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The EuroQol 5-dimension 5-level (EQ-5D-5L) instrument is among the most used preference-based quality of life (QOL) measures for cost–utility analysis. Each dimension is evaluated on five levels. The aim of this study was to clarify whether the EQ-5D-5L, which consists of only five items, correlates with profile-based QOL measures in Japanese oral cancer patients during the perioperative period. One hundred participants with oral cancer undergoing radical therapy completed QOL assessments before treatment, at treatment completion, and 1 and 3 months after treatment using the EQ-5D-5L and Functional Assessment of Cancer Therapy – Head & Neck instrument (FACT-H&N, Japanese version). To clarify how the EQ-5D-5L reflects the FACT-H&N, multiple regression analyses were performed using FACT-H&N subscales. The ceiling effect of the EQ-5D-5L was investigated. The EQ-5D-5L moderately correlated with the FACT-H&N over the entire perioperative period (rs = 0.586, P

Owing to the insufficient specificity of the anti-myeloproliferative leukemia protein (MPL) antibody in the original version of this Article, Figure 6 and parts of Figures 2a, 4e, and 5a do not represent the correct information. The corrected version of Figure 6 is in this correction and those of Figures 2a, 4e, and 5a are shown in the supplemental information.

Stress in yttria stabilized zirconia (YSZ) thin films was controlled by using various substrates, which had different thermal expansion coefficient (TEC), and electrical properties of the films were measured to study the relationship between the stress filed and electrical properties. Thin films of YSZ were deposited by PLD method on Al2O3 and AlN substrates. Because TEC of YSZ is larger than that of the substrates, tensile stress field was introduced into the films at room temperature. Measured stress value by XRD was varied from 0.7 to 1.7 GPa at R.T. This value is significantly higher than literature value. However, the films also showed different lattice volume on the different substrates. Although electrical properties in the films showed different tendencies by the substrates, both stress field and lattice volume were different. Hence, stress dependence of electrical properties was not clearly observed.

About 12,000 train crews (drivers and conductors) are engaged in the train operations of East Japan Railway Company (JRE). Everyday roll call operation (attendance/leaving management for train crews) is one of the indispensable duties to enhance safe and reliable transportation services. Paper roll call lists were used for roll call operations until last spring. Managers had to print out the roll call lists and write down information for the crews by the day before each roll call. When managers take roll calls using lots of paper roll call lists, there are some risks with checking their watches, writing real approval times and examiner names. Because there are about 300 train crews in large crew depots, it has been difficult for new managers to remember all the names of train crews. Some managers set alarm clocks to prevent crews from being late. Owing to these situations, managers couldn’t concentrate on their main duties which are making decisions and instructing crews. To solve these problems, the authors developed a new function called “Train Crew Working Management” using 21.5-inch slate PCs in July 2015. Those show all the information needed for each roll call operation and identify train crews and managers by identification (ID) cards using Near Field Communication (NFC). When train crews are late, the system beeps so that managers can notice. Mistakes have been reduced by this new function. Moreover, managers have been able to concentrate on their main duties. The authors believe that crew depots’ business will become more efficient and smart by expanding this function.

We investigated the effects of short-term WBVT program for rehabilitation after ACL reconstruction on postural control, knee position sense, and knee laxity. This review was restricted to randomized controlled trials, which investigated the rehabilitation effects of WBVT on physical function compared with conventional rehabilitation program. Data from a total of 99 participants with ACL reconstruction in 3 studies were included. Articles with high risk of bias were included based on the criteria of Cochrane Review Guideline. Furthermore, based on the International Society of Musculoskeletal and Neuronal Interactions recommendation, the lack of information on the WBV settings was found in them. Meta-analysis showed that, after WBVT intervention, no significant standardized mean difference (SMD) was observed in postural stability (n = 3; -0.58[-1.32-0.16], p = 0.13) with large heterogeneity (I2 = 67%) and knee laxity (n = 2; -0.10[-0.50-0.70], p = 0.74) with no heterogeneity (I 2 = 0%), whereas a significant SMD was observed in position sense (n = 2; SMD = -1.44[-2.22- -0.67],p = 0.0003) with large heterogeneity (I 2 = 85%). We concluded that WBVT might be a promising alternative exercise therapy for rehabilitation after ACL reconstruction. However, to clarify the effects of WBVT on prevention from re-injury after returning to sports activities, future studies with longer term WBVT with better quality are strongly

Growing evidence suggests that personality trait is associated with longevity, however, the mechanistic link has not been fully elucidated. The aim of this study was to investigate the association between personality traits and longevity and to investigate mediating pathways of this link in the very old. In a cohort of 460 senior (200 men and 260 women) aged 85 years or older living in the community, personality traits were assessed with NEO five-factor inventory, which consists of conscientiousness, agreeableness, neuroticism, openness, and extraversion. Activity of daily living (ADL), Cognitive function (mini-mental state examination), wellbeing (WHO5), leisure time physical activity (time spent for walking and exercise per week), denture wearing during sleep at night, and body mass index were assessed at the baseline, and all-cause mortality was followed-up for 6 years. Extraversion and conscientiousness showed significant positive association with wellbeing and physical activity, while neuroticism was negatively associated with wellbeing and cognitive function. Agreeableness was associated with being woman and wellbeing. During the study period, 151 (32.8%) persons died. In a multivariate cox proportional hazard model adjusted for demographics and potential confounders, only neuroticism was significantly associated with all-cause mortality (hazard risk for the highest tertile, 1.63, 95% confident interval, 1.05–2.52, p=0.029). Our results suggest that extraversion and conscientiousness were associated with wellbeing and health behavior, however, the two traits has limited impacts on mortality beyond 85 years. Neuroticism was significantly associated with mortality independently from wellbeing, cognition, and health behaviors.

