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Introduction Hormonal contraceptives are among the most effective forms of reversible contraception, but many other compounds, including some antiretrovirals, have clinically meaningful drug–drug interactions (DDIs) with hormonal contraceptives. Islatravir is a novel human immunodeficiency virus nucleoside reverse transcriptase translocation inhibitor currently in clinical development for treatment and prevention of HIV infection. A phase 1 clinical trial was conducted to evaluate the DDI of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE). Methods This was an open‐label, two‐period, fixed‐sequence, DDI clinical trial in healthy, postmenopausal or bilaterally oophorectomized females aged 18 through 65 years in the United States between October 2016 and January 2017. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7‐day washout. Islatravir, 20 mg, was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of islatravir. Pharmacokinetic samples for plasma LNG and EE concentrations were collected pre‐dose and up to 120 hours post‐dose in each period. Safety and tolerability were assessed throughout the trial by clinical assessments, laboratory evaluations and examination of adverse events. Results and Discussion Fourteen participants were enrolled. The pharmacokinetics of LNG and EE were not meaningfully altered by co‐administration with islatravir. For the comparison of (islatravir + LNG/EE)/(LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for LNG AUC0–inf and C max were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE, the GMRs (90% CI) for AUC0–inf and C max were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co‐administration of all three drugs was generally well tolerated. Conclusions The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.

BackgroundDenosumab, a human IgG2 monoclonal antibody with high affinity for RANKL, is approved for treatment of bone erosion (ER) in patients with RA, based on the results of clinical trials. However, its effectiveness in combination with conventional therapy in RA patients has not been fully investigated in clinical practice.ObjectivesThis exploratory study aimed to compare, in patients receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) for treatment of RA, the effectiveness of combined use of csDMARD and denosumab vs csDMARD alone, in terms of inhibition of ER determined by HR-pQCT.MethodsDetail protocol of this open-label, randomized, parallel-group study has been published previously.1 RA patients with moderate or low disease activity and progressive ER were eligible, and were randomly assigned to receive denosumab in addition to the csDMARD (denosumab) group or to continued use of the csDMARD alone (csDMARD) group. Denosumab was administered every 6 months during the 12-month study period. The primary endpoint was change in ER-depth at the second and third metacarpal bones, determined by HR-pQCT at month 6. For the primary endpoint, a linear mixed effect model analysis was performed using treatment group, sex, anti-cyclic citrullinated peptide (CCP) antibody (positive vs negative), and baseline disease activity (DAS28-ESR) as fixed effects, patients as random effects, and baseline values as covariates. For extension data, measurement time-point and the interaction between treatment group and measurement time-point was further added as fixed effects. The adverse events (AEs) were recorded.ResultsA total of 46 patients were randomized to denosumab and csDMARD groups (both N=23), and baseline characteristics were similar between both groups. Although the difference was not significant, the estimate mean (95%CI) change of ER-depth at month 6 from baseline as the primary endpoint was −0.57 (−1.52, 0.39) in the denosumab group vs −0.22 (−0.97, 0.53) in the csDMARD group, respectively. At months 6 and 12, ER-depth, -width, and -volume (extension data) were numerically lower in the denosumab group than in the csDMARD group (Table 1). Compared with patients in the csDMARD group, those in the denosumab group had significantly higher volumetric bone mineral density (vBMD) at month 12. AEs were reported in 12 (52.2%) and 13 (56.5%) of patients in the denosumab and csDMARD groups, respectively. The most common AEs of denosumab groups was hypocalcemia (reported in 4), and all the events were causally related with denosumab. Serious AEs were reported in 1 (4.3%) and 2 (8.7%) of patients in the denosumab and csDMARD groups, and which were not related to treatment drug.Table 1.ER and microstructure in denosumab group vs csDMARD groupMonthDenosumab group (n=21)csDMARDs group (n=22)Difference (Denosumab- csDMARDs)n1Estimate Means [95%CI]n1Estimate Means [95%CI]Estimate Means [95%CI]ER-depth617−0.46 [−1.31, 0.39]25−0.20 [−0.89, 0.49]−0.27 [−0.86, 0.32]1217−0.56 [−1.41, 0.29]22−0.20 [−0.90, 0.49]−0.35 [−0.95, 0.24]ER-width617−0.26 [−1.10, 0.57]25−0.06 [−0.73, 0.61]−0.20 [−0.81, 0.40]1217−0.27 [−1.10, 0.56]22−0.03 [−0.70, 0.64]−0.24 [−0.85, 0.38]ER-volume616−6.21 [−23.89, 11.46]24−1.71 [−16.07, 12.66]−4.51 [−16.67, 7.65]1217−6.25 [−23.94, 11.44]21−3.18 [−17.56, 11.20]−3.07 [−15.32, 9.17]vBMD6426.41 [2.78, 10.03]442.46 [−1.33, 6.24]3.95 [−0.05, 7.94]12389.20 [5.46, 12.95]423.66 [−0.15, 7.46]5.55 [1.46, 9.63]*These were extension data.This is the efficacy analysis set which excluded 3 patients from the full analysis set.*; pn, number of patients; n1, number of measurement pointsConclusionOur results suggest that adding denosumab to csDMARD therapy may help prevent ER, promote ER repair, and improve bone microstructure.References[1]Iwamoto N, et al., Trials. 2019;20(1):1–8.Disclosure of InterestsNaoki Iwamoto Speakers bureau: Daiichi Sankyo Co., Ltd., Grant/research support from: Daiichi Sankyo Co., Ltd., Ko Chiba Speakers bureau: Daiichi Sankyo Co., Ltd., Shuntaro Sato: None declared, Kazuteru Shiraishi: None declared, Konosuke Watanabe: None declared, Nozomi Ohki: None declared, Akitomo Okada: None declared, Tomohiro Koga: None declared, Makiko Kobayashi Employee of: Daiichi Sankyo Co., Ltd. (retired at submission), Kengo Saito Employee of: Daiichi Sankyo Co., Ltd., Naoki Okubo Employee of: Daiichi Sankyo Co., Ltd., Atsushi Kawakami Speakers bureau: Daiichi Sankyo Co., Ltd., Grant/research support from: Daiichi Sankyo Co., Ltd.

