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Resistance to streptomycin in bacterial cells often results from a mutation in the rpsL gene that encodes the ribosomal protein S12. We found that a particular rpsL mutation (K87E), newly identified in Escherichia coli, causes aberrant protein synthesis activity late in the growth phase. While protein synthesis decreased with age in cells in the wild-type strain, it was sustained at a high level in the mutant, as determined using living cells. This was confirmed using an in vitro protein synthesis system with poly(U) and natural mRNAs (GFP mRNA and CAT mRNA). Other classical rpsL mutations (K42N and K42T) tested did not show such an effect, indicating that this novel characteristic is typical of ribosomes bearing the K87E mutant form of S12, although the K87E mutation conferred the streptomycin resistance and error-restrictive phenotypes also seen with the K42N and K42T mutations. The K87E (but not K42N or K42T) mutant ribosomes exhibited increased stability of the 70S complex in the presence of low concentrations of magnesium. We propose that the aberrant activation of protein synthesis at the late growth phase is caused by the increased stability of the ribosome.

In the preceding article,¹ we outlined the discovery and structure−activity relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (Ki for ETA receptor:  0.015 ± 0.004 nM; for ETB receptor:  41 ± 21 nM).

Modifications to the ETA/B mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ETA receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ETA receptor (Ki = 0.0042 ± 0.0038 nM) and an ETA/B receptor selectivity up to 29 000 (Ki = 130 ± 50 nM for the human cloned ETB receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ETA receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a “pyrimidine binding pocket” might exist in the ETA receptor.

Although recent papers have suggested that psychological factors are implicated in the experience of infertility, few studies have assessed this relationship in a sample of Japanese infertile women. This study was carried out in order to clarify whether Japanese infertile women experience emotional distress. A cross-sectional questionnaire study was performed to assess the psychological states of 101 infertile women compared to 81 healthy pregnant women. The hospital anxiety and depression scale (HADS) and the profile of mood states (POMS) were administered. These questionnaires produced scores for depression/dejection, anxiety, aggression/hostility, lack of vigour, fatigue, tension anxiety, and confusion. The HADS and the POMS scores of infertile women were significantly higher than those of pregnant women, except for fatigue score. Infertile women with positive HADS indicating emotional disorders (39/101, 38.6%) were significantly (P = 0.0008, chi(2) test) more than those of pregnant women (13/81, 16.0%) when the threshold was set at 12/13 of total HADS scores. The HADS scores were not affected by the women's age, duration of infertility, experience of conception, routine tests, and work states. In this Japanese population, infertile women reported higher levels of emotional distress than pregnant women, suggesting psychological support is needed for infertile women.

Abstract: Background. The aim of this study was to investigate the clinical effectiveness of a structured group intervention program for Japanese patients with breast cancer. Methods. Fifty-seven patients with breast cancer participated in this program. The scores for the Profile of Mood States (POMS) and the Dealing with Illness Inventory were compared before and after intervention. As 5 patients failed to complete the program and 5 did not complete the inventories, the results for 47 patients were analyzed. As intravenous chemotherapy was presumed to cause severe distress, 7 patients who received this treatment during the period covered by the sessions were excluded. The scores of the remaining 40 patients were compared. Results. In the 40 patients, there were significant differences between the before and after intervention scores for Depression, Lack-of-Vigor, Tension-Anxiety, Confusion, and Total Mood Disturbances. Scores for coping strategies and methods, such as passive–resignation, cognitive–passive/ruminative, and avoidance were decreased, as expected; however, scores for active–expressive/information-seeking, and active–reliance on others were, unexpectedly, decreased. Conclusion. This study demonstrated the short-term effectiveness of structured interventions for Japanese patients with breast cancer, especially in alleviating psychological distress.

The objective of the study was to evaluate the effect of pretreatments such as gonadectomy in male and female rats, and gonadotropin-releasing hormone agonist (GnRHa) administration in female rats, on levels of secretion of melatonin, using an organ culture of pineal glands. Gonadectomy 2 weeks before the animal was killed increased the amount of melatonin secreted into the medium by the pineal glands of female rats but not of male rats. The increase in in vitro melatonin secretion after ovariectomy in female rats was prevented by estrogen replacement. Ovariectomy 3 and 4 weeks before death also significantly increased the amount of melatonin secretion. Administration of GnRHa 2 weeks before decapitation significantly decreased serum estradiol concentrations and significantly increased melatonin secretion by the pineal glands of female rat. GnRHa administration 3 or 4 weeks before decapitation also significantly decreased serum estradiol concentrations, but did not increase pineal secretion of melatonin. The results indicate that ovariectomy increases melatonin secretion from organ-cultured pineal glands and that this increase is suppressed by estrogen in adult female rats. In contrast, orchiectomy in male rats does not influence in vitro secretion of melatonin. These results suggest that the GnRH-gonadotropin system may participate in the regulation of pineal melatonin secretion in adult female rats.