On magnetic recording disks, a surface lubricant film has been widely used in order to reduce friction and wear. It is very important to analyze the lubricant film on the disk directly. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a suitable technique for direct analysis of lubricant films because of its high surface sensitivity for the information about organic chemical structure. In this study, we investigated the effect of thickness and molecular weight of Z-Dol lubricants on the intensity of the Z-Dol end-group ion. ToF-SIMS results revealed that the calculated intensities of Z-Dol end-group ions from free lubricant films are proportional to free lubricant thickness, and decrease with the increase in molecular weight. By investigating the calculated intensities of Z-Dol end-group ions from free lubricant films, we concluded that it is possible to compare molecular weights of lubricant films on the disks.

Exogenous stimulation of skeletal muscle or tendon is often used to improve range of motion. Despite substantial research efforts, however, the effects of vibration on flexibility have not been clarified. In this review, we investigated the effects of acute and chronic intervention programs which used vibration to improve flexibility in young healthy individuals. Effect size was calculated using data from a total of 600 participants in 19 studies before and after the introduction of vibration-based intervention, and a total of 324 participants in 13 studies on the additive effects of vibration compared with the identical conditions without vibration. Sub-group analyses were performed based on intervention period, type of exercise, and type of vibration. Meta-analysis showed that vibration interventions had significant effects on flexibility (standardized mean difference [SMD]=-0.79, 95% confidence interval [CI]=-1.14- -0.43; p0.001), albeit with the possibility of heterogeneity (I(2)=75%). Another meta-analysis revealed a significant additive effect of vibration on flexibility compared with the identical condition without vibration (SMD=0.25, 95%CI=0.03-0.48; P=0.03), with small heterogeneity (I(2)=0%). The risk of publication bias was low judged from Kendall's τ statistic. We concluded that the use of vibration might lead to additive improvements in flexibility.

We present a new, multi-domain parallel computational method for simulation of unsteady flows involving a primary object, a long wake region and, possibly, a secondary object affected by the wake flow. The method is based on the stabilized finite element formulation of the time-dependent Navier—Stokes equations of incompressible flows. In the multi-domain computational method the entire simulation domain is divided into an ordered sequence of overlapping subdomains. The flow data computed over the leading subdomain is used for specifying the inflow boundary conditions for the next subdomain. The subdomain corresponding to the wake would not involve any objects, hence the mesh constructed over this domain would be structured. A special-purpose finite element implementation for structured meshes is used for the wake domain to achieve much higher computational speeds compared to a general-purpose implementation. We present verification studies for the multi-domain method and special-purpose implementation, followed by two numerical examples. The first example is the wake behavior behind a circular cylinder. The second one is the aerodynamic effect of tip vortices released from a leading wing on a trailing wing placed in the far wake.

Adlayer structures of Cl, Br, and I on the Cu(111) surface have been investigated using in-situ scanning tunneling microscopy (STM) in solution and ex-situ low-energy electron diffraction (LEED) in ultrahigh vacuum. The atomic structure of Cu(111)−(1 × 1) was observed by in-situ STM in a perchloric acid solution. Complementary use of LEED and in-situ STM revealed (p × √3) centered-rectangular phases for Cl and Br, in which the structures are compressed almost linearly with potential. In the case of iodine monolayer, a (√3 × √3)R30° structure was consistently observed in the potential range investigated. The compression in the adlayers of Cl and Br on Cu(111) can be explained in terms of the difference in their van der Waals diameters.

The dynamic process of underpotential deposition (UPD) of copper on iodine-modified Pt(111) electrode in sulfuric acid solution was investigated by in situ scanning tunneling microscopy and ex situ low-energy electron diffraction. Prior to the copper deposition, iodine adlayer structures were characterized by both techniques. It was found that well-ordered iodine adlayers with the structures of (3 × 3) and ( × )R19.1° could be prepared by immersion of the electrode in a solution containing iodide ions under potential control. It was also found that the interconversion of the two structures was very slow. After the UPD of copper on the iodine-modified Pt electrode, the iodine atoms formed a c(p × R-30°) structure with a p value of ca. 2.6 on the (1 × 1) copper adlayer on Pt(111). After the copper was stripped, the electrode exhibited a mixture of (3 × 3) and ( × )R19.1° structures of iodine on Pt(111).

