Search

Nanoscale interconnects are an important component of molecular electronics. Here we use X-ray spectromicroscopy techniques as well as scanning probe methods to explore the self-assembled growth of insulated iron nanowires as a potential means of supplying an earth abundant solution. The intrinsic anisotropy of a TiO 2 (110) substrate directs the growth of micron length iron wires at elevated temperatures, with a strong metal-support interaction giving rise to ilmenite (FeTiO 3 ) encapsulation. Iron nanoparticles that decorate the nanowires display magnetic properties that suggest other possible applications.

The insertion of conventional colonoscopes can sometimes cause patients to experience pain during the procedure owing to the stretching of the mesentery. In this study, a prototype of a robotic colonoscope with a double-balloon and double-bend tube based on the conventional double-balloon endoscope was developed to simplify insertion and prevent the overstretching of the colon. Both the outer and inner tubes were confirmed to be free from interference from wires and sheaths. Additionally, all functions such as tip bending, inflation and deflation of the balloons, and actuator-driven pulling and pushing of the inner tube were operated properly. During the insertion test, the device could be reached the cecum of a colon model in approximately 442 s when operated by a non-medical operator. In addition, the device did not overstretch the colon model, thereby suggesting that the insertion mechanism can follow the shape of the colon model. As a result, the developed mechanism has the potential to navigate through a highly-bent colon without overstretching., (© 2023. The Author(s).)

The growth plates are cartilage tissues found at both ends of developing bones, and vital proliferation and differentiation of growth plate chondrocytes are primarily responsible for bone growth. C-type natriuretic peptide (CNP) stimulates bone growth by activating natriuretic peptide receptor 2 (NPR2) which is equipped with guanylate cyclase on the cytoplasmic side, but its signaling pathway is unclear in growth plate chondrocytes. We previously reported that transient receptor potential melastatin-like 7 (TRPM7) channels mediate intermissive Ca 2+ influx in growth plate chondrocytes, leading to activation of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) for promoting bone growth. In this report, we provide evidence from experiments using mutant mice, indicating a functional link between CNP and TRPM7 channels. Our pharmacological data suggest that CNP-evoked NPR2 activation elevates cellular cGMP content and stimulates big-conductance Ca 2+ -dependent K + (BK) channels as a substrate for cGMP-dependent protein kinase (PKG). BK channel-induced hyperpolarization likely enhances the driving force of TRPM7-mediated Ca 2+ entry and seems to accordingly activate CaMKII. Indeed, ex vivo organ culture analysis indicates that CNP-facilitated bone growth is abolished by chondrocyte-specific Trpm7 gene ablation. The defined CNP signaling pathway, the NPR2-PKG-BK channel-TRPM7 channel-CaMKII axis, likely pinpoints promising target proteins for developing new therapeutic treatments for divergent growth disorders., Competing Interests: YM, AI, RK, NO, TY, FL, TK, HN, YU, IY, TH, KN, SK, MN, YM, HA, KN, HT No competing interests declared, (© 2022, Miyazaki et al.)

Spin Polarized Low Energy Electron Microscopy (SPLEEM) is a powerful tool to reveal the magnetic structure of ferromagnetic surfaces on the atomic depth scale level[1-3]. With aberration corrected LEEM and a high brightness spin polarized electron gun, high spatial resolution will provide more details for ultra-thin ferromagnetic film studies. This study reports the first realization of aberration corrected SPLEEM (AC-SPLEEM). The performance of the setup was tested on ferromagnetic Fe nanoscale islands on a W(110) single crystal, with spatial resolution of 3.3 nm in spin asymmetry images., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim of the present study was to evaluate the effects of build conditions and angle acuteness on edge reproducibility of the casting patterns fabricated using a digital light process. The prism-shaped patterns with various vertex angles were fabricated in three build orientations. The height from the base to the vertex angle point of the fabricated pattern was measured and the incomplete height was calculated as the discrepancy between the original and measured heights. Two-way ANOVA revealed that the vertex angle and build orientation and their interaction were significant (p<0.05). The incomplete height significantly decreased with an increase of the vertex angle. When the vertex angle was 20° and the build-up direction was parallel to the edge of vertex angle and perpendicular to the triangular base, the incomplete height was the smallest. Therefore, build orientation and angle acuteness influenced the edge reproducibility of the casting patterns fabricated using a digital light process.

A fiberglass-reinforced composite resin (FRP) block using a plain woven fiberglass sheet for CAD/CAM has been introduced in dental practice. The aim of the present study was to evaluate the effects of the fiberglass sheet orientation on the flexural properties of an FRP block. The flexural properties of five types of fiberglass sheet-assigned specimens were examined using a three-point bending test. A one-way analysis of variance revealed that the orientation of fiberglass sheet significantly influenced the flexural strength, 0.2% yield strength, and flexural modulus. The values of the flexural properties of the FRP were the largest when the fiberglass sheets were perpendicular to the applied force, and the smallest when the fiberglass was parallel to the same. The flexural properties of the FRP block were anisotropic and they were significantly influenced by the orientation of fiberglass sheet.

We demonstrate a new method of cleaning superlattice (SL) photocathodes using atomic hydrogen that allows an increased number of repeat activations. GaAs/GaAsP SL photocathodes were activated with either conventional heat cleaning or atomic hydrogen cleaning. Repeated heat cleaning was found to gradually lower the quantum efficiency (QE) of the photocathodes, while a relatively constant QE was maintained over repeated atomic hydrogen cleaning. These results show that atomic hydrogen cleaning allows a greater number of photocathode cleanings without a loss of performance. Analyses of SL photocathodes indicated that the degradation resulting from heat cleaning can likely be attributed to the build-up of residual Cs compounds as well as damage to the GaAs cap layer. The present study also determined the 1/e lifetime for a GaAs/GaAsP SL photocathode to be 7 h at an initial current of 2.2 µA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: Malignant effusion is associated with high serum and plasma levels of vascular endothelial growth factor (VEGF). There are no biomarkers of outcome for bevacizumab treatment in patients with malignant pleural effusion (MPE). We previously reported that carboplatin-paclitaxel plus bevacizumab was effective for patients with advanced non-squamous non-small cell lung cancer (NSCLC) and MPE, although we did not evaluate the relationship between treatment outcomes and plasma or pleural effusion levels of VEGF. Therefore, this study evaluated whether plasma or pleural effusion VEGF might predict bevacizumