterior descending coronary artery were compared with those of various anti-heart failure agents (cardiotonic, vasodilator and diuretic). Carperitide (0.1-1 microgram/kg/min) dose-dependently decreased the elevated left ventricular end-diastolic pressure (LVEDP). No significant changes in cardiac contractility (LV dP/dtmax) and heart rate (HR) were noted, although cardiac output (CO) tended to reduce during the infusion of carperitide. Nitroglycerin (NG; 3 micrograms/kg/min) and furosemide (1 mg/kg) also decreased LVEDP, but the potency was less than that of carperitide. Sodium nitroprusside (SNP; 10 micrograms/kg/min) and dobutamine (10 micrograms/kg/min) caused a reduction in LVEDP and increased CO with an increase in HR. Hydralazine (H; 100 micrograms/kg/min) increased CO without reduction in LVEDP and induced a pronounced increase in HR. Double product (systolic blood pressure x HR), an index of myocardial oxygen consumption, was significantly reduced by carperitide, but significantly increased by DB and H. Carperitide, unlike NG, SNP, H and DB, increased urine volume and urinary electrolyte excretion. These results suggest that carperitide will be an useful therapeutic agent for the treatment of CHF.

MICs of a newly developed benzoxazinorifamycin derivative, KRM-1648, for Mycobacterium avium complex (MAC) were determined by the BACTEC 460 TB system and compared with those of other known antimicrobial agents. The radiometric method gave a fast, accurate, and reproducible MIC for each antimicrobial agent. MICs of KRM-1648 for 30 strains of MAC (10 strains each of M. avium isolated from AIDS and non-AIDS patients and of Mycobacterium intracellulare isolated from non-AIDS patients) were measured. The MICs, ranging from 0.004 to 0.0625 microgram/ml, were the lowest of all tested drugs, including rifampin, rifabutin, streptomycin, kanamycin, isoniazid, ethambutol, ofloxacin, ciprofloxacin, sparfloxacin, and clarithromycin. The MICs were 2 to 512 and 1 to 32 times lower than those of rifampin and rifabutin, respectively. With rifampin and ethambutol, there were some differences between the MICs for M. avium isolated from AIDS patients (American) and those for M. avium from non-AIDS patients (Japanese). Moreover, appreciable differences between the MICs of some drugs against M. avium and M. intracellulare isolated from non-AIDS patients were found. Many strains of M. avium were more susceptible to ofloxacin than M. intracellulare, but, conversely, M. avium was more resistant to rifampin, streptomycin, ethambutol, and clarithromycin than M. intracellulare.

Small losses of NaCl, KBr, TICI, KRS-5, CsI, and PbI(2) near 10 microm were measured using an improved differential infrared spectrophotometer with an accuracy better than 0.1% in transmittance. TlCl shows relatively large intrinsic multiphonon absorption, whereas the others show only impurity loss. PbI(2), with the possibility of glass formation, shows its infrared absorption proportional to exp(-omega/37.5), where omega is the frequency in cm(-1).

To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial.We enrolled 38 active RA patients, including 32 patients who showed an inadequate response toor = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR).Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%).These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.

Heme oxygenase catalyzes the oxidation of heme to biliverdin and carbon monoxide. The gene encoding the truncated soluble rat heme oxygenase-1 (Metl-Pro267) was cloned. The enzyme protein was expressed in E. coli JM109 and purified to homogeneity. The molecular weight of the recombinant enzyme was 30 kDa as assessed by SDS-polyacrylamide gel electrophoresis. From a 3-L culture, about 90 mg of the purified enzyme was routinely obtained. The dependency of the heme oxygenase reaction catalyzed by the soluble enzyme on the NADPH-cytochrome P-450 reductase concentrations and the effect of catalase on the reaction were examined to compare with the purified membrane-bound form of heme oxygenase-1 (Yoshida and Kikuchi, 1978b). The activity of the soluble enzyme was inhibited at high concentrations of NADPH-cytochrome P-450 reductase and the inhibition was not alleviated by addition of catalase unlike the membrane-bound form. The ferric iron of the heme-heme oxygenase complex was in a typical high spin state at acidic to neutral pH (pH 6.5-7.0) but conversion to low spin state was observed at basic pH (pH 9-10). The heme bound to heme oxygenase was converted to biliverdin at a stoichiometric ratio of unity in the presence of NADPH-cytochrome P-450 reductase system. During the heme degradation of the heme-heme oxygenase complex under atmospheric oxygen, several intermediates, that is, oxygenated heme and verdoheme, were spectrally discriminated.