Supplemental material, Supplemental Material1 for Factors predictive of long-term mortality in lupus nephritis: a multicenter retrospective study of a Japanese cohort by K Ichinose, M Kitamura, S Sato, K Fujikawa, Y Horai, N Matsuoka, M Tsuboi, F Nonaka, T Shimizu, S Fukui, M Umeda, T Koga, S Kawashiri, N Iwamoto, M Tamai, H Nakamura, T Origuchi, T Nishino and A Kawakami in Lupus

Aims To examine the efficacy and safety of once-weekly dulaglutide 0.75 mg monotherapy compared with once-daily liraglutide 0.9 mg in Japanese patients with type 2 diabetes (T2D) for 52 weeks. Methods We conducted a phase III, randomized, 52-week (26-week primary endpoint), active- and placebo-controlled trial comparing 492 Japanese patients (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70). Participants and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide (open-label comparator); after 26 weeks, patients randomized to placebo were switched to once-weekly dulaglutide 0.75 mg (open-label). The present paper reports results for patients treated with dulaglutide and patients treated with liraglutide for 52 weeks. Results At week 52, dulaglutide decreased HbA1c significantly from baseline compared with liraglutide [least squares mean difference: −0.20; 95% confidence interval (CI) −0.39, −0.01; p = 0.04]. At week 52 (last observation carried forward), dulaglutide significantly decreased pre- and post-dinner blood glucose (BG) levels, the mean of seven-point self-monitored BG profiles, the mean of all postprandial BG levels and circadian variation compared with liraglutide. Body weight was generally stable in both groups through 52 weeks. The most frequently reported adverse events were nasopharyngitis, constipation, nausea and diarrhoea. Eight dulaglutide-treated (2.9%) and four liraglutide-treated (2.9%) patients reported hypoglycaemia, with no event being severe. Conclusions Monotherapy with once-weekly dulaglutide 0.75 mg was effective and safe in Japanese patients with T2D, with better glycaemic control compared with once-daily liraglutide 0.9 mg.

Supplemental material, Supplementary Figure for The efficacy of adjunct tacrolimus treatment in pregnancy outcomes in patients with systemic lupus erythematosus by K Ichinose, S Sato, Y Kitajima, Y Horai, K Fujikawa, M Umeda, S Fukui, A Nishino, T Koga, S Y Kawashiri, N Iwamoto, M Tamai, H Nakamura, T Origuchi, I Yasuhi, H Masuzaki and A Kawakami in Lupus

Supplemental material, Supplementary Table for The efficacy of adjunct tacrolimus treatment in pregnancy outcomes in patients with systemic lupus erythematosus by K Ichinose, S Sato, Y Kitajima, Y Horai, K Fujikawa, M Umeda, S Fukui, A Nishino, T Koga, S Y Kawashiri, N Iwamoto, M Tamai, H Nakamura, T Origuchi, I Yasuhi, H Masuzaki and A Kawakami in Lupus

Aims To examine the efficacy and safety of once-weekly dulaglutide monotherapy (0.75 mg) compared with placebo and once-daily liraglutide (0.9 mg) in Japanese patients with type 2 diabetes. Methods This was a phase III, 52-week (26-week primary endpoint), randomized, double-blind, placebo-controlled, open-label comparator (liraglutide) trial comparing 492 Japanese patients with type 2 diabetes (dulaglutide, n = 281; liraglutide, n = 141; and placebo, n = 70) who were aged ≥20 years. Patients and investigators were blinded to treatment assignment for dulaglutide and placebo but not for liraglutide. The primary objective evaluated the superiority of dulaglutide versus placebo on change from baseline in glycated haemoglobin (HbA1c) at 26 weeks. Analyses were performed on the full analysis set. Results At 26 weeks, once-weekly dulaglutide was superior to placebo and non-inferior to once-daily liraglutide for HbA1c change from baseline [least squares mean difference: dulaglutide vs placebo −1.57% (95% confidence interval −1.79 to −1.35); dulaglutide vs liraglutide −0.10% (95% confidence interval −0.27 to 0.07)]. The most frequently reported adverse events were nasopharyngitis, constipation, diarrhoea, nausea, abdominal distension and decreased appetite; only decreased appetite was different between the dulaglutide and liraglutide groups [dulaglutide, n = 2 (0.7%); liraglutide, n = 8 (5.8%); p = 0.003]. Nine (1.8%) patients experienced hypoglycaemia [dulaglutide, n = 6 (2.1%); liraglutide, n = 2 (1.5%); placebo, n = 1 (1.4%)], with no event being severe. Conclusions In Japanese patients with type 2 diabetes, once-weekly dulaglutide (0.75 mg) was superior to placebo and non-inferior to once-daily liraglutide (0.9 mg) for reduction in HbA1c at 26 weeks. Dulaglutide was safe and well tolerated.