Abstract:  Fatigue is one of the most frequent symptoms in cancer patients. However, the precise causes of this fatigue are still unknown, and this situation makes it difficult to combat the problem. The present study was conducted to investigate factors correlated with fatigue in disease-free breast cancer patients. A group of 134 randomly selected ambulatory breast cancer patients who had undergone successful surgical treatment participated. They completed the Cancer Fatigue Scale, the Hospital Anxiety and Depression Scale, the Mental Adjustment to Cancer Scale, and an ad hoc questionnaire detailing physical symptoms, social support, and demographic variables at home and returned them by mail the following day. Multiple regression analysis revealed that fatigue was significantly correlated with dyspnea, insufficient sleep, and depression, and that these three variables accounted for a total of 46% of variance in fatigue. Factors concerned with the cancer and treatment, such as disease stage, lymph node metastasis, number of days since operation, past intravenous chemotherapy, radiotherapy, current use of fluoropyrimidine compounds, and current use of tamoxifen citrate were not correlated with fatigue. The results suggest that fatigue in this population is determined by current physical and psychological distress rather than by the cancer itself and prior cancer treatments, and that the management of dyspnea, insomnia, and depression might be important in reducing fatigue in this population.

Background.The purpose of this study was to investigate physicians' perspectives on do-not-resuscitate (DNR) orders at Tokai University hospital, where a euthanasia-like accident occurred several years ago.

In Japan the type A behavior pattern, particularly its component of hostility, is known to have less value as a risk for coronary artery disease (CAD) than in the United States. We developed a questionnaire (Japanese Coronary-prone Behavior Scale [JCBS]) to investigate the behavioral correlates with CAD among contemporary Japanese persons. The JCBS was administered to 419 Japanese men undergoing coronary angiography; 310 of them had angiographic or clinical evidence or both of CAD, and 109 had no evidence of CAD. The group with CAD had more coronary risk factors than the group without CAD, but the two groups did not differ in type A behavior pattern as assessed with the Jenkins Activity Survey. Stepwise discriminant analysis, in which standard coronary risk factors were forced into the model, revealed that inclusion of nine JCBS items (scale C) in the model resulted in the best discrimination between the two groups. Cross-validation results showed that the error-rate estimates for the discriminant models that consisted only of standard coronary risk factors, only of scale C items, and of their combination were 34.7, 32.4, and 27.0%, respectively. The scale C items represented a job-centered lifestyle, social dominance, and suppressed overt type A behaviors. These results indicate that an independent behavior pattern prone to CAD is discernible among Japanese men and suggest that the behavior pattern may contain characteristics that can be differentiated from those that constitute the type A behavior pattern. (Am Heart J 1997;134:1029-36.)

Phosphatidylinositol 3-kinase (PI 3-kinase) is stimulated by association with a variety of tyrosine kinase receptors and intracellular tyrosine-phosphorylated substrates. We isolated a cDNA that encodes a 50-kDa regulatory subunit of PI 3-kinase with an expression cloning method using 32P-labeled insulin receptor substrate-1 (IRS-1). This 50-kDa protein contains two SH2 domains and an inter-SH2 domain of p85alpha, but the SH3 and bcr homology domains of p85alpha were replaced by a unique 6-amino acid sequence. Thus, this protein appears to be generated by alternative splicing of the p85alpha gene product. We suggest that this protein be called p50alpha. Northern blotting using a specific DNA probe corresponding to p50alpha revealed 6.0- and 2.8-kb bands in hepatic, brain, and renal tissues. The expression of p50alpha protein and its associated PI 3-kinase were detected in lysates prepared from the liver, brain, and muscle using a specific antibody against p50alpha. Taken together, these observations indicate that the p85alpha gene actually generates three protein products of 85, 55, and 50 kDa. The distributions of the three proteins (p85alpha, p55alpha, and p50alpha), in various rat tissues and also in various brain compartments, were found to be different. Interestingly, p50alpha forms a heterodimer with p110 that can as well as cannot be labeled with wortmannin, whereas p85alpha and p55alpha associate only with p110 that can be wortmannin-labeled. Furthermore, p50alpha exhibits a markedly higher capacity for activation of associated PI 3-kinase via insulin stimulation and has a higher affinity for tyrosine-phosphorylated IRS-1 than the other isoforms. Considering the high level of p50alpha expression in the liver and its marked responsiveness to insulin, p50alpha appears to play an important role in the activation of hepatic PI 3-kinase. Each of the three alpha isoforms has a different function and may have specific roles in various tissues.

