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Introduction As Chimeric Antigen Receptor T-cell (CAR-T) therapy gains its clinical advantage in the management of diffuse large B cell lymphoma (DLBCL), accumulating evidence shows that it often accompanies cardiac dysfunction. Previous retrospective studies indicated the potential involvement of cytokine release syndrome (CRS) in cardiac dysfunction after CAR-T therapy, but no prospective study has reported the time course of cardiac dysfunction. Moreover, the relationship between the severity of CRS and cardiac dysfunction after CAR-T therapy remains unclear. Purpose The objectives of this study are to prospectively examine the sequential changes in cardiac markers overtime after CAR-T therapy and to clarify the association between the grade of CRS and cardiac markers. Methods In this prospective observational study, 30 DLBCL patients who underwent CAR-T therapy from July 2020 to March 2022 were enrolled. Before and after the treatment, the level of cardiac biomarkers and echocardiographic index were sequentially collected. We classified all patients into two groups according to the severity of CRS after CAR-T therapy, namely low-CRS group (CRS Results The average age of participants was 59.6 years, and 9 patients (30%) were female. The average duration of DLBCL was 2.7 years. The CRS showed its peak severity on day 3. The number of patients in low- and high-CRS group was 13 and 17, respectively and tocilizumab was administrated for 46% and 71% of the patients in low- and high-CRS group, respectively. At the baseline before CAR-T therapy, there were no significant differences in cardiac parameters between the two groups. During the follow-up, sequential measurements of cardiac biomarkers revealed that high-CRS group showed significantly higher NT-proBNP level compared to that of low-CRS group (NT-proBNP; 90pg/ml vs. 623pg/ml, p=0.0001, respectively) and both had their peak on day 3, whereas troponin T level did not show any differences. Likewise, sequential measurements of echocardiographic parameters revealed that high-CRS group showed significantly increased E/A compared to low-CRS group on day 7 (E/A; 0.77 vs. 0.90, p=0.021, respectively), but not in the later phase. The parameters for systolic function including GLS and EF and parameters for diastolic function such as E/e' and LAVI did not alter among the two groups throughout the follow-up. Conclusion In the patients who underwent CAR-T therapy for DLBCL, the elevation of NT-proBNP level and increase in E/A was transiently observed within a week and correlated with the severity of CRS. Funding Acknowledgement Type of funding sources: None.

Background Lately interstitial lung disease (ILD) has been recognised more and more as a manifestation of primary systemic vasculitis, particularly among patients with microscopic polyangiitis (MPA), which is predominantly a disease of the elderly in Japan. Another primary systemic vasculitis that occurs frequently in the elderly is Giant Cell Arteritis (GCA) and one of the unusual manifestations of GCA includes non-productive cough that can occur in about 10% of patients. It is speculated that vasculitis in the area of cough receptors results in this manifestation. There have been only anecdotes about the association of GCA with ILD and it is unknown whether ILD is truly prevalent in patients with GCA. Objectives Here we systematically reviewed chest images of patients with GCA and investigated the prevalence of CT scan abnormality consistent with ILD among patients with GCA. Methods Single centre retrospective chart review was conducted at St. Luke’s International Hospital in Tokyo. The charts of patients with the diagnosis of GCA who were seen from March 2004 till August 2017 were extracted. The clinical data were obtained. Pulmonary images were reviewed by one of the authors, who is a pulmonologist and characteristics of the pulmonary lesions based on computed tomography (CT) of the lung were recorded. Results Forty-six patients had a diagnosis of Giant Cell Arteritis. Thirty-nine of them had a chest CT scan. The mean age of the patients was 69±17 years and 27 patients (58%) were female. Ten patients (26%) had abnormality in the CT scan. The abnormality included linear infiltrates beneath the posterior aspect of the pleura in the lung bases (n=9), ground glass opacities (n=3), honeycombing (n=3), and reticulonocular infiltrates (n=2). Two patients received prednisolone for ILD, ILD of whom were stable. No patients died during the median follow up of 14.5 months. Conclusions Chest CT abnormality consistent with mild ILD was prevalent among patients with GCA. The prognosis of these patients appears to be favourable and these patients responded to prednisolone. Disclosure of Interest None declared

Hybrid varieties have not become commercially successful in perennial and self-incompatible forage crops because of their severe inbreeding depression and/or ineffectiveness in commercial seed production. Here, a modified synthetic variety (MSV), a breeding method for forage crops is proposed, where specific combining ability (SCA) is exploited in a way different from that in hybrids. As Syn-l seeds from only two of its parental clones are used to produce its Syn-2, its performance in Syn-2 partially depends on the SCA between the two seed parents. The inbreeding coefficient of MSVs can be as low as that of conventional synthetic varieties sold today. To evaluate its advantages, 15 modified synthetic strains (MSSs) of timothy were developed from a set of Syn-l seeds of a conventional synthetic strain (CSS) having six parental clones. An MSS (Syn-2) showed a yield level equivalent to and a disease score significantly lower than the CSS (Syn-1) in a field test. The diallel crossing analysis implied that the SCA effects are influential for yield, and that MSV or other SCA-exploiting breeding methods have the potential to improve the yield level of timothy effectively.