We have measured the discrete $\gamma$ rays from thermal neutron capture on enriched gadolinium targets ($^{155}$Gd and $^{157}$Gd) using the ANNRI Germanium Spectrometer at JPARC. The photo-peak efficiencies were calibrated from 0.2 to 9 MeV using $\gamma$ rays from the standard radioactive sources ($^{60}$Co, $^{152}$Eu) and prompt $\gamma$ rays from $^{35}$Cl$(n,\gamma)$ reaction. We have calculated the relative intensities of discrete $\gamma$ rays from $^{157}$Gd$(n,\gamma)$ reaction. We found that our data are in fair agreement with the values published by NNDC (CapGam). We present the relative intensities of discrete $\gamma$ rays from $^{155}$Gd$(n,\gamma)$ reaction measured for the first time.

Introduction. Understanding the genetic architecture of scleroderma (SSc) susceptibility is vital both in gene discovery and in determining the influence of previously identified susceptibility variants. It is particularly important in understanding disease mechanism in a disease with few therapies and great morbidity and mortality. Methods. We selected 557 cases from the Australian Scleroderma Cohort Study (ASCS), for genotyping with the Immunochip, a custom Illumina Infinium genotyping array containing 196 524 rare and common variants shown to be important in a wide variety of autoimmune disorders. A total of 4537 controls were taken from the 1958 British Birth cohort. Genotype data were analysed with PLINK. Samples and SNPs with low call rates were excluded, as were SNPs in Hardy-Weinberg disequilibrium or with less than two occurrences of the minor allele. Eigenstrat was used to analyse population structure. The final data set consisted of 505 cases, 4491 controls and 146 867 SNPs. Allelic association analyses were conducted using Fisher's exact test. Genotype clusters were manually examined for all associations of P < 10−5 since calling is difficult for some rare variants. Results. Significant and suggestive associations were detected at seven loci. Several of these have been previously implicated in scleroderma susceptibility (HLA-DRB1 and STAT4) and several are novel associations, including SNPs near PXK (P = 4.4 × 10−6) and CFDP1(P = 2.6 × 10−6). The strongest associations were with SNPs in the Class II region of the MHC. One of the most strongly associated SNPs [rs4639334; P = 1.6 × 10−8; odds ratio (OR) = 1.8] is in linkage disequilibrium (r2 = 0.46) with the Class II allele HLA-DRB1*11:01. This allele has been associated with SSc. Another strongly associated SNP is rs2857130 (P = 1.6 × 10−8; OR = 0.67), which lies in the promoter region of HLA-DRB1, but is not in LD with any classical MHC alleles. Outside the MHC, there were six regions of association with P < 10−5,including the confirmed SSc locus at STAT4. Several SNPs implicate a locus at PXK, which has been previously associated with SLE but not with SSc. The remaining associations are novel for both SSc and SLE and require replication. Of particular interest is a rare variant located within a non-coding RNA on chromosome 6q21 which was ∼20 times more frequent in cases than controls. We are currently dissecting the potential biological implications of this locus. Conclusions. This pilot study has confirmed previously reported SSc associations, revealed further genetic overlap between SSc and SLE, and identified putative novel SSc susceptibility loci including a rare allele with major effect size

Background Monocytes can differentiate into either proinflammatory, microbicidal M1 macrophage or anti-inflammatory M2 macrophage subtypes. In addition to macrophages, regarding monocyte subsets, M1 monocytes and M2 monocytes mirroring the M1/M2 macrophage polarization concept were suggested. Little is known regarding the relationships between osteoclastogenesis and M1/M2 monocyte subsets. Objectives We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast differentiation ability and clinical characteristics in patients with rheumatoid arthritis (RA). Methods Peripheral blood mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We defined positive CD14, CD68 and CCR2 monocytes as M1 monocytes, and in separate tubes, we defined positive CD14, CX3CR1 and CD163 or CD206 monocytes as M2 monocytes. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate osteoclast differentiation in vitro. We defined osteoclasts as tartrate-resistant acid phosphatase (TRAP) staining-positive cells with >3 nuclei. We counted the osteoclasts in the whole wells of a 96-well dish. Pit formation assays were performed to evaluate function of osteoclasts. Results Forty RA patients and 20 healthy donors were included. Twenty-two patients (55%) were ACPA-positive. The median M1/M2 ratio was 0.59 (0.31–1.11, IQR). There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated osteoclast number in vitro in RA patients (ρ=0.81, p The ACPA-positive patients had significantly higher M1/M2 ratio in vivo (p=0.028) (E) and significantly greater numbers of osteoclasts in vitro (p Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis (β-coefficient 16.3, p RA patients with M1/M2 ratio >1 (having relatively more M1 monocytes) had higher erythrocyte sedimentation rates (p=0.011) and C-reactive protein (p=0.032) than RA patients with M1/M2 ratio ≤1. M1-dominant monocytes in vitro produced higher concentrations of IL-6 upon stimulation with lipopolysaccharide than M2 monocytes (p=0.032). Conclusions The M1/M2 ratio is strongly correlated with the in vitro differentiation of osteoclasts in patients with RA. The RA patients with positive ACPA had higher M1/M2 ratio and higher numbers of osteoclasts. M1 and M2 monocyte subsets may become a new target of treatments for RA. Disclosure of Interest None declared

Diabet. Med. 28, 96–99 (2011) Abstract Aims Previous studies have implicated reduced serum bilirubin concentrations in the development of cardiovascular disease. The aim of this study was to examine whether bilirubin may explain the high incidence of vascular complications in haemodialysis patients with Type 2 diabetes. Methods We compared serum bilirubin concentrations, as well as other known aetiological risk factors for cardiovascular disease, in 206 Type 2 diabetes patients on haemodialysis with those in 741 Type 2 diabetes patients not receiving haemodialysis, and evaluated the association between serum bilirubin concentration and cardiovascular disease incidence. Results Incidences of cardiovascular disease and systolic blood pressure were higher; however, BMI and serum total cholesterol were lower in haemodialysis patients compared with those in patients without haemodialysis. Serum total (0.30 ± 0.10 vs. 0.74 ± 0.26 mg/dl, 0.005 ± 0.002 vs. 0.013 ± 0.004 mmol/l, P