The therapeutic efficacy of the benzoxazinorifamycin KRM-1648 was studied in an experimental rabbit infection system with avian Mycobacterium avium. The infected rabbits died from Yersin type infections, a peculiar type of experimental bovine tuberculosis characterized by a very rapid course, enlargement of the spleen and liver, and septic infection, 14 to 20 days after bacterial challenge, as evidenced by bacteremia and severe bacterial loads in the visceral organs. Histopathologic studies of the visceral organs of the infected rabbits revealed the development of numerous typical granulomatous lesions. This experimental rabbit infection system, features of which resemble certain features of disseminated M. avium complex infections in AIDS patients, was used to evaluate the therapeutic efficacy of KRM-1648, a newly synthesized benzoxazinorifamycin. KRM-1648 given orally at 25 and 50 mg/kg of body weight reduced the incidence and degree of bacteremia in infected rabbits and protected against subsequent death. Moreover, the drug allowed almost complete recovery of infected rabbits by week 7. KRM-1648 cleared infections in the lungs, liver, spleen, and kidneys and restored histopathologic features of healthy tissue in the visceral organs. KRM-1648 exhibited a more potent therapeutic effect against M. avium infection than rifampin and clarithromycin.

In a digital library environment, we propose a novel support concept that is like a reference service in real libraries. Based on the concept, we have developed a prototype, called DOLPHIN, using a frame based knowledge base to support reference services in a digital library. DOLPHIN can guide the user to the appropriate service.

Among a series of newly-synthesized benzoxazinorifamycins, 2 of the 3'-hydroxy-5'-(4-alkyl-1-piperazinyl) derivatives, named KRM-1648 and KRM-2312, whose respective alkyl residues are isobutyl and isopropyl, were examined for efficacy against nude mouse-model leprosy. KRM-1648 completely inhibited the growth of leprosy bacilli inoculated into nude mouse footpads, even 6 months after the medication had been stopped, when given orally at a daily dose of 0.6 mg/kg, 5 or 6 times weekly, during 3-5 months postinoculation. In comparison, the growth inhibition by KRM-2312 was incomplete under the same conditions, though it was still stronger than that by rifampicin. Complete growth inhibition by KRM-1648 was also observed when it was given orally at a dose of 1 or 3 mg/kg twice weekly during the same period. In contrast, the growth inhibition by rifampicin was only slight at 1 mg/kg and partial at 3 mg/kg under the same condition.

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDS-associated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracellulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracellulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDS-associated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in present study.

Rats were given i.p. injections of Adriamycin (4 mg/kg body weight) for 6 consecutive days. Electron spin resonance spectrometry with spin labeling and a trapping technique was applied to heart mitochondria obtained from treated and control animals, in order to examine the physical response of heart mitochondrial membrane affected by Adriamycin. The Adriamycin treatment resulted in a decrease of membrane fluidity (and an increase in order parameter S), with concomitant dysfunction of respiratory responses. The generation of hydroxyl radicals from mitochondria was enhanced in the Adriamycin-treated group. In addition, superoxide dismutase activity in the mitochondrial matrix was found to decrease. The heart mitochondria of Adriamycin-treated animals contained a large amount of lipid peroxide. These results suggest that the enhancement of hydroxyl radical formation in mitochondria affected by Adriamycin is one of the factors involved in Adriamycin-induced cardiotoxicity.