PSR B1259-63 is a radio pulsar orbiting a Be star in a highly eccentric orbit. Soft and hard X-rays are observed from this unique system. We apply the shock powered emission model to this system. The collision of the pulsar and Be star winds forms a shock, which accelerates electrons and positrons to the relativistic energies. We derive the energy distribution of relativistic electrons and positrons as a function of the distance from the shock in the pulsar nebula. We calculate the X-rays and γ-rays emitted from the relativistic electrons and positrons in the nebula at various orbital phases, taking into account the Klein–Nishina effect fully. The shock powered emission model can explain the observed X-ray properties approximately. We obtain from the comparison with observations that a fraction of ∼0.1 of the pulsar spin-down luminosity should be transformed into the final energy of relativistic electrons and positrons. We find that the magnetization parameter of the pulsar wind, the ratio of the Poynting flux to the kinetic energy flux, is ∼0.1 and may decrease with distance from the pulsar. We predict the flux of 10 MeV–100 GeV γ-rays which may be nearly equal to the detection threshold in the future projects.

PSR 1259-63 is a radio pulsar orbiting a Be star in a highly eccentric orbit. Soft and hard X-rays are observed from this binary system. We apply the shock powered emission model to this system. The collision of the pulsar and Be star winds forms a shock, which accelerates electrons and positrons to the relativistic energies. We derive the energy distribution of relativistic electrons and positrons as a function of the distance from the shock in the pulsar nebula. We calculate the X-rays and $\gamma$-rays emitted from the relativistic electrons and positrons in the nebula at various orbital phases, taking into account the Klein-Nishina effect fully. The shock powered emission model can explain the observed X-ray properties approximately. We obtain from the comparison with observations that a fraction of $\sim 0.1$ of the pulsar spin-down luminosity should be transformed into the relativistic electrons and positrons. We find that the magnetization parameter of the pulsar wind, the ratio of the Poynting flux to the kinetic energy flux, is $\sim 0.1$ immediately upstream of the termination shock of the pulsar wind, and may decrease with distance from the pulsar. We predict the flux of 10 MeV - 100 GeV $\gamma$-rays which may be nearly equal to the detection threshold in the future projects., Comment: 18 pages, 9 figures, accepted for publication in PASJ

We aimed to determine the intensity of muscle stimulation required to prevent structural failure as well as bone and skeletal muscle loss after denervation-induced disuse.Seven-week-old rats (weight, 198-225 g) were randomly assigned to age-matched groups comprising control (CON), sciatic nerve denervation (DN) or direct electrical stimulation (ES) one day later [after denervation] with 4, 8 and 16 mA at 10 Hz for 30 min/day, six days/week, for one or three weeks. Bone architecture and mean osteoid thickness in histologically stained tibial sections and tension in tibialis anterior muscles were assessed at one and three weeks after denervation.Direct ES with 16 mA generated 23-30% maximal contraction force. Denervation significantly decreased trabecular bone volume fraction, thickness and number, connectivity density and increased trabecular separation in the DN group at weeks one and three. Osteoid thickness was significantly greater in the ES16 group at week one than in the DN and other ES groups. Trabecular bone volume significantly correlated with muscle weight.Relatively low-level muscle contraction induced by low-frequency, high-intensity electrical muscle stimulation delayed trabecular bone loss during the early stages (one week after DN) of musculoskeletal atrophy due to disuse.

1. Since limited information is available about alterations of cytochrome P450 levels in diabetic animals other than rat, expression of P450s in the liver and kidney of the streptozotocin (STZ)-induced diabetic mouse was investigated. 2. The mRNA levels of CYP2B10, 3A11, 4A10 and 4A14 in the liver were increased in the STZ-induced diabetic mouse of both sexes. The CYP2B9 mRNA level was increased in the liver of the male diabetic mouse. These alterations were observed even at 2 weeks after administration. Insulin treatment restored these changes. The findings were consistent with changes reported in rat. 3. The levels of hepatic CYP1A2 and 2E1 and renal 2E1 and 4A did not change in the diabetic mouse at any time-point examined. No changes were seen in CYP2A- or 2C-related proteins in the diabetic mouse. These findings were in contrast to those in rat. 4. The results indicate that mouse P450s respond to insulin-dependent diabetes mellitus differently from those of the rat, and suggest that the expression of P450s in diabetes is not generally the same across animal species.