The maple aphid infests maple trees the whole year round, but in spring its feeding site is restricted to buds, growing shoots and inflorescences. Some differences in the time of budding and the number of inflorescences are found among maple trees, and the favourable feeding site of the aphid distributes contagiously both in time and space. Early budding contributes to lower the mortality of fundatrices, but late budding prepares suitable feeding site for winged aphids in the second generation. Each winged aphid can produce either larvae or aestivating dimorphs depending upon the host tree condition. Dispersal of winged females and their ability in producing both larvae and aestivating dimorphs contribute to exploit the feeding site efficiently. Zusammenfassung Zur Wirkung von Knospung und Blute der Ahornbaume auf die Populationsentwicklung der Ahorn-Blattlaus, Periphyllus californiensis Shinji (Hom., Aphididae) P. californiensis befallt die Ahornbaume wahrend des ganzen Jahres, saugt jedoch im Fruhjahr nur an Knospen und Bluten. Es wurden individuelle Unterschiede im Knospen und Bluhen der Baume festgestellt. Das Saugen breitet sich dann raumlich und zeitlich schadlich aus. Ein fruhes Austreiben der Knospen tragt dazu bei, die Sterblichkeit der Fundatrices zu verringern, wahrend spates Austreiben geeignete Saugstellen fur die geflugelten Tiere der 2. Generation schafft. Jede geflugelte Blattlaus kann — in Abhangigkeit von den Wirtsbaumbedingungen — entweder Larven oder uberwinternde Dimorphen hervorbringen. Diese Fahigkeit, in Verbindung mit der Ausbreitung der geflugelten Weibchen, ermoglicht es der Population, die Saugstellen effizient auszunutzen.

Angiogenesis is the formation of new capillary blood vessels from preexisting vessels. It is involved in many normal and diseased conditions, as well as in the application of tissue-engineered products. Th ere has been extensive eff ort made to develop strategies for controlling pathological angiogenesis and for promoting vascularization in biomedical engineering applications. Central to advancing these strategies is a mechanistic understanding of the angiogenic process. Angiogenesis is tightly regulated by local tissue environmental factors, including soluble molecules, extracellular matrices, cell-cell interactions, and diverse mechanical forces. Great advances have been made in identifying the biochemical factors and intracellular signaling pathways that mediate the control of angiogenesis. Th is review focuses on work that explores the biophysical aspect of angiogenesis regulation. Specifi cally, we discuss the role of cell-generated forces, counterforces from the extracellular matrix, and mechanical forces associated with blood fl ow and extravascular tissue activity in the regulation of angiogenesis. Because angiogenesis occurs in a mechanically dynamic environment, future investigations should aim at understanding how cells integrate chemical and mechanical signals so that a rational approach to controlling angiogenesis will become possible. In this regard, computational models that incorporate multiple epigenetic factors to predict capil- lary patterning will be useful.

Copper migration continues to be an important consideration in new and emerging interconnect technologies. As line dimensions shrink and new low k materials are introduced into the integrated circuit (IC) structure, the danger of electrical failure due to copper migration increases. The search for better barriers and new copper alloys that resist migration is being sought. Important considerations for copper migration are the adhesion characteristics, which add to the electrical failure phenomenon and also help determine the survivability of the metallic layers in the IC build up process. To understand the survivability issues, we have employed a combination of experimental and modeling studies to determine how the combination of metallic layers may interact. Both the experimental tests and the modeling have been found to be consistent and simple molecular models can be used to predict gross failure trends. These studies have directed us toward newer barrier and copper alloys layers that should be useful in the next generation.

We report on preparation of Ir and IrO2 electrodes and its applications to planar and three-dimensional (3D) PZT capacitors solely by MOCVD using a novel liquid Ir precursor, Ir(EtCp) (CHD). Continuous 15–50 nm-thick Ir films with a pure metallic phase were successfully grown at 250-350°C on SiO2/Si without an incubation time. Ir electrodes showed 40–60% step coverage on stepped substrates with aspect ratios of 0.5–2.0. Fatigue free planar and 3D-Ir/PZT/Ir capacitors with 2Pr of 27–36 μ C/cm2 were successfully fabricated solely by MOCVD. IrO2 electrodes were grown at 400°C by 2-step MOCVD using surface oxidized Ir seeds. Planar PZT capacitors with IrO2 bottom and Ir top electrodes showed D-E hysteresis loops with 2Pr of 27 μ C/cm2 and endurance property with no degradation up to 1010 switching cycles by bipolar pulses of ± 5 V and 500 kHz.

The paper begins with the introduction of Atlantic salmon into the local ecosystems of the Pacific Northwest (Puget Sound), and describes potential interactions with native salmonids. Specific sections review possible hybridization between Atlantic and Pacific salmon, genetic dilution and alteration of the gene pool, the colonization of the aquatic environment by Atlantic salmon, and finally the interactions of wild salmon and genetically altered transgenics. This is followed by possible epidemics and transmission of waterborne disease, and reviews the potential for cultured Atlantic salmon, a non-native species, to introduce new diseases into the local ecosystem. There are nine specific items, from the diseases which might be involved, to potential interactions, and current policies for disease control. After a review of the potential ecological impacts in the Pacific Northwest, specifically the interaction with Pacific salmon and predation, there are three parts on the effects of artificial propagation practices in the region in general, the impacts of the introduction of various non-indigenous salmonid species, and a comparison of escapes or releases of propagated Atlantic and Pacific salmon. The last part examines the potential effects of Atlantic salmon vis-a-vis the Biological Status Reviews of west coast Pacific salmon stocks carried out by the National Marine Fisheries Service. The review ends by summarizing the varying degrees of risk carried by these issues.