American black bears, Ursus americanus, are seasonal breeders with a mating season in late spring to early summer. The objectives of this study were to determine whether there are seasonal changes in spermatogenesis and immunolocalization of testicular steroidogenic enzymes, and to correlate these changes with peripheral steroid concentrations. Three captive mature bears were maintained in open cages during the summer season and provided with chambers for denning during the winter. Testicular biopsies and blood samples were obtained from anaesthetized bears on 12 March, 15 June, 12 October and 15 January. Steroidogenic enzymes were immunolocalized using polyclonal antisera raised against bovine adrenal cholesterol side-chain cleavage cytochrome P450 (P450scc), human placental 3 beta-hydroxysteroid dehydrogenase (3 beta HSD), porcine testicular 17 alpha-hydroxylase cytochrome P450 (P450c17) and human placental aromatase cytochrome P450 (P450arom). Spermatogenesis changed seasonally: spermatogonia and degenerating spermatocytes were observed in October; spermatogonia and primary spermatocytes were present in January; spermatogonia, spermatocytes and round spermatids were present in March; and spermatogonia through spermatozoa were present in June. P450scc and P450c17 were immunolocalized in spermatids and Leydig cells in June, whereas in October these enzymes were present only in Leydig cells. 3 beta HSD was localized in Leydig cells in June and October with more intense staining in June. Localization of P450arom changed seasonally: no immunostaining in October; positive immunostaining in Sertoli cells in January; more extensive immunostaining in Sertoli cells, peritubular-myoid cells and round spermatids in March; and strong immunostaining in Sertoli cells and round and elongating spermatids in June. Serum testosterone and oestradiol concentrations changed seasonally: testosterone and oestrogen were low in October and January, slightly higher in March, and high in June. The present study demonstrates that in the black bear seasonal changes in spermatogenesis are accompanied by changes in the immunolocalization of testicular steroidogenic enzymes that are correlated with changes in serum testosterone and oestradiol concentrations. The presence of P450arom in Sertoli cells at the beginning of testicular recrudescence suggests that aromatase and oestrogen may play a role in re-initiating spermatogenesis.

Exercise with whole-body vibration (WBV) is becoming popular as an alternative to conventional training or as supplementary training. However, despite increasing research efforts in this field, additive effects of WBV on muscle performance remain unclarified. In this review, we investigated the additive effects of long-term WBV on muscle strength and power. This meta-analysis was restricted to randomized controlled trials lasting for at least 5 weeks comparing exercise with and without WBV, or comparing only WBV exposure and control. Data from a total of 314 participants in 10 studies on knee extension muscle strength, and 249 participants in 7 studies on countermovement jump height were pooled using random-effect models. Meta-analysis showed significant additional effects of WBV on muscle strength (standardized mean difference [SMD]=0.76, 95% confidence interval [CI]=0.21-1.32; p=0.007) and countermovement jump (SMD=0.87, 95% CI=0.29-1.46; p=0.003). Based on these findings, we concluded that the use of WBV would lead to greater improvements in both knee extension muscle strength and countermovement jump than under identical conditions without WBV.

Granulosa-cumulus and cumulus-corona expansion as well as aromatase localization within ovarian follicles were monitored during the preovulatory period in superovulated cattle that were blood sampled every 2'nd h for LH analyses. Granulosa-cumulus as well as cumulus-corona expansion were studied by means of transmission electron microscopy and computerized image analysis. Localization of aromatase, an enzyme involved in estrogen synthesis, was determined immunocytochemically using anti-human placental aromatase cytochrome P-450 antisera. Nuclear oocyte maturation was determined by aceto:orcein staining. Significant cell dissociation within the granulosa-cumulus stalk occurred before the breakdown of the germinal vesicle, i.e. the oocyte nucleus, during the period up to 5-7 h after the LH peak, i.e. the highest LH concentration during the surge. Significant increase in intercellular spacing between the cumulus-corona cells occurred at 13-15 and 19-21 h after the LH peak. Before the LH peak all layers of granulosa cells were immunocytochemically stained for aromatase. At 5-7 h after the LH peak, however, only the granulosa cell layers located near the basal lamina were stained, and at all later intervals staining was absent. The granulosa cells of primary and secondary follicles, the interstitial gland cells, the theca interna cells and the oocytes in all follicles were immunocytochemically unstained.

WAF1 inhibits cyclin-cyclin dependent kinase complexes, causing arrest in the cell cycle. We report that interleukin-1 (IL-1) regulates the levels of WAF1 protein and mRNA in human fibroblasts. Further studies showed that 12-O-tetradecanoyl phorbol 13-acetate (TPA) enhanced the accumulation of WAF1; cells refractory to TPA still increased their levels of WAF1 mRNA when exposed to IL-1. IL-1 also increased transcription of WAF1 by 13-fold and WAF1 mRNA became 2-fold more stable in cells stimulated with IL-1 (t1/2 = 2 h) as compared to untreated cells (t1/2 = 1 h). In summary, IL-1 induces expression of WAF1, and this occurs by increased transcription of WAF1 and stabilization of WAF1 mRNA. Our data also indicate that the induction of WAF1 mRNA by IL-1 occurs through a pathway independent of protein kinase C activation.

The effects of resistance training (RT) combined with whole-body vibration (WBV) on muscle fitness, particularly muscle hypertrophy and neuromuscular performance, are not well understood. We investigated the effects of WBV in healthy, untrained participants after a 13-week RT course by performing magnetic resonance imaging and by measuring maximal isometric (with electromyography) and isokinetic knee extension strengths, isometric lumbar extension torque, countermovement-jump, knee extension endurance, and sit-ups. Thirty-two individuals (22-49 years old) were randomly assigned to RT groups with (RT-WBV, n=16) or without WBV (RT, n=16). Following the RT course, significantly higher increases in the cross-sectional areas of m. psoas major (vs baseline values) and erector spinae muscle (vs the RT group) were observed in the RT-WBV group (+10.7%, P0.05; +8.7%, P0.05) compared with the RT group (+3.8%, P=0.045; 0.0%). Higher increases from baseline were also observed in maximal isometric force, concentric knee extension torque, countermovement-jump, and maximal isometric lumbar extension torque in RT-WBV (+63.5%; +76.7%, +15.0%, and +51.5%, respectively; P0.05) than in those of RT (+25.6%, P=0.001; +17.8%, P=0.18; +11.3%, P=0.001; and +26.4%, P0.001, respectively). The WBV-induced increases in muscle hypertrophy and isometric lumbar extension torque suggest a potential benefit of incorporating WBV into slow-velocity RT programs involving exercises of long duration.