Phosphatidylinositol 3-kinase, which is composed of a 110-kDa catalytic subunit and a regulatory subunit, plays important roles in various cellular signaling mechanisms. We screened a rat brain cDNA expression library with 32P-labeled human IRS-1 protein and cloned cDNAs that were very likely to be generated by alternative splicing of p85alpha gene products. These cDNAs were demonstrated to encode a 55-kDa protein (p55alpha) containing two SH2 domains and an inter-SH2 domain of p85alpha but neither a bcr domain nor a SH3 homology domain. Interestingly, p55 alpha contains a unique 34-amino acid sequence at its NH2 terminus, which is not included in the p85alpha amino acid sequence. This 34-amino acid portion was revealed to be comparable with p55PIK (p55gamma) in length, with a high homology between the two, suggesting that these NH2-terminal domains of p55alpha and p5 gamma may have a specific role that p85 does not. The expression of p55alpha mRNA is most abundant in the brain, but expression is ubiquitous in most rat tissues. Furthermore, it should be noted that the expression of p85alpha mRNA in muscle is almost undetectably low by Northern blotting with a cDNA probe coding for the p85alpha SH3 domain, while the expression of p55alpha can be readily detected. These results suggest that p55 alpha may play an unique regulatory role for phosphatidylinositol 3-kinase in brain and muscle.

Summary Twenty-six cases with spontaneous carotid-cavernous fistulas were followed up for periods ranging between 4 months and 9 years 8 months. A complete regression of symptoms without reappearance for more than 6 months was noted in 19 cases, a marked improvement in 2 cases, and a moderate regression in 3 cases. In 2 cases, symptoms have continued for 9 years 8 months and for 1 year. The regression of symptoms was usually delayed in patients less than 60 years old, in cases in which the symptoms developed slowly, and in cases with multiple draining veins. According to our observations a regression of symptoms may occur after very slight changes of haemodynamics.

A fiber circular polarizer, composed of a metal-coated fiber polarizer and a λ/4 platelet fabricated on a birefringent fiber, has been demonstrated. The λ/4 platelet was made by cutting a birefringent fiber to an appropriate length. The device structure was designed by stress analysis simulation using a finite element method to set the angle θ = π/4 between the fiber polarizer axis and the birefringent fiber major axis. The 17.6-dB maximum extinction ratio was obtained when the left- and right-circularly polarized light was launched into the device. It is assumed that such a fiber circular polarizer will operate as a quasi-isolator, because the light reflected from the output, the main factor backing the light source, is eliminated.

A simple and novel fabrication technique for a fiber-type polarizer has been developed, and the polarization characteristics of the polarizer have been investigated. The polarizer is formed from a single-mode fiber composed of a concentric core and a silica cladding having a B_2O_3-doped silica portion. The cladding is etched off asymmetrically by utilizing the etching-speed difference between pure silica and B_2O_3-doped silica in 49% HF. The Al film is subsequently evaporated onto the etched portion. The extinction ratios of polarizers with various buffer-layer thicknesses were measured at two wavelengths, λ = 1.15 μm and λ = 1.29 μm. The maximum measured extinction ratio was 37 dB at λ = 1.29 μm for a 4-cm-long polarizer.

Nonlinear optical properties of high-Δ, small-core singlemode fibres were investigated. Results indicated that such fibres have low stimulated Raman scattering critical powers and large frequency chirping. In addition, 43% coupling efficiency was achieved in the direct coupling between highΔ fibres and an edge-emitting LED.

High-Δn, small-core single-mode fibres have been fabricated with the VAD method. Results have been obtained for fibres having cores of Δn = 2.9% and diameter = 2.3 μm and Δn = 1.9% and diameter = 2.8 μm. Minimum losses for a Δn = 2.9% fibre and a Δn = 1.9% fibre are 0.82 dB/km at 1.61 μm and 0.68 dB/km at 1.62 μm. Other fundamental properties have been measured.

Chromatic dispersion of two orthogonal polarization modes has been investigated for various kinds of PANDA fibers. In high-birefringence fiber with modal birefringence B = 7.9 × 10^−4, the zero-dispersion wavelength for the x-polarization mode (λ_0x = 1.307 μm) was 6 nm shorter than that for the y-polarization mode (λ_0y = 1.313 μm). Chromatic dispersion of the fiber at 1.55-μm wavelength was σx = 18.3 psec/km-nm and σy = 16.1 psec/km-nm for the x- and y-polarization modes, respectively.

The letter investigates the dispersion of GeO2 glass core and F-doped GeO2 glass cladding single-mode optical fibre. It is estimated that the total dispersion goes to zero at about λ = 1.77 μm. The material dispersions of these glasses are also measured. Material dispersion of GeO2 glass, which contains fluorine of 0.41 wt%, vanished at λ = 1.722μm. This occurs at λ = 1.734 μm for pure GeO2 glass.

The Faraday effect in stress-birefringent silica fibre is discussed theoretically and measured experimentally. In the red and infra-red spectral range, the Verdet constant is found to be VH = 2.0 × 10−35v2 rad/A, where v is the optical frequency in hertz.