TiAlN coatings are receiving increasing attention for use as hard coating materials because of their unique combination of wear and oxidation resistance. In this work, boron ion implantation has been used to further improve the wear resistance of TiAlN coatings. TiAlN coatings were implanted with boron ions at 75 keV with a dose range of 1.0×1017–1.0×1018 cm−2. The composition and crystallographic structure of as-deposited and implanted TiAlN coatings were characterized by X-ray photoelectron spectroscopy (XPS) and glancing angle X-ray diffraction. XPS results revealed that boron ions showed a near-Gaussian distribution over a depth range of approximately 300 nm. Boron ion implantation led to formation of two new phases, TiB2 and BN, in the implanted region. The microhardness of TiAlN was increased by boron ion implantation. The friction coefficient of TiAlN was found to decrease with increasing dose of boron ions. Wear loss of TiAlN was significantly reduced by a high dose of boron ion implantation. The improved wear resistance of TiAlN was attributed to the hardening effect and formation of TiB2 and BN.

This study was designed to demonstrate that dopaminergic stimulation would result in decreased smoking behavior and nicotine intake, whereas dopaminergic blockade would result in increased smoking behavior and nicotine intake, in the same subjects. In prior human studies, a dopaminergic antagonist, haloperidol, increased smoking and/or nicotine intake, and a dopamine agonist, bromocriptine, decreased smoking. The smoking behavior of 20 heavy smokers was observed on two separate visits in a randomized, double-blind, repeated-measures-within-subject design. In the drug-reversal design, either bromocriptine (2.5 mg) or haloperidol (2.0 mg) was administered at each 5-h session, during which subjects smoked their own cigarettes ad libitum. Smoking topography was measured using a thermistor flow detector apparatus. Subjects smoked their cigarettes faster (p0.05) and total puffing time was greater (p0.05) with haloperidol than with bromocriptine. There was a trend for both a shorter latency to smoke (p0.10, one-tailed) during time of expected peak drug concentration and for a shorter inter-cigarette interval with haloperidol than with bromocriptine (p0.10, one-tailed). Shiffman-Jarvik Withdrawal Scale craving subscale scores increased significantly more with haloperidol than with bromocriptine (p0.05). Mean Profile of Mood States (POMS) scores differed significantly for only one subscale (Confusion: bromocriptinehaloperidol; p0.05). These data support the hypothesis that nicotine mediates reinforcement from smoking via dopamine, and that smoking behavior can be manipulated within the same subjects in opposite directions by alternately stimulating and blocking dopamine.

Erectile dysfunction (ED) is a common complication of diabetes mellitus. Erythrocyte aldose reductase (AR) has been implicated in a variety of diabetic complications. The subjects were 62 diabetic patients, of whom 25 were treated with hemodialysis (chronic renal failure CRF group) and the remaining 37 did not have chronic renal failure (DM group). The controls were 20 healthy volunteers age-matched to the patients. The level of AR was measured by the quantitative determination kit for AR in all patients and controls. In this study, ED was diagnosed by 5-item version of the International Index of Erectile Function (IIEF-5). The average level of AR in the CRF group was significantly higher than that in the DM group and controls (P

The combined ion implantation of Nb at 1173 K and Al at 973 K on a γ-TiAl based alloy Ti–48Al–1.3Fe–1.1V–0.3B (at.%) was conducted with a dose of 3.0×10 17 ions/cm 2 and at an accelerating voltage of 50 kV for each element with different sequences. The implanted layer was contaminated by C during the Nb implantation at 1173 K. The isothermal oxidation behavior of the above-treated alloys was investigated at 1173 K for 349.2 ks in air using a thermobalance. Auger electron spectroscopy (AES), X-ray diffractometry (XRD) and scanning electron microscopy (SEM) were employed to characterize the modified layer and oxide scale. The Al + Nb implanted alloy shows excellent long-term oxidation resistance due to the formation of a continuous and compact Al 2 O 3 oxide scale. The co-existence of Nb and C in conjunction with the Al enrichment in the modified layer could inhibit the inward diffusion of O and prolong the beneficial effect of Nb and thus lead to the formation of the above protective scale. To the contrary, the oxidation rate of the Nb + Al implanted alloy remained very low in the first about 100 ks exposure and then accelerated. It is concluded that the C beneficial effect derived from the Nb and C layer formed during the 1173 K Nb implantation was weakened by the following Al implantation. The rapid consumption of Nb and fast inward diffusion of O finally contributed to the poor long-term oxidation resistance of the Nb + Al implanted alloy.

The isothermal oxidation behavior of Ti–48Al–1.3Fe–1.1V–0.3B (at.%) implanted with C, Nb or C+Nb was investigated at 1173 K for 349.2 ks in air. Dose was 3.0×1021 ions per m2 and the acceleration voltage was 50 kV for each element. The purpose of this study is to improve the high-temperature oxidation resistance of the alloy by suitable implantation process and clarify the effects of C, Nb and their interaction on the formation of the oxide scale. Thermobalance, auger electron spectroscopy (AES) and scanning electron microscopy (SEM) were used to characterize the oxidation behavior and the scale structure. It was found that the C implantation is harmful to the long-term oxidation resistance, the Nb implantation significantly decreases the oxidation rate, and the C+Nb implantation can further improve the beneficial effect of the Nb implanted alloy and thus gives the best oxidation resistance. It was also found that for the C implantation, the C rich layer can act as a barrier to the inward diffusion of O in the early stage of the oxidation, but this effect will disappear after oxidation for about 3.6 ks due to the fast consumption of C. The presence of Nb can promote the formation of an Al enriched layer in the external scale. The co-existence of Nb and C would enhance their respective stability remained in the external scale or substrate with high peak concentration and thus prolong and intensify their respective beneficial effects. The significant improvement of the oxidation resistance of the C+Nb combined implantation is attributed to the above respective C and Nb beneficial effect and their interaction during the oxidation.