Very small-angle neutron scattering (VSANS) was used to develop a nondestructive inspecting technique for predicting the residual life time of turbine blades made from single crystal Ni-base superalloy. The VSANS curves, obtained from single crystalline CMSX-4 samples with the various degrees of damage, clearly show the first order peak of the lamellar structure created by a sequence of γ and γ' phases in this material. The peak shifts in the direction of lower scattering vector magnitudes when the creep damage increases, which reflects a corresponding increase of the period of the lamellar structure. According to the VSANS data, the interphase distance in the samples increases gradually (but does not grow rapidly) with increasing creep damage when the latter is < 54% of the creep leading to rupture. Thus, the interphase distance is a sensitive parameter which can be used to describe the morphological changes in Ni-base superalloys related to creep damage. The results are consistent with those obtained from scanning electron microscopy.

The purpose of this study was to investigate the functional interrelationship between synergistic muscle activities during low-level fatiguing contractions. Six human subjects performed static and dynamic contractions at an ankle joint angle of 110° plantar flexion and within the range of 90–110° (anatomic position = 90°) under constant load (10% maximal voluntary contraction) for 210 min. Surface electromyogram records from lateral gastrocnemius (LG), medial gastrocnemius (MG), and soleus (Sol) muscles showed high and silent activities alternately in the three muscles and a complementary and alternate activity between muscles in the time course. In the second half of all exercise times, the number of changes in activity increased significantly ( P < 0.05) in each muscle. The ratios of active to silent periods of electromyogram activity were significantly higher ( P< 0.05) in MG (4.5 ± 2.2) and Sol (4.3 ± 2.8) than in the LG (0.4 ± 0.1), but no significant differences were observed between MG and Sol. These results suggest that the relative activation of synergistic motor pools are not constant during a low-level fatiguing task.

The coexistence state of antiferromagnetism (AF) and superconductivity (SC) has been observed in five-layered cuprates. However, this coexistence state disappears, and the AF phase and SC phase lose contact in the doping phase diagram toward double- and single-layered cuprates. We investigate the mechanism of the disappearance of the coexistence of AF and SC in disordered cuprate superconductors in order to understand these doping phase diagrams. In single- and double-layered cuprates, electrons on the CuO$_2$ plane experience the disorder effect through inhomogeneity in the charge reservoir layer. These impurity potentials can be effectively enhanced toward the underdoped region by the effect of many-body corrections that involve an increase in charge susceptibility. As a result, strong disorder effects are expected particularly in the competing regions of AF and SC, where the coexistence phase of AF and SC is extremely suppressed. We show the validity of this suppression mechanism by considering the Aslamazov-Larkin-type vertex correction to the effective impurity potential in the effective mean-field phase diagram., Comment: 32 pages, 18 figures

There is convergent evidence that exercise increases psychological well-being; however, the mechanism of this psychological effect of exercise is not yet completely understood. The purpose of this study was to examine the effects of aerobic exercise training on brain structure and psychological well-being in young adults.University students who had not regularly exercised were divided into training group (N.=15) and control group (N.=15). The training group performed a total 30 periods of aerobic exercise training, while the control group never performed. Whole-brain magnetic resonance imaging scans and mental health questionnaire examinations were performed before and after the exercise training period for all of the participants. A voxel-based morphometry (VBM) analysis was used to compare the changes in gray-matter volumes in the two groups. VBM is an objective whole-brain technique for characterization of regional cerebral volume and tissue concentration differences in structural magnetic resonance images.The results of VBM analysis revealed no change in gray-matter volume in the training group, although the gray-matter volume of the left insula was significantly decreased in the control group after the exercise training period. The training group exhibited significant improvement in some scores on the mental health questionnaire after the exercise training period, compared with the control group.These findings suggest that aerobic exercise training may inhibit gray-matter volume loss in the insula, and that a relationship may exist between preservation of insula gray-matter and improvement of psychological well-being by aerobic exercise training.

We investigate the possibility of unconventional spin density wave (SDW) in the attractive Hubbard model with finite spin polarization. We show that pairing and density fluctuations induce the transverse d-wave SDW near the half-filling. This novel SDW is related to the d-wave superfluidity induced by antiferromagnetic spin fluctuations, in the sense that they are connected with each other through Shiba's attraction-repulsion transformation. Our results predict the d-wave SDW in real systems, such as cold Fermi atom gases with population imbalance and compounds involving valence skipper elements.

Research into collaborative mixed reality (MR) or augmented reality has recently been active. Previous studies showed that MR was preferred for collocated collaboration while immersive virtual reality was preferred for remote collaboration. The main reason for this preference is that the physical object in remote space cannot be handled directly. However, MR using tangible objects is still attractive for remote collaborative systems, because MR enables seamless interaction with real objects enhanced by virtual information with the sense of touch. Here we introduce "tangible replicas"(dual objects that have the same shape, size, and surface), and propose a symmetrical model for remote collaborative MR. The result of experiments shows that pointing and drawing functions on the tangible replica work well despite limited shared information.