Previous anatomical and histochemical studies suggested that interstitial cells were the only steroidogenic cells in the theca layer of small follicles of the chicken ovary. However, the precise cellular site of steroid production in the small follicles is not certain. Therefore, our goal was to identify steroidogenic cells in small follicles (less than 10 mm in diameter) of the chicken ovary which have not entered the follicular hierarchy by localizing steroidogenic enzymes with immunocytochemistry. Polyclonal antisera used were anti-cholesterol side-chain-cleavage cytochrome P450 (P450scc), anti-17 alpha-hydroxylase cytochrome P450 (P450c17), and anti-aromatase cytochrome P450 (P450arom) for pregnenolone-, androgen-, and estrogen-producing cells, respectively. Ovaries were collected 2 hr after oviposition and embedded in Paraplast after fixation with 4% paraformaldehyde, 10% formaldehyde, or Bouin's solution. Tissues were sectioned (4-6 microns) and sections were mounted on poly-L-lysine coated slides. Sections were incubated overnight at room temperature with each specific antiserum raised in rabbits against cytochrome P450 steroidogenic enzymes or normal rabbit serum as a control and were immunostained with an avidin-biotin-peroxidase complex. Immunoreactivity for the P450 enzymes was absent in the granulosa layer but was present in the theca layer of the small follicles (less than 10 mm in diameter). Interstitial cells in the single theca layer of cortical follicles embedded in the ovarian cortex (less than 1 mm in diameter) contained P450scc and P450c17. Cells which contained P450arom, identified as aromatase cells, surrounded the interstitial cells in the theca layer.(ABSTRACT TRUNCATED AT 250 WORDS)

CGS 14796C, C14H20N4.C4H6O4, Mr = 362.43, monoclinic, C2/c, a = 28.148 (4), b = 9.722 (1), c = 19.200 (2) A, beta = 133.06 (1) degree, V = 3838.88 A3, Z = 8, Dx = 1.26 Mg m-3, lambda (Cu K alpha) = 1.5418 A, mu 0.702 mm-1, F(000) = 1552, T = 294 K, R = 0.075 for all 3285 reflections. The structure is composed of linear chains of alternating CGS 14796C and succinic acid molecules. The CGS 14796C molecule is in an extended conformation.

(+/-)-3-(4-Aminophenyl)-3-ethyl-2,6-piperidinedione, C13H16N2O2, Mr = 232.3, monoclinic, P2(1)/n, a = 16.895 (2), b = 8.519 (1), c = 8.762 (1) A, beta = 95.71 (1) degree, V = 1254.9 (2) A3, Z = 4, Dx = 1.23 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.785 cm-1, F(000) = 496, T = 294 K, R = 0.064 for all 3676 reflections. The molecule is L shaped with the p-aminophenyl and the piperidinedione groups forming the vertical arm and the base, respectively. The polar imide half of the piperidinedione group is in front of the L for the active + enantiomer and at the back for the less-active - enantiomer. The structure is very similar to that of phenobarbital. Intermolecular interactions include one strong and one weak hydrogen bond and an apparent interaction between one of the amino H atoms with the pi cloud of the phenyl ring.

The crystal and molecular structures of 4-(5,6,7,8-tetrahydroimidazo[l,5-a]pyridin-5-yl)benzonitrile hydrochloride (CGS 16949A) and bis(p-cyanophenyl)imidazo-l-yl methane hemisuccinate (CGS 18320B) have been determined as part of structure-activity relationship studies of non-steroidal aromatase inhibitors. CGS 18320B crystallizes with two inhibitor molecules in the asymmetric unit that are similar in conformation. The cyanophenyl groups and the imidazole moieties in the CGS 18320B molecules display a propellor-like arrangement. The orientation of the imidazole ring in CGS 16949A, which is constrained by the piperidine ring, differs by about 80o from the orientations in both CGS 18320B molecules. The conformations of both compounds are consistent with the proposed model (Banting et al. (1988) J. Enz. Inhibit., 2, 216) for inhibitor binding by positioning of the cyanophenyl group in the steroid A-ring binding site and interaction of the imidazole nitrogen with the iron of the haem.

Development plans of high resolution image sensors for satellites are increasing these days. The data transmission capacity of onboard equipment is reaching up to several times as large as the down link circuit capacity provided by present satellites. High-speed data compression is required in order to transmit the image data to ground stations in real-time. IDCP (Image Data Compression Processor) is space-born data compression processor with automatic bit-rate control function, which was developed under NASDA (National Space Development Agency of Japan) contract for Advanced Land Observing Satellite (ALOS). A new radiation hardened one-chip image data compression LSI (Large Scale Integrated Circuit), which has adaptive quantization function, was developed in order to comply with high-speed data compression requirement as well as constant bit rate transmission requirement.