The combined ion implantation of Si+Nb at room temperature and at 1173 K with C contamination was employed to improve the oxidation resistance of a γ-TiAl based alloy [Ti–48Al–1.3Fe–1.1V–0.3B (at%)]. The implantation was conducted with a dose of 3.0×1021 ions/m2 and at an accelerate voltage of 50 kV for each element. The isothermal oxidation behavior of above treated alloys was tested at 1173 K for 349.2 ks in air. The oxide scales formed by short-term and long-term oxidation were characterized by AES, SEM and XRD. It was found that the alloy implanted with Si+Nb at 1173 K with C contamination shows excellent long-term oxidation resistance in comparison to that of the room temperature Si+Nb implanted alloy, although the latter also significantly lowers the oxidation rate of non-implanted alloy. A continuous, compact and thus a protective Al2O3 layer was formed in the scale of the alloy implanted with Si+Nb at 1173 K with C contamination after long-term oxidation, and this layer contributed to the best oxidation resistance. It is also indicated that the introduction of Si into Nb modified layer and, in particularly C in conjunction with Nb and Si in the modified layer can further effectively favor the formation of the continuous Al2O3 layer in the scale on alloy during high temperature oxidation.

The isothermal oxidation behavior of a γ-TiAl-based alloy Ti–48Al–1.3Fe–1.1V–0.3B (at.%) at 1123 K for 360 ks in air, which was treated by a combination process of pure Al film deposition with a thickness of approximately 0.2 and 0.4 μm by IBAD and the following pre-diffusion treatment of 873 K/86.4 ks in vacuum, respectively, was studied. It was found that the Al film was transformed into a layer of TiAl3 through the pre-diffusion process. The isothermal oxidation resistance of the γ-TiAl-based alloy was improved by this kind of treatment especially that with 0.2 μm thickness Al film showed a considerable enhancement effect. The thickness of Al film formed by IBAD is a key factor of this kind of treatment since the microstructure of the TiAl3 layer transformed by the following pre-diffusion treatment strongly depends on it. It is concluded that the existence of a layer of TiAl3 which is rich in Al could favor the formation of Al2O3 and therefore retarded the diffusion rate during oxidation.

Plasma-based ion implantation (PBII) of nitrogen into chrome plated-steel is discussed with regard to dimensional homogeneity, depth distribution and the possibility of combining different implantation modes. A stainless holder with 60×10 mm 2 trenches at depths of 60, 40, 20 and 10 mm was made. The chromium-plated steel plates were fixed on the bottom of the trenches and treated by PBII under various conditions. The depth profiles and chemical bonds were measured with X-ray photoelectron spectroscopy (XPS) combined with Ar sputtering. The primary results confirmed that nitrogen PBII could introduce a significant amount of nitrogen into the chrome-plated layers in a shorter time than a conventional beam-line implanter. The implanted nitrogen was observed to combine with chromium. The depth profiles of nitrogen were the same for samples set on holder surfaces both facing and reversed to the RF source, which suggested homogeneous implantation in all directions. The PBII treatment was found to be homogenous for the trenches with an aspect ratio less than 4 without sample manipulation. A rapid elevation in temperature occurred during PBII treatment. Control of the target temperature remains as a future challenge.

γ-TiAl (Ti–50Al at.%) alloys were implanted with Nb ions at an acceleration energy of 50 keV, at a dose of 1.2×1017 ions/cm2. The cyclic-oxidation behavior of the unimplanted and Nb+-implanted TiAl specimens was investigated at 850°C in static air and in air with a flow velocity of 12.0 m/s (1000 ml/min). In static air, the unimplanted TiAl specimen showed rapid oxidation during a transition period of about 80 hr, after which partial scale spallation occurred and a net mass loss was observed. In flowing air, the whole scale spalled off after each cycle. On the other hand, Nb-ion implantation led to the formation of an adherent protective Al2O3 scale during oxidation in both static and flowing air, thereby significantly improving the cyclic-oxidation resistance of γ-TiAl alloys. A remarkable deference in the initial-oxidation behavior between unimplanted and Nb+-implanted specimens was also observed. A mixed TiO2/A2O3 scale on the unimplanted specimen developed at a high growth rate during the very initial stage of oxidation. In contrast, the initial scale growth rate was significantly decreased by Nb-ion implantation and an Al2O3-rich layer was found present as the inner part of the initial scale on Nb+-implanted TiAl. Flowing air appeared to cause severe scale spallation during oxidation of unimplanted TiAl, but not to have any influence on the adhesion of the scale on Nb+-implanted TiAl.

Two-dimensional carbon-fiber reinforced carbon-carbon (C/C) composites were implanted with boron ions with 70–360 keV energy, then annealed in an argon atmosphere at 1550°C, and finally coated with a CVD-SiC coating of 50 μm. Isothermal and cyclic oxidation tests were performed on the CVD-SiC coated C/C composites in flowing dry air at 1300°C. The CVD-SiC coated C/C composites with boron ion implantation exhibited largely lower weight loss than those with a direct SiC coating. A thin boron carbide layer was formed in the surface region of the C/C composites by boron ion implantation. This boron carbide layer was found to contribute to enhancing the oxidation resistance of the CVD-SiC coated C/C composites.