We investigated the expression of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and KDR/Flk-1) during muscle regeneration by immunohistochemistry and real-time RT-PCR. On days 5 and 7 after the induction of injury, VEGF and Flt-1 were detected in the cytoplasm and KDR/Flk-1 in the cytoplasm and on cell membranes of the same regenerating muscle fibers. The levels of these proteins in the regenerating muscle fibers gradually decreased until day 20. In contrast, these proteins were not detected in the fibers of normal muscle. This suggests that regenerating muscle fibers express VEGF and its receptors in response to injury. In addition, we found that the VEGF mRNA transcript transiently increased after 12 h of muscle injury and then returned to the basal levels observed in normal muscles on day 1. The expression of Flt-1 and KDR/Flk-1 mRNA transcripts also peaked on day 3 and then returned to the basal levels observed in normal muscles on day 10. These findings suggest that regenerating muscle fibers are an important source of VEGF and that VEGF signaling through Flt-1 and KDR/Flk-1 may be involved in the process of muscle regeneration in vivo.

This paper presents a technique to deal with both discrete and continuous state space systems in POMDPs for reinforcement learning while keeping the state space of an agent compact. First, our computational model for MDP environments, where a concept of "state space filtering" has been introduced and constructed to make properly the state space of an agent smaller by referring to "entropy" calculated based on the state-action mapping, is extended to be applicable in POMDP environments by introducing the mechanism of utilizing effectively of history information. Then, it is possible to deal with a continuous state space as well as a discrete state space. In this, the mechanism of adjusting the amount of history information is also introduced so that the state space of an agent should be compact. Moreover, some computational experiments with a robot navigation problem with a continuous state space have been carried out. The potential and the effectiveness of the extended approach have been confirmed through these experiments

The coupling theory is applied to analyze loss characteristics of the NRD-guide bends. Besides the operating LSM/sub 01/ mode, the parasitic LSE/sub 01/ mode is generated at bends as a result of the mode conversion. A rigorous expression for the coupling coefficient between these two modes is derived and then employed in the two-mode coupling equations to be solved for the bending loss analysis. Design diagrams, which are useful for optimizing the strip width against a given curvature radius to build a Iossless bend, are constructed for 90 and 180° NRD-guide bends. It is shown that the field profile at a bend always shifts inwards. This confirms the previous experimental prediction. It is found that the periodic spikes on the loss versus frequency curve of a bend, which have been observed before, can be interpreted as being caused by resonances of the parasitic mode between the transition horns fixed at both ends of the bend, and that the true bending loss itself is normally restricted within a reasonable level. As an application of the present theory, a Iossless 180° bend with a curvature radius of 5 mm was fabricated with polystyrene and tested at 50 GHz. The measured bending loss was less than 0.3 dB.

Extended abstract of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indiana, USA, August 4 – August 8, 2013.

In this paper, a methodology for modeling and controlling of resources circulation systems is studied. We propose a model structure by introducing two kinds of submodels: a physical model and an information model. The physical model is used for simulating the flow of materials and products, while the information model is used for a decision-making on production, consumption, recycling/reuse, discard etc. Moreover, we implement an additional top-level component, a supervisor, who observes the global behavior of the system and controls it indirectly. Based on the proposed approach, we implement a prototype of simulation model. Through some computer simulations, we examine influences of the decision making as well as the indirect control on the resources circulation.

A 74-year-old female patient underwent total gastrectomy, splenectomy and D2 lymph node dissection for gastric cancer with non-dissectible paraaortic lymph node metastasis. Pathological examination revealed a high level of metastasis of dissected lymph nodes. The patient received daily oral administration of 100 mg TS-1, a novel oral anticancer agent. Each treatment course consisted of a four-week administration followed by two drug-free weeks. A partial response was obtained after the second course and a complete response was observed in the middle of the fourth and after the sixth course. The treatment was stopped because of grade 2 anemia in the middle of the seventh course, but no other adverse effect was observed. Complete response of the treatment persisted for twelve months and the patient has now been in good health without a recurrence for twenty months after surgery. Although the prognosis of gastric cancer with a high level of lymph node metastasis is poor, TS-1 therapy may have a potent efficacy in gastric cancer patients with a high level of lymph node metastasis such as the current case.

A gene encoding an endo-beta-1,4-glucanase, which is highly resistant to high temperature, protease and surfactant treatment, was isolated from Aspergillus niger IFO31125 and designated as eng1. The deduced amino acid sequence encoded by eng1 showed high homology with the sequence of a not-well-characterized cellulase encoded by eglB which has not yet been shown to be a stable enzyme. To confirm the sequence of the gene encoding the highly stable endo-beta-1,4-glucanase, the cloned gene was expressed in the yeast Saccharomyces cerevisiae, in which no cellulase activity was found, and the gene product was purified and subjected to enzymatic characterization. The enzyme retained 56% of the initial activity after 1 h of incubation at 80 degrees C and was stable in the range of pH 3.0-10.0. The optimal temperature for enzyme activity was 70 degrees C and the optimal pH was 6.0. The enzyme was highly protease-resistant and retained more than 80% of the initial activity after protease treatment for 3 d at 40 degrees C. The enzyme was also resistant to various surfactants. From these results, eng1 was confirmed to encode a very stable endo-beta-1,4-glucanase.