Most Internet users use search engines to get information on the WWW. However, users cannot be content with the output of search engines because it's hard to express the user's own interest as a search query. Therefore, we propose a system which provides users with keywords related to user interest. Users can recall keywords expressing user's hidden (not described in a search query) interest as search keywords. The system includes an interface to restructure a part of the user's search query. Users can compose a new search query expressing concrete user interest with the interface. Previous refinements are simple modifications of the search queries, for example, adding narrow keywords or relational keywords. However, the restructuring described in the paper includes replacement of the search keywords.

In conclusion we have achieved the growth of a GalnNAs lattice matched to GaAs by MOCVD using DMHy as a nitrogen source. Also using a GaInNAs lattice matched to GaAs, we have succeeded in obtaining the room-temperature pulsed operation of GaInNAs-GaAs laser diode at a wavelength of 1.3 /spl mu/m. The MOCVD method using DMHy as a nitrogen source is promising for the growth of GaInNAs for 1.3 /spl mu/m range laser diodes.

Background Biologic agents might suppress the immune response to influenza vaccines, but, the report is limited to the number of papers. Objectives The aim is the study to compare antibody titers change after multiple dose influenza vaccination for rheumatoid arthritis (RA) patients who have been treat with abatacept (ABT), tocilizumab (TCZ), golimumab (GLM). Methods In 1356 cases of RA patients registered in Nagoya medical center, patients using biologics were 532 cases. Of which, 134 patients with RA (ABT; n=37, TCZ; n=80, and GLM; n=17) received twice inactive trivalent influenza vaccination (A/H1N1, A/H3N2, B/B-1 strains). The second inoculation was one month after the first. Antibody titer were measured before and one and two month after vaccination using the haemagglutination inhibitory assay. Results The rate of pre-inoculation (17.60% - 20.00%) which was low at all Biologics for H1N1. TCZ, and GLM showed a similar effect, in Seroprotection rate was observed effect a single and multiple times inoculations. Compared to other agents, single and multiple times inoculations also, it had to be limited in ABT but was observed effects. In Seroconversion rate, TCZ, GLM was found effective in both single, and multiple times inoculations even in Seroconversion rate. But, ABT had been limited to the effect. The rate of pre-inoculation was (48.80% - 41.20%) higher in all Biologics for H3N2. Single, and multiple times inoculations, in Seroprotection rate showed an effect together with all drugs. In Seroconversion rate even acknowledged the effect of all drugs, too. In the GLM and ABT group for type B, the effect of multiple doses was not observed, but it showed effect a little in the TCZ group. On the whole, TCZ group were observed effects of the vaccine most in Biologics, the effect of multiple doses were high. Conclusions We reported in EULAR2013, TCZ group were good response, and that there is less response tendency for ABT group, even compared with controls (RA patients treated by MTX) in effect by single dose of a vaccine, In our result, it was considered, the effect of multiple doses is not small, and should be performed if possible multiple doses in all Biologics. In ABT group, We think the low effect of the vaccine in a single dose, and the effect of multiple doses was low in fact, but multiple doses can be beneficial in some serotypes. References Kapetanovic MC, Saxne T, Nilsson JA, et al. Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients. Rheumatology (Oxford) 2007;46:608–11. Kubota T, Nii T, Nanki T, et al. Anti-tumor necrosis factor therapy does not diminish the immune response to influenza vaccine in Japanese patients with rheumatoid arthritis. Mod Rheumatol 2007;17:531–3. Mori S, Ueki Y, Hirakata N, et al. Impact of tocilizumab therapy on antibody response to influenza vaccine in patients with rheumatoid arthritis.Ann Rheum Dis 2012;71:2006–2010. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1975

Background Biological agents (“biologics”), such as anti-tumor necrosis factor (TNF) agents and interleukin-6 (IL-6) inhibitors, have been widely used in recent years for the treatment of rheumatoid arthritis (RA) to achieve remission. A concomitant treatment of methotrexate (MTX) with biologics is recommended for RA patients refractory to MTX, particularly younger patients who need a high quality of daily life with less joint destruction and physical dysfunction. Although RA is one of the systemic autoimmune diseases that can often occur in women of reproductive age, the evidence of successful treatment of patients who are pregnant or planning for pregnancy is limited due to a lack of prospective case-control studies. Objectives Use of Tocilizumab (TCZ), such as interleukin-6 inhibitors, is recommended for patients who can not use the MTX. A strategy that includes RA treatment, a safe pregnancy and a healthy fetus is clearly needed. Most cases of TCZ prescribed to pregnant RA patients were found to produce satisfactory outcomes, but further information on the association between TCZ and pregnancy is lacking. The aim of this retrospective study is to investigate the details of TCZ use in pregnant RA patients, from planning the pregnancy to actual delivery, and to examine the pregnancy outcomes of RA patients treated before or at conception with TCZ. Methods In 1356 cases of RA patients registered in Nagoya medical center, patients using biologics were 532 cases. Of which, patients treated with TCZ were 111 examples. 7 pregnancies were identified and observed from the 111 patients treated with TCZ Results 7 pregnancy of patients in the TCZ use six cases (one case of preterm low birth weight infants), abortion was 1 cases. They age were from 28 years to 42 years. Five cases was (washout period was from 2 months to 11 months) pregnant after Biologics free. One case was continued TCZ during pregnancy. Medical condition had worsened during pregnancy are three cases, there were four cases of what deterioration was observed after delivery. Conclusions TCZ is a pregnancy risk category C drug, according to the US FDA. The category C risk summary states the following: “Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks”. Japanese drug information states that TCZ should be administered to pregnant patients only if the benefits outweigh the risks; therefore, TCZ use in pregnant RA patients is not necessarily prohibited. Still, some review papers have concluded that TCZ should be discontinued three months before conception reported that IL-6 was the one of the causes of preterm premature rupture of membranes (PPROM) and that TCZ inhibited IL-6-mediated matrix metalloproteinase-2 and -9 secretion from human amnion cells. Although their study showed that TCZ might be useful for treating PPROM, the data on TCZ and pregnancy in humans were too limited to make conclusions on safety or suggestions on prescriptions. References Ostensen M, et al.Treatment with biologics of pregnant patients with rheumatic diseases. Curr Opin Rheumatol. 2011; 23: 293-8. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1417