Cyclins are known to activate cyclin-dependent protein kinases, which are essential for cell cycle progression in eukaryotes. We isolated full-length cDNAs encoding rice mitotic cyclins named CycA1; os; 1 and CycB2;os;1, which are related to A- and B-type cyclins, respectively, from animals. To characterize the function of these mitotic cyclins, as well as that of another B-type cyclin, CycB2;os;2, each cDNA was introduced into yeast cells. When cDNAs encoding CycA1;os;1, CycB2;os; or CycB2;os;2 were overexpressed in the yeast mutant DLI, which is deficient in G1 cyclins, the mutant phenotype was rescued, indicating that these mitotic cyclins are functional in yeast cells. When the cDNA encoding CycB2;os;1 was expressed in the wild-type yeast strain, the cells lost the ability to grow, whereas the expression of either cycA1;os: 1 or cycB2;os;2 did not inhibit growth. In situ hybridization of these mitotic cyclin genes with rice root apices and counterstaining of chromosomes with a DNA-specific dye revealed that cycA1;os;1 is expressed from the G2 phase to the early M phase, while transcripts of cycB2:os;1 and cycB2;os;2 accumulated until the end of mitosis. Our results indicate that these B2-type cyclins may be involved in the control of mitosis, in combination with a G2/M-phase CDK.

The geographical variations in trophic structure of the plankton community, as defined by total and relative carbon biomass of phytoplankton (PP), bacteria (BA), heterotrophic nanoflagellates (HNF), microzooplankton (MZ), and herbivorous (HNZ) and carnivorous net-zooplankton (CNZ), were investigated along an inshore‐offshore transect from the innermost part of Osaka Bay to the Pacific Ocean off Kii Channel, Japan, in June 1991. Based on physico-chemical properties of the water and topographical features, the transect was divided into three trophic areas, i.e. eutrophic, mesotrophic and oligotrophic ones. The average carbon biomass of the total plankton community was highest (438 mg m )3 ) in the inshore eutrophic area, and declined steeply offshore (141 and 26.6 mg m )3 in the mesotrophic and oligotrophic areas, respectively). In the offshore oligotrophic area, the relative biomass of BA to PP and the relative biomass of small heterotrophs (i.e. BA, HNF and MZ) to the total heterotrophs were higher than in the other areas, indicating that the microbial food chain predominated. In the mesotrophic area, the biomass of HNZ (primarily copepods) was conspicuously high, even higher than that of PP, suggesting that the traditional grazing food chain prevailed. Because of this short food chain, a productive fishing ground is formed there. In the eutrophic area, the biomass of HNZ was much smaller relative to the enormous biomass of PP, indicating that a considerable amount of primary production was not utilized directly by the metazoan zooplankton. However, the relative contribution of the small heterotrophs to the total heterotrophs’ biomass was higher in this area, as in the oligotrophic area.

Silicon infiltration has been used to form a functionally gradient layer on two-dimensional carbon–carbon (2D-C/C) composites. 2D-C/C composites were infiltrated with silicon at temperatures above the melting point of silicon in a NH 3 -containing atmosphere. Some of silicon-infiltrated C/C composites were then coated with a CVD–SiC coating. Electron probe microscopic analysis, X-ray diffraction and secondary ion mass spectroscopy were employed to characterize the surface layer derived by silicon infiltration. Isothermal and cyclic oxidation tests on the C/C composites were carried out at temperatures up to 1550°C in air. A functionally gradient (Si 3 N 4 +SiC)/C layer was formed in the surface region of the C/C composites. Combined with an outer CVD–SiC coating, this composition-graded layer could provide excellent oxidation resistance for C/C composites.

Nonsmokers and smokers were compared for olfactory sensitivity to two odors associated with cigarettes: nicotine and menthol. Smokers were tested twice--while nonabstinent, and after 16-20 h of smoking abstinence. Smokers showed a higher olfactory threshold for nicotine than did nonsmokers, but the same threshold for menthol. Furthermore, when the smokers were abstinent, they showed a lower olfactory threshold for nicotine than when they were nonabstinent, but again, the same threshold for menthol. These results suggest a nicotine specific olfactory deficit in smokers that is reduced during abstinence.

Single-release and modified single-release statistical models were evaluated as means to generate reliable survival estimates from release-recapture studies of migrant salmonid smolts in the Snake and Columbia rivers of the northwestern United States. Monte Carlo simulation studies were used to assess robustness of estimation methods to violations of model assumptions. To field test model assumptions, passive integrated transponder tagged chinook salmon (Oncorhynchus tshawytscha) smolts were released on seven consecutive days in 1993 above Lower Granite Dam on the Snake River. These releases were used to estimate sampling variability of survival estimates for comparison with model-based variance estimates and to assess mixing of detected and nondetected individuals. Field results satisfied model assumptions. The average survival estimate from point of release to the tailrace of Lower Granite Dam (31 km) was 0.902 ± 0.004 (mean ± SE). From the tailrace of Lower Granite Dam to the tailrace of Little Goose Dam (60 km) the average survival estimate was 0.859 ± 0.013.

The ability of carbonaceous particles (AST-120), originally developed as an enteral adsorbent of uremic toxins, to quench nitric oxide (NO) was tested. NO in solutions prepared by two methods [NO gas bubbling and NO generating system, i.e., decomposition of 1-hydroxy-2-oxo-3-(aminopropyl)-3-isopropyl-1-triazene] were determined by a NO-specific reduction of carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide using an electron paramagnetic resonance spectrometry. NO concentrations were less in samples containing increasing concentrations of AST-120. In a separate study, nitrite concentrations in lipopolysaccharide-treated RAW264 cells were significantly less in incubation medium containing AST-120. Thus, AST-120 may be applicable as an enteral anti-NO agent.