The alpha(1)-adrenoceptor-antagonistic and steroid 5alpha-reductase-inhibitory actions of Z-350 [(S)-4-{3-{4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-y l]propoxy}benzoyl}indole-1-yl}butyric acid hydrochloride] were investigated in rabbits and rats in vivo. Z-350 (1-30 mg/kg), administered intraduodenally, dose-dependently inhibited phenylephrine-induced increases in prostatic urethral pressure with an ED(50) value of 3.8 mg/kg in anesthetized male rabbits, whereas the effects on mean blood pressure and orthostatic hypotensive response were weaker when compared with other alpha(1)-adrenoceptor antagonists, tamsulosin and prazosin. Z-350 (1-10 mg/kg p.o.) dose-dependently inhibited the prostatic steroid 5alpha-reductase activity in rats with an ED(50) value of 2.8 mg/kg. The daily oral administration of Z-350, at==10 mg/kg for 7 days, significantly reduced the prostatic growth induced by testosterone in castrated rats, with no effect on dihydrotestosterone-induced prostatic growth. These results indicate that Z-350 exhibited alpha(1)-adrenoceptor-antagonistic and 5alpha-reductase inhibitory actions at almost equal doses in vivo, and was expected to improve the bladder outlet obstruction associated with benign prostatic hyperplasia with smaller cardiovascular adverse effect.

We report a patient with T-cell non-Hodgkin's lymphoma (NHL) who relapsed after treatment with relatively intensive third-generation chemotherapy, VACOP-B, and who was safely and effectively treated with allogeneic peripheral blood stem cell transplantation (allo PBSCT) with double conditioning. The first conditioning consisted of carboplatin and etoposide. Twenty-one days later, the second conditioning was performed with cytosine arabinoside, cyclophosphamide, and total body irradiation (AraC/Cy/TBI). Between the periods of the first and second conditioning, autologous (auto) PBSCT (4.4 x 10(5) colony-forming units granulocyte/macrophage (CFU-GM)/kg, 3.8 x 10(6) CD34+ cells/kg) was performed to rescue marrow aplasia after the first conditioning. After the second conditioning, allo PBSCT (2.1 x 10(5) CFU-GM/kg, 8.2 x 10(6) CD34+ cells/kg) was performed from a human leukocyte antigen-identical sibling. Marrow reconstitution after allo PBSCT was rapid. Grade I acute graft-vs.-host disease (GVHD) involving skin and chronic GVHD on the eye was observed. No severe transplantation-related complications occurred. With a follow-up of 22 months after allogeneic PBSCT, the patient is alive without evidence of the disease. This case shows that allo PBSCT with intensive double conditioning may become a new treatment strategy to achieve long-term disease-free survival for young NHL patients of resistant relapse with a great deal of tumor burden and invasion of lymphoma cells in bone marrow.

Adult spinal cats were trained initially to perform either bipedal hindlimb locomotion on a treadmill or full-weight-bearing hindlimb standing. After 12 wk of training, stepping ability was tested before and after the administration (intraperitoneal) of the glycinergic receptor antagonist, strychnine. Spinal cats that were trained to stand after spinalization had poor locomotor ability as reported previously, but strychnine administration induced full-weight-bearing stepping in their hindlimbs within 30–45 min. In the cats that were trained to step after spinalization, full-weight-bearing stepping occurred and was unaffected by strychnine. Each cat then was retrained to perform the other task for 12 wk and locomotor ability was retested. The spinal cats that were trained initially to stand recovered the ability to step after they received 12 wk of treadmill training and strychnine was no longer effective in facilitating their locomotion. Locomotor ability declined in the spinal cats that were retrained to stand and strychnine restored the ability to step to the levels that were acquired after the step-training period. Based on analyses of hindlimb muscle electromyographic activity patterns and kinematic characteristics, strychnine improved the consistency of the stepping and enhanced the execution of hindlimb flexion during full-weight-bearing step cycles in the spinal cats when they were trained to stand but not when they were trained to step. The present findings provide evidence that 1) the neural circuits that generate full-weight-bearing hindlimb stepping are present in the spinal cord of chronic spinal cats that can and cannot step; however, the ability of these circuits to interpret sensory input to drive stepping is mediated at least in part by glycinergic inhibition; and 2) these spinal circuits adapt to the specific motor task imposed, and that these adaptations may include modifications in the glycinergic pathways that provide inhibition.