To clarify the mechanism of hepatocyte apoptosis induced by tumor necrosis factor-alpha (TNF-alpha), caspase cascade and ceramide formation were investigated in the liver of D-galactosamine (GalN)-sensitized mice treated with TNF-alpha.Seven-week-old male BALB/c mice were intraperitoneally injected with 20 mg GalN 30 min prior to the intravenous injection of recombinant mouse TNF-alpha (0.5 microg/mouse). Cytochrome c release and processing of procaspases in the liver were analyzed by Western blotting. Activities of caspases were measured using chromogenic peptides as substrates. Ceramide content was determined using Escherichia coli diacylglycerol kinase.Apoptosis of hepatocytes was observed in mice treated with both GalN and TNF-alpha (GalN/TNF-alpha), but not GalN or TNF-alpha alone. Activation of caspases-9 and -3, and cytochrome c release were observed only in liver from mice treated with GalN/TNF-alpha. In a cell-free system, processing of procaspases-9 and -3, and cytochrome c release were observed in the postnuclear fraction of liver obtained from GalN/TNF-alpha-treated mice, but not in that from control mice. Processing of procaspase-3 was inhibited by a caspase-9 inhibitor, but not by inhibitor for caspase-8 or -2. In a reconstitution assay system, procaspase-9 processing occurred, when both cytosol and membrane fractions were obtained from the liver of mice treated with GalN/TNF-alpha. Ceramide accumulation was observed only in apoptotic liver and preceded cytochrome c release and caspase activation.Cytochrome c release and caspase-9 activation are required for the activation of executor caspase-3 in TNF-alpha-induced hepatocyte apoptosis, but caspases-8 and -2 play, if any, a minimal role. Ceramide may be implicated in this apoptotic process.

Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant disease that has a wide variety of clinical symptoms.1 There is a correlation between age at onset and clinical symptoms. Progressive myoclonus epilepsy (PME) is a usual feature of juvenile DRPLA; but late adult DRPLA patients usually experience cerebellar ataxia and hyperkinetic involuntary movements such as choreoathetosis, often without myoclonus or epilepsy.2 We report two unrelated patients with infantile DRPLA. ### Patient 1. The patient is a 4-year-old boy and the second child of healthy, nonconsanguineous Japanese parents without a family history of neurologic diseases. His father is 39 years old and his mother is 35 years old. He has a healthy 8-year-old brother. There were no major problems in the neonatal periods. He developed normally until age 6 months when his mother noticed decreased activity. At age 1 year, he could stand with support; but he began to regress slowly and became irritable. At age 2 years, he had difficulty controlling his head and swallowing, sometimes showing dystonic posture. …

We highlight some recent methods developed by the Team for Advanced Flow Simulation and Modeling http://www.mems.rice.edu/TAFSM/ for computation of parachute aerodynamics and fluid-structure interactions. This class of problems involve several computational challenges, including computation of unsteady long-wake flows generated by cargo aircraft carrying paratroopers and the affect of that unsteady wake on a parachute crossing it, as well as parachute aeromechanics simulations that take into account the changes in the parachute shape. Among the numerical methods we have developed to address these challenges are: a multi-domain method for computation of long-wake flows and flow around objects placed in such wakes, methods for the simultaneous solution of the fluid and structural mechanics equations governing the aeromechanics of a parachute. and advanced mesh moving methods. Our presentation here includes numerical examples that demonstrate the new computer simulation capabilities offered by the methods we have developed.

Tumor necrosis factor alpha (TNF-alpha) binding to the TNF receptor (TNFR) initiates apoptosis and simultaneously activates the transcription factor, nuclear factor-kappaB (NF-kappaB), which suppresses apoptosis by an unknown mechanism. Pretreatment with TNF-alpha or interleukin-1beta (IL-1beta), which activated NF-kappaB in the liver, dramatically prevented TNF-alpha-induced liver-cell apoptosis in D-galactosamine (GalN)-sensitized mice, but not anti-Fas antibody-induced hepatotoxicity. This protective effect of TNF-alpha continued for 5 hours after TNF-alpha administration, a time course similar to that found in NF-kappaB activation after TNF-alpha administration. In mice treated with adenoviruses expressing a mutant form of IkappaB, the antiapoptotic effect of TNF-alpha was inhibited in part. Prior TNF-alpha administration was not found to block the activation of caspase-8, although caspase-3 was inhibited in mice treated with TNF-alpha plus GalN/TNF-alpha compared with mice treated with GalN/TNF-alpha. These results indicate that TNFR and Fas independently regulate murine apoptotic liver failure, and that a rapid defense mechanism induced by the activation of NF-kappaB blocks death-signaling at the initiation stage of hepatic apoptosis mediated by TNFR, probably downstream of caspase-8, but not by Fas.