Newly synthesized rifamycin derivatives, KRM-1648, KRM-1657, KRM-1668, KRM-1686, and KRM-1687, having the chemical structures of 3'-hydroxy-5'-(4-alkylpiperazinyl)-benzoxazinorifamycins (alkyl residues: isobutyl, propyl, sec-butyl, sec-butyl [R configuration], and sec-butyl [S configuration], respectively), were studied for their in vitro antimycobacterial activities. Representative (KRM-1648) MICs for 90% of the strains tested, determined by the agar dilution method on 7H11 medium, of various pathogenic mycobacteria (9 species, 174 strains) were as follows (in micrograms per milliliter): Mycobacterium tuberculosis (rifampin [RMP]-susceptible strains), less than or equal to 0.0125; M. tuberculosis (RMP-resistant strains), 12.5; M. kansasii, 0.05; M. marinum, less than or equal to 0.0125; M. scrofulaceum, 0.1; M. avium, 1.56; M. intracellulare, 0.1; M. fortuitum, greater than 100; and M. chelonae subsp. abscessus and M. chelonae subsp. chelonae, greater than 100. These values are more than 64 times lower than those of RMP, except for the values against RMP-resistant M. tuberculosis (8 times lower) and those against rapid growers, including M. fortuitum and M. chelonae (the same as those of RMP). The other derivatives had similar levels of in vitro activity against these mycobacteria. When murine peritoneal macrophages in which M. intracellulare was phagocytosed in vitro were cultured in the presence of the benzoxazinorifamycins (1 microgram/ml), much more rapid killing of the organisms ingested in the macrophages was seen compared with when the same amount of RMP was added to the medium. The addition of benzoxazinorifamycins at the concentration of 0.05 micrograms/ml caused more marked suppression of intracellular growth of the organisms compared with addition of RMP. KRM-1648 and KRM-1657 inhibited intracellular growth of M. tuberculosis, and their efficacies were much greater than that of RMP.

One of the three C-P bond formation steps, defined as step 5 in the bialaphos (BA) biosynthetic pathway, was analyzed using a new BA non-producing mutant NP71. The mutant was derived from a BA producer by gene replacement of an unidentified region next to the gene responsible for the step 5 deficiency of the mutant NP213, obtained by conventional mutation procedures. Biochemical analysis of these two mutants indicated that NP71 was defective in the formation of carboxyphosphonoenolpyruvate (CPEP), while NP213 lacked the enzyme CPEP phosphonomutase, which catalyzed the intramolecular rearrangement of CPEP.

A different domain observation technique by modulation of a polarizing plane has been developed for Nd-Fe-B sintered magnets. A liquid crystal element inserted in a longitudinal Kerr microscope is used as an optical modulator to acquire a reference image needed to enhance Kerr contrast by image processing. Domain images of the Nd-Fe-B magnet can be clearly observed by this technique in a high magnetic field up to 4.4 kOe. It was found that polishing of the sintered magnet reduced its coercive force. (c) 2007 American Institute of Physics.

症例は40才,男性.呼吸困難,発熱を主訴として入院.成人呼吸窮迫症候群(ARDS)と血栓性血小板減少性紫斑病(TTP)の病態であり,抗生物質,ステロイド薬,血漿投与と人工呼吸により救命し得た.経過中血清学的にオウム病とコクサッキーA9ウイルスの混合感染症であることが判明した.これらの感染症のTTP合併は世界的に報告がなく,またTTP合併がARDS発症に極めて関係が深い貴重な症例と考えた.

The authors have successfully applied a novel two-longitudinal-mode LD to generate a CW THz electromagnetic wave by photomixing (difference frequency generation). The LD developed for this purpose radiates, two optical waves simultaneously with a separation of /spl sim/0.9 THz and larger.

A laser diode system that shows simultaneous oscillation at two frequencies using a biperiodic binary grating as an external cavity has been developed for frequency-multiplexed optical-communication systems and optical data processing systems.