This study was designed to assess the effects of exercise training (Tr) following an etidronate treatment (E) on bone mineral density (BMD) of the femur and trabecular bone of the tibia in ovariectomized (ovx) rats. Female Wistar rats were ovariectomized (ovx) or sham-operated (sham) at 15 weeks of age and divided into five experimental groups: sham; ovx; ovx + E; ovx + Tr; ovx + E + Tr. Etidronate treatment of 5 mg/kg, 5 days/week was administered for 2 weeks and exercised on a treadmill for 30 m/min, 60 min/day, 5 days/week for 10 weeks. BMD of the femur and the trabecular bone area of the proximal tibia were significantly (p < 0.05) higher in E and/or Tr compared to ovx groups. However, the cortical region was not affected significantly by ovariectomy. The area partially filled with the trabecular bone at the constant width was observed only in the E rats. The number of osteoclasts in E group was significantly lower (p < 0.05) than in the ovx and ovx + Tr groups. The ovx + Tr rats had a higher number of osteoblasts (p < 0.05) than the ovx and ovx + E groups. There was a significant interaction between ovx + Tr and ovx + E on BMD in the proximal region of the femur (p < 0.05) and trabecular bone area of the tibia (p < 0.001). These results suggest that the etidronate treatment for 2 weeks beforehand influenced the effects of subsequent exercise training on maintaining the BMD in the proximal femur and the trabecular bone area of the tibia.

To clarify whether the expression of the WT1 gene in leukemic cells is aberrant or merely reflects that in normal counterparts, the expression levels of the WT1 gene were quantitated for normal hematopoietic progenitor cells. Bone marrow (BM) and umbilical cord blood (CB) cells were fluorescence-activated cell sorting (FACS)-sorted into CD34+ and CD34- cell populations, and the CD34+ cells into nine subsets (CD34+ CD33-, CD34+ CD33+, CD34+ CD38-, CD34+ CD38+, CD34+ HLA-DR-, CD34+ HLA-DR+, CD34+ c-kit(high), CD34+ c-kit(low), and CD34+ c-kit-) according to the expression levels of CD34, CD33, CD38, HLA-DR, and c-kit. Moreover, acute myeloid leukemic cells were also FACS-sorted into four populations (CD34+ CD33-, CD34+ CD33+, CD34- CD33+, and CD34- CD33-). FACS-sorted normal hematopoietic progenitor and leukemic cells and FACS-unsorted leukemic cells were examined for the WT1 expression by quantitative reverse transcriptase-polymerase chain reaction. The WT1 expression in the CD34+ and CD34- cell populations and in the nine CD34+ subsets of BM and CB was at either very low (1.0 to 2.4 x 10(-2)) or undetectable (10(-2)) levels (the WT1 expression level of K562 cells was defined as 1.0), whereas the average levels of WT1 expression in FACS-sorted and -unsorted leukemic cells were 2.4 to 9.3 x 10(-1). Thus, the WT1 expression levels in normal hematopoietic progenitor cells were at least 10 times less than those in leukemic cells. Therefore, we could not find any normal counterparts of BM or CB that expressed the WT1 at levels comparable with those in leukemic cells. These results indicate an aberrant overexpression of the WT1 gene in leukemic cells and imply the involvement of this gene in human leukemogenesis.

We have employed alpha-interferon (IFN-alpha), an anti-viral agent, in the treatment of severe idiopathic sudden sensorineural hearing loss (ISSHL). Forty-two patients were studied and had an average hearing ability ofor = 70 dB before treatment. We also examined 2'-5' oligoadenylate synthetase (2,5A-S) activity, one of the parameters indicating anti-viral activity of IFN, to investigate the relationship between the suppression of viral proliferation and prognosis and explain the pathogenesis of ISSHL. Complete recovery was found in 27 patients (64.3%) after IFN therapy. Increased 2,5A-S activity was observed on the 3rd day of IFN therapy in 24 of the 27 patients who completely recovered. No severe adverse events were reported after IFN therapy. Findings suggest that IFN therapy may be effective and safe in the treatment of ISSHL and calls for further investigation.