Two isozymes of porcine aromatase, the placental and the blastocyst forms, were expressed in CHO cells using the mammalian cell transfection method. Using an 'in-cell' assay (a 3H-water release method), catalytic parameters of the porcine placental aromatase were found to be very similar to those of the human enzyme; however, the activity of the blastocyst isozyme was found to be one-thirtieth that of the placental isozyme. Product isolation assay (using testosterone as the substrate) revealed that the major steroid products were 17beta-estradiol and 19-nortestosterone. The product ratio of estradiol/19-nortestosterone was found to be 94 : 6 for the porcine placental form, 6 : 94 for the porcine blastocyst form, and 92 : 8 for the human wild-type aromatase. Therefore, the porcine blastocyst aromatase isozyme catalyzes mainly androgen 19-desmethylation rather than aromatization. In addition, inhibition profile analyses on the placental and blastocyst isozymes were performed using three steroidal inhibitors [4-hydroxyandro-stenedione (4-OHA), 7alpha-(4'-amino)phenylthio-1, 4-androstandiene-3,17-dione (7alpha-APTADD), and bridge (2, 19-methyleneoxy) androstene-3,17-dione (MDL 101,003)], and four nonsteroidal inhibitors [aminoglutethimide (AG), CGS 20267, ICI D1033, and vorozole (R83842)]. While the two isozymes of porcine aromatase share 93% amino-acid sequence identity, our results indicate that the two porcine aromatase isozymes have distinct responses to various aromatase inhibitors.

A patient with autosomal dominant polycystic kidney disease (ADPKD) on maintenance hemodialysis (HD) experienced spreading back pain with a sudden onset, and was diagnosed with thoracic aortic dissection. Reports of ADPKD with aortic dissection are rare. Hypertension, which is essentially universal both among ADPKD and hemodialysis patients, is a known risk factor for aortic dissection. Additionally, some reports have indicated that patients with ADPKD have aortic fragility. We suspect that aortic dissection may be less rare than presently apparent among HD patients with ADPKD.

Recurrence of IgA nephropathy (IgAN) following renal transplantation has been described in 40-50% of such patients and it usually has a good outcome. We present the case of a 20-yr-old woman with IgAN who developed end-stage renal failure in 1995. In November 1996, she received a kidney from a living-related donor and was treated with tacrolimus, azathioprine and steroids. Zero- and one-hour biopsies were performed, which revealed minor glomerular abnormalities in light microscopy, thin basement membrane disease (TBMD) in electron microscopy. Eight months later she developed microscopic hematuria and proteinuria; however, the graft function was normal. Renal biopsy revealed an IgAN that is thought to be due to recurrence of the original disease.

Our purpose was to investigate the relation between the dominant sperm anomaly and sperm morphology and the outcome of intracytoplasmic sperm injection (ICSI).Two hundred ninety-five patients who underwent a total of 181 cycles of in vitro fertilization (n = 168) and/or 217 cycles of ICSI (n = 177) between July 1995 and May 1997 at Keio University Hospital were investigated.The rates of fertilization and pregnancy were 63.3 and 27.8%, respectively, in ICSI cycles withor = 4% normal forms. When the percentage of strictly normal morphology wasor = 4, the fertilization rate was lower in the case of severely tapered head (13.0%; n = 4) than in the cases of other deformities in ICSI. The acrosomal defect made no difference in the fertilization rate with ICSI.The predominant abnormal form affects the ICSI outcome in the case ofor = 4% normal forms.

A truncate form of human aromatase cDNA that corresponds to the recently identified rat cortical type aromatase mRNA variant (Yamada-Mouri et al., J. Steroid Biochem. Molec. Biol., 60: 325-329, 1997) has been generated, and the amino-terminus deleted form of the enzyme has been expressed in CHO cells. The resulting product lacking 102 residues from the N-terminus of aromatase (i.e. 102-aromatase) showed an extremely low enzyme activity using an 'In-cell' assay. A strong aromatase activity, however, was observed for the delta102-aromatase using an in vitro method on the solublized preparations. The in vitro activity was dependent on both incubation time and NADPH concentration as well as inclusion of NADPH-cytochrome P450 reductase in the assay mixture. The average turnover rate of aromatization of the reconstituted delta102-aromatase was 6.8 min(-1). The results of the immunosuppression assay suggested that delta102-aromatase still holds the epitope interactive to MAb3-2C2, a monoclonal antibody raised agaist human placental aromatase P450. Furthermore, the IC50 values of MAb3-2C2 were determined to be 24 and 23 microg/ml for the whole homogenate and the 105,000 x g precipitate fractions prepared from the truncated aromatase expressing cells, respectively, whereas an IC50 of 1.3 microg/ml was shown for the full-length human aromatase. These results indicate that the delta102-aromatase P450 can be expressed and is catalytically competent as the full-length enzyme, but the epitope structure for the monoclonal antibody MAb3-2C2 is altered from that of the native enzyme. In addition, the intracellular distribution of delta102-aromatase may be different from that of the wild-type enzyme, explaining why very low activity was measured using an 'In-cell' assay.