A new preform fabrication technique for realising long lengths of polarisation-maintaining optical fibres is described. The technique is shown to produce stress-induced birefringent fibres with symmetry and uniformity along the length in the stress-applying parts. The resultant 8.3 km-long fibre whose relative refractive-index difference is 0.6% has been obtained with a crosstalk of −23 dB at 1.15 μm wavelength, where the loss is 1.7 dB/km.

Polarisation characteristics of single mode fibres with asymmetrical refractive index pits on both sides of the core have been investigated. The modal birefringence of the single mode fibre measured at λ=1.15 μm was 5×10−5. It was confirmed that the state of polarisation was stable and was scarcely affected by the ambient conditions such as concentrated force, twists of the fibre, and temperature variations.

A very low loss single-mode fibre with a minimum loss of 0.20 dB/km at a wavelength of 1.55 μm is attained; this loss reaches the ultimate lower loss limit of silica-based optical glass fibre. The loss mechanism is also discussed.

Chromatic dispersion properties of the Ti:LiNbO_3 optical waveguide have been investigated. Dispersion values of the waveguide fabricated in Z-cut LiNbO_3 were σ_TE = − 2.0 fsec cm^−1 nm^−1 at a wavelength of 1.3 μm and σ_TE = –1.3 fsec cm^−1 nm^−1 at a wavelength of 1.5 μm. Measurement results were compared with theoretical values that take into account the bulk dispersion data and the waveguide dispersion characteristics.

Optical pulse compression at 1.5 µm has been conducted. 20 ps (FWHM) optical pulses from a Tl: KCl-colour-centre laser were compressed into pedestal-free 1.2 ps pulses using a large-positive-dispersion fibre and a grating pair. In addition, 280 fs pulses were obtained from the resultant 1.2ps through the soliton compression effect in a negative-dispersion fibre.

Single-mode fibres with 8.2% Δ and a 1.4µm diameter-GeO2 core have been prepared for efficient stimulated Raman effect. When pumping a 2.7 m-long fibre by a Q-switched and mode-locked Nd:YAG laser (λ=1.064µm), the first Stokes light (λ=1.114µm) and second Stokes light (λm=1.169µm) have been observed at the input peak power levels of 24 W and 40 W, respectively. These results indicate that the above critical power levels are approximately 10−2 ∼ 10−3 smaller than those for the high-silica single-mode fibre.

A preform dimension control technique in the VAD process has been developed using chemical dry etching with fluoride gas applied to silica glass particles in an oxyhydrogen flame. Wholly synthesised VAD single-mode fibre preforms have been fabricated using this technique with high adjustment accuracy of outer/core diameter ratio. These preforms have exhibited excellent structural characteristics.

A low-loss polarisation-maintaining optical fibre with low crosstalk is presented. The minimum transmission loss is 0.35 dB/km at 1.54 μm and crosstalk is −32 dB at 1.56 μm in a 1 km length. The relative refractive index difference between core and cladding is 0.3%, and the modal birefringence is 2.8 × 10−4.

A single-polarisation single-mode (SPSM) fibre with crosstalk of −40 dB in a 3.2 km length has been demonstrated. No crosstalk degradation was found for lengths of more than 0.2 km. The two polarisations of the fundamental mode were split with a high modal birefringence of 8.5×10−4, which was produced by PANDA structure. The transmission loss was 2.8 dB/km at 1.56 μm.

A transmission loss of 0.25 dB/km at 1.57 μm wavelength, which is comparable to that found in commercially available single-mode fibres, has been demonstrated in PANDA optical fibres. A crosstalk of −29 dB in a 2.4 km length, which corresponds to the mode coupling coefficient of 5.2 × 10−7 m−1, has been found in the 1.55 μm wavelength region.

An 11 km-long polarisation-maintaining optical fibre with crosstalk up to −25.2 dB and −22.5 dB at 1.30 μm and 1.56 μm, respectively, is presented. Transmission loss is 1.2 dB/km at 1.3 μm and has a minimum value of 0.79 dB/km at 1.56 μm.

Low-loss single-mode fibres with GeO2-doped SiO2 cores have been made by the c.v.d. method and the loss spectrum from 0.6 to 1.8 μm measured. The minimum loss of the fibre with suitably designed parameters, characterised by the refractive-index difference and the core diameter, was 0.75 dB/km at 1.05 μm.

Low-loss and highly birefringent single polarisation fibres have been fabricated. The minimum transmission loss and the modal birefringence of the fibre with refractive-index difference Δ=0.61% was 0.62 dB/km at λ=1.52 μm and 8.5×10−5 at λ=1.15 μm, respectively. The state of linear polarisation was stable against the handling conditions such as bending, twists, concentrated force, and temperature variations.