The gastroprotective agent ecabet sodium (ecabet, 12-sulfodehydroabietic acid monosodium salt) increases the formation of prostaglandin (PG) E2 and I2 by gastric mucosa. In the present study, we examined the effect of ecabet on metabolism of arachidonic acid (AA) in rat gastric mucosal cells. Ecabet (0.1-10 mM) concentration- and time-dependently potentiated the release of [14C]AA from gastric mucosal cells prelabeled with [14C]AA and simultaneously increased the production of PGE2 and PGI2. The ecabet-mediated increases in [14C]AA release and PGE2 production were both partly depressed by mepacrine (30 and 100microM) and Ca2+ chelation. Ecabet, however, showed no effect on gastric phospholipase A2 (PLA2) activity and [Ca2+]i in the gastric mucosal cells. Ecabet and other dehydroabietic acid derivatives, 12-carboxydehydroabietic acid monosodium salt and mono[16-(12-sulfodehydroabietyl)]succinic acid monosodium salt, which potentiated the liberation of [14C]AA, increased the membrane fluidity of gastric mucosal cells assessed by using diphenylhexatrienepropionic acid (DPH-PA) as the probe, while 12-sulfamoyldehydroabietic acid showed no effect on either the AA liberation or the membrane fluidity. Ecabet (0.1-10 mM) increased the membrane fluidity concentration- and time-dependently in accordance with its facilitating effect on AA release. In conclusion, ecabet increases the synthesis of PGE2 and PGI2 by gastric mucosal cells through promoting the release of AA, which is partly dependent on PLA2 and Ca2+. The ecabet-induced increase in membrane fluidity may be involved in part in the liberation of AA from the gastric mucosal cells.

We examined the effects of methotrexate (MTX) on the level of nitric oxide (NO) produced by peritoneal macrophages from rats with adjuvant-induced arthritis (AA) ex vivo. During the development of AA, paw swelling increased and LPS enhanced the capacity of peritoneal macrophages to produce NO and prostaglandin E2 (PGE2). MTX (0.1 mg/kg, p. o.) treatment for 21 days reduced the paw swelling, and inhibited the increased NO and PGE2 production. However, when MTX (0.1 mg/kg, p. o.) was administered to rats with established AA, these parameters were not significantly influenced. In normal rats, MTX (0.1 mg/kg, p. o.) treatment for 21 days did not change NO and PGE2 production of LPS-stimulated macrophages. On the other hand, macrophages from normal and AA rats cultured in the presence of MTX (1, 10 and 100 µM), were activated by LPS in vitro. MTX did not influence NO or PGE2 production by LPS-stimulated macrophages in normal and AA rats. By contrast, indomethacin (IM) (1.0 mg/kg, p. o.) treatment for 21 days reduced the paw swelling, and inhibited NO and PGE2 production in AA rats. IM inhibited significantly PGE2 production, but did not influence NO production by LPS-stimulated macrophages in vitro. These results suggest that MTX treatment reduces NO production in peritoneal macrophages in AA rats, and these actions of MTX may have an inhibitory effect without the modulation of PGE2.

Background Rheumatoid factor is known to be associated with smoking, malignancy, hepatitis B or C as well as many rheumatologic disorders not limited to rheumatoid arthritis. However, there have been no large-scale studies to prove these relationships. We conducted a retrospective study and presented the results at American college of rheumatology meeting in November 2011. This additional study was not planned at that time. Objectives Age, smoking, malignancy, hepatitis B, and hepatitis C were confirmed as a risk factor and diabetes mellitus came up as a risk factor at the previous analysis. We performed analyses to describe these risk factors further including rheumatoid factor titers and hemoglobin A1c. Methods St. Luke’s International Hospital Center for Preventive Medicine performs annual health examinations for more than 30,000 people each year, and rheumatoid factor is checked routinely during these examinations. The data in 2004 was obtained from the St. Luke’s Center for Preventive Medicine, including rheumatoid factor, past medical history (hypertension, hyperlipidemia, diabetes, ischemic heart disease, malignancy, hepatitis B or C), pulmonary function test and BMI. The people with known rheumatologic disorders were excluded. Additionally values of hemoglobin A1c and rheumatoid factor titer were obtained this time. These data were analyzed statistically. Results A total of 31,207 patients were evaluated. The mean age was 49.1 and men consists of 50.7% of the group and women 49.3%. 6.8% had positive rheumatoid factor. As age increases, the rate of positive rheumatoid factor increases. However, there was no correlation between titer and age in multiple linear regression analysis. Multivariate logistic regression analysis with age and sex correction revealed smoking, malignancy hepatitis B and hepatitis C were risk factors for positive rheumatoid factor. Redefined DM (past medical history of diabetic mellitus and hemoglobin A1c greater than 6.5%) was no longer significant risk factor. Each odds ratio was as below. Smoking 1.08 (95% confident interval (CI): 1.02 - 1.15, P value Conclusions The relationship between positive rheumatoid factor and conventionally estimated risk factors such as smoking, malignancy, hepatitis B, and hepatitis C is confirmed again. Diabetes Mellitus was no longer risk factor for positive rheumatoid factor among non-rheumatologic patients. The patients with hepatitis B showed statistically significantly higher rheumatoid factor titer. These factors are things to consider for patients with positive rheumatoid factor without clinical rheumatologic disorders. Disclosure of Interest None Declared