We report a case of acute renal failure associated with cryoglobulinemic glomerulonephritis. The patient, a 49-year-old woman, was referred to our hospital because of acute nephritic syndrome. After admission, she developed oliguria, and hemodialysis was instituted. Renal biopsy was performed and the specimens showed moderate endocapillary proliferation, large deposits filling the capillary lumen ("intraluminal thrombi"), and a double-contoured appearance, which are typical morphologic features of cryoglobulinemic glomerulonephritis. Immunoelectrophoresis showed a monoclonal increase of IgM kappa. On the basis of these findings, we diagnosed type II essential mixed cryoglobulinemia. Cryofiltration was performed with oral administration of prednisolone. Following the start of therapy, the patient's renal function gradually improved. Because of severe hypoproteinemia, cryofiltration was discontinued after three sessions. However, renal function recovered and was maintained with prednisolone only. This case shows that acute oliguric renal failure caused by cryoglobulinemic glomerulonephritis can be reversible if immunosuppressive therapy, together with plasmapheresis in more severe cases, is instituted promptly.

A functional role for stimulated nitric oxide (NO) production was tested in the TCR-triggered death of mature T lymphocytes. In purified peripheral human T cell blasts or the 2B4 murine T cell hybridoma, apoptotic cell death induced by immobilized anti-CD3 was blocked by inhibitors of NO synthase (NOS) in a stereospecific and concentration-dependent manner. This effect appeared to be selective since apoptotic death induced by anti-Fas Ab or the steroid dexamethasone was not affected by NOS inhibitors. TCR-stimulated expression of functional Fas ligand was attenuated in a stereospecific manner by NOS inhibitors, but these compounds did not inhibit TCR-stimulated IL-2 secretion or CD69 surface expression. Nitrosylated tyrosines, a stable marker for NO generation, were immunochemically detected in T cells using flow cytometry. TCR signals induced NO production, as measured by an increase in nitrotyrosine-specific staining. NOS enzymatic activity was detected in lysates of 2B4 cells, and Western blot analysis suggests that the activity is due to expression of the neuronal isoform of NOS. Thus, T cells have the capacity to generate NO upon Ag signaling, which may affect signal transduction, Fas ligand surface expression, and apoptotic cell death of mature T lymphocytes.

Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase (NOS) activity in vitro and in vivo. In in vitro studies with the use of a cytosolic fraction from penile tissue, the inactivation was found to depend on NADPH, time, and the concentration of guanabenz. The L-, but not the D-, isomer of arginine could protect from the inactivation, suggesting an active site-directed event. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (kinact) of 38.5 microM and 0.179 min-1, respectively. In in vivo studies, guanabenz was shown to inhibit penile cytosolic NOS activity in a dose- and time-dependent manner. Treatment of rats with guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately one-half in the NOS activity of the penile cytosolic fraction with a concomitant loss in the amount of immunodetectable NOS protein. Treatment for 4 days at a dose of 0. 5 mg/kg/day showed a similar decrease in activity, whereas a dose of 0.05 mg/kg/day showed no effects. Due to the multitude of processes that are regulated by NO, the inactivation of NOS is a potential mechanism to be considered in a variety of biological effects associated with drugs.

Although testosterone is the principal sex steroid produced by the testis, estrogen is known to be produced by both Leydig and Sertoli cells during different developmental periods. Additionally, evidence is unfolding to suggest that germ cells might also participate in the synthesis of estrogen within the male reproductive tract. We have recently reported that the messenger ribonucleic acid (mRNA) for P450 aromatase (P450arom), the enzyme that converts androgen to estrogen, is synthesized by rat germ cells. Therefore, the present study was conducted to determine which germ cell types synthesize active P450arom and to measure the activity of this enzyme in germ cells throughout spermatogenesis and in maturing sperm during epididymal transit. First, P450arom activity was measured in pachytene spermatocytes, round spermatids, and a mixture of round spermatids, elongating spermatids, and residual bodies using the tritiated water (3H2O) assay. Second, sperm isolated from different regions of the epididymis were assayed for P450arom activity. Sperm isolated from the caput epididymis with attached efferent ductules had the higher P450arom activity, whereas sperm isolated from the corpus and cauda epididymides had lower P450arom activity. The decrease in P450arom activity in cauda sperm was further confirmed by immunocytochemistry. On the basis of these observations, we conclude that rat testicular germ cells from pachytene spermatocytes through elongating spermatids and epididymal sperm contain active P450arom and that sperm lose aromatase activity as they mature during epididymal transit. Therefore, both post-pachytene rat germ cells and epididymal sperm are capable of estrogen synthesis and are an additional, potentially significant, source of estrogen in the male reproductive tract.

In the current study, we ran a chemosensity test on 7 human undifferentiated carcinoma cell lines against 10 anticancer compounds using MTT assay. Efficacy was estimated by comparing fifty percent inhibitory concentration (IC50) with the peak plasma concentration. The results showed that the 7 cell lines could be divided into two groups which had different (high or low) chemosensitivity, and that in the high sensitivity group, ACD, VCR, and etoposide were indicated as useful drugs. Our results suggest that it may be impossible to rescue all undifferentiated carcinoma patients by chemotherapy alone because the tumor may consist of 2 clones which have a different chemosensitivity.