小児特発性ネフローゼ症候群 (NS) では大部分の症例がグルココルチコイド療法により寛解するが，NSの発症病理に関するグルココルチコイドの役割は十分に解明されておらず，また治療抵抗性を認める症例の原因も明らかではない。我々はNS患者を中心にステロイド感受性に関するグルココルチコイドの分子作用機序についてその遺伝子転写調節の細胞内メッセンジャーであるグルココルチコイドレセプター (GR) とその発現制御因子についての解析を行った。その結果，頻回再発型ならびにステロイド抵抗性ネフローゼ症候群にGR発現量の低下を高頻度に認め，これらの症例ではGR Down regulationによるステロイド依存性転写調節障害が示唆された。またレセプタ一結合蛋白である熱ショック蛋白はGR発現量と相関することよりグルココルチコイドーGR系の情報伝達が阻害されステロイド抵抗性の原因となることが示唆された。

Molecular mechanics and dynamics have become a standard analysis tool used in drug design and synthesis, but it has not generally been used as part of structural and mechanical analysis. The need for such tools is an obvious extension of structure-property correlations known in polymer formulation, engineering, and manufacture. This study probes the use of mechanics and dynamics techniques to help explain property trends found in hydrated polybenzimidazole (PBI).

Previous studies have implicated reduced serum bilirubin concentrations in the development of cardiovascular disease. The aim of this study was to examine whether bilirubin may explain the high incidence of vascular complications in haemodialysis patients with Type 2 diabetes.We compared serum bilirubin concentrations, as well as other known aetiological risk factors for cardiovascular disease, in 206 Type 2 diabetes patients on haemodialysis with those in 741 Type 2 diabetes patients not receiving haemodialysis, and evaluated the association between serum bilirubin concentration and cardiovascular disease incidence.Incidences of cardiovascular disease and systolic blood pressure were higher; however, BMI and serum total cholesterol were lower in haemodialysis patients compared with those in patients without haemodialysis. Serum total (0.30 ± 0.10 vs. 0.74 ± 0.26 mg/dl, 0.005 ± 0.002 vs. 0.013 ± 0.004 mmol/l, P0.0001) and indirect (0.17 ± 0.08 vs. 0.70 ± 0.23 mg/dl, 0.003 ± 0.001 vs. 0.012 ± 0.004 mmol/l, P0.0001) bilirubin were lower in haemodialysis patients compared with those in patients without haemodialysis. Stepwise regression analysis demonstrated that age (β = 0.109, F = 5.959, P0.05), duration of diabetes (β = -0.112, F = 6.048, P0.05), sex (β = -0.123, F = 8.623, P0.05), cardiovascular disease events (β = -0.099, F = 5.131, P0.05) and presence of haemodialysis (β = -0.626, F = 201.727, P0.01) were independent factors for serum total bilirubin. Logistic regression demonstrated that age (OR 1.089, 95% CI 1.044-1.136; P0.0001), duration of diabetes (OR 1.029, 95% CI 1.001-1.059; P = 0.0423), body mass index (OR 1.115, 95% CI 1.001-1.242; P = 0.0487), habit of smoking (OR 2.445, 95% CI 1.046-5.716; P = 0.0391) and serum total bilirubin (OR 0.192, 95% CI 0.037-0.989; P = 0.0484) were independent factors for cardiovascular disease events.Low serum bilirubin concentration could be one of the important factors for the high incidence of cardiovascular disease in Type 2 diabetes patients receiving haemodialysis.

MOS capacitors were fabricated on an n‐type 6H‐SiC epitaxial layer, and charge induced in the nMOS capacitors by 15 MeV oxygen ion microbeams was measured using Transient Ion Beam Induced Current (TIBIC). The peak amplitude of TIBIC signals decreases and the fall time increases with increasing number of incident ions. The TIBIC signal peak value can be refreshed to its original value by applying a forward bias of +1 V to the oxide electrode. Since the values of the effective bias applied to gate oxide are changed by the charge state of deep hole traps, the decrease and refreshment of TIBIC peak can be interpreted in terms of change in the effective gate bias due to charge trapping and recombination by deep hole traps, respectively.

Formalin-ether sedimentation (MGL) is a well-known technique for the examination of faeces for parasites, but some recent reports have indicated that its efficiency is not as high as originally thought. We reevaluated the recovery efficiency of the original MGL (O-MGL) technique to modify it. We subsequently adopted the following modified MGL technique (M-MGL): filtration by three layers of gauze and washing, adjustment to pH 3, retreatment of plug, and use of 1.5 g of faeces. We also compared five faecal examination techniques (including the O-MGL and the M-MGL) for three parameters: recovery efficiency, sensitivity, and mean number of eggs detected. The highest sensitivity was obtained by the M-MGL (95%), followed by the commercially available kit (Kit; 90%), O-MGL (76%), Kato-Katz (KK; 57%), and direct smear (DS; 50%). The mean numbers of Ascaris lumbricoides eggs recovered by the techniques were in order M-MGL (148 eggs), Kit (97), O-MGL (41), KK (11), and DS (6). This M-MGL technique has the advantage not only of the above-mentioned three parameters, but also the ease of microscopic observation and the concentration index. The parameters of the O-MGL technique were not necessarily sufficient compared with the other techniques. It seems that the improved M-MGL technique in the present study is applicable for field surveys, particularly when the survey is done in areas of low parasite endemicity.