The effect of 2-[(2-dimethylaminobenzyl)sulfinyl]-1-(3-methylpyridine-2-yl)imidazole (T-330), on rat gastric H+/K+-ATPase was studied in vitro and in vivo in comparison with the irreversible proton pump inhibitor omeprazole. T-330 and omeprazole inhibited rat gastric H+/K+-ATPase at pH 6.1, and their IC50 values were 75 microM and 4.6 microM, respectively. Recovery from the T-330-inhibited H+K/+-AtPase activity was effected by beta-mercaptoethanol at concentrations above 10 microM, whereas significant recovery from the inhibition by omeprazole required 100 mM. When intraduodenally administered, T-330 (0.6-10 mg/kg) induced a more potent yet shorter-lasting inhibition of both gastric H+/K+ -ATPase activity and gastric acid secretion than did omeprazole (2.5-40 mg/kg). Recovery of the gastric H+/K+-ATPase activity depressed by omeprazole was completely blocked by an inhibitor of protein synthesis, cycloheximide, whereas that by T-330 was not prevented. This indicates that restoration of the enzyme activity after inhibition in vivo by T-330 does not require de novo synthesis of the enzyme in contrast to inhibition by omeprazole. beta-Mercaptoethanol (1 mM) fully restored the H+/K+-ATPase activity inhibited in vivo by T-330 but not by omeprazole. These observations indicate that T-330 reversibly inhibits gastric H+/K+-ATPase, resulting in a short-lasting antisecretory effect, and that the sulfhydryl groups of the enzyme are involved in the action of T-330.

We determined the mechanism of the gastroprotective effects of ecabet sodium (ecabet), a new antiulcer drug. Ecabet (12.5-100 mg/kg p.o.) dose-dependently protected gastric mucosa from ethanol-induced injuries in rats, as determined with the use of both macroscopic and microscopic analyses. Both inhibition of prostaglandin (PG) formation by indomethacin (5 mg/kg s.c.) and functional ablation of capsaicin-sensitive sensory nerves (CPSN) by systemic administration of capsaicin (125 mg/kg s.c.) partly reduced the gastroprotective activity of ecabet (25 and 100 mg/kg p.o.). Ecabet increased rat gastric mucosal PGE2 formation. The treatment with indomethacin but not capsaicin decreased the ecabet-induced increase in PGE2 formation. Inhibition of nitric oxide (NO) formation by NG-monomethyl-L-arginine (L-NMMA; 100 mg/kg i.v.) partly reversed the gastroprotective effect of ecabet and completely reversed that of capsaicin at an oral dose of 0.5 mg/kg, respectively. The effect of L-NMMA was abolished by pretreatment with L-arginine (100 mg/kg i.v.) but not with D-arginine (100 mg/kg i.v.). The gastroprotective activity of ecabet (25 mg/kg p.o.) was fully reversed by pretreatment with indomethacin in combination with L-NMMA or CPSN ablation. On the contrary, a combination of L-NMMA and CPSN ablation did not have additional effect on the suppression by either treatment alone. These findings indicate that the gastroprotection by ecabet is cooperatively mediated by endogenous PGs and CPSN-related endogenous NO.

The development of the heart conduction system is controversial. Our previous study demonstrated anti-Leu-7 antibody to cross-react with the cells of the conduction system in the embryonic rat heart. Thus, detailed analysis of the development of the conduction system was performed by immunohistochemical reaction with the use of the antibody.Horizontal serial sections of hearts obtained from embryonic and neonatal rats were treated for immunohistochemical reaction with anti-Leu-7 antibody, and three-dimensional images were reconstructed by computer graphics. Images were analyzed by superimposing the results on scanning electron micrographs.The development of the rat heart conduction system starts at 10 days and is completed by 18 days of gestation. The presence of three internodal tracts (INT1, -2, and -3) and two primordia of the atrioventricular node were confirmed in this process. INT1 and -3 pass through the septum spurium. INT2 follows the same route as the posterior internodal tract of James, but the other two INTs showed no correlation to previously described tracts. The sinuatrial node and INTs were found to be derivatives of the so-called S-A ring, and the bundle of His and bundle branches were found to be derived from the B-V ring. In this study, no immunoreactivity was observed in cells of the truncobulbar portion.Three internodal tracts and two atrioventricular node primordia were observed in the developing heart. The paths of the three internodal tracts showed intimate relationships with the internal structures of the heart. The developmental significance of the septum spurium, sinus septum, and venous valve was discussed.

The interfacial atomic structures of 3C-SiC/Si(0 0 1) and the dislocation core structures related to generation and annihilation of stacking faults are clarified by aberration-corrected transmission electron microscopy combined with image processing called the ‘image subtraction and improved deconvolution (ISD)’ method. Details of the intrinsic interfacial structure are explained in terms of a two-dimensional network of partial edge dislocations and Lomer dislocations. Around the junction of the interface and a {1 1 1} stacking fault, a seven-membered ring of Si and C atom columns and interfacial steps are observed. On the other hand, a six-membered ring is observed at the intersection of two {1 1 1} stacking faults. Based on the results, the formation mechanism of the intrinsic interfacial structure and stacking faults during the growth process is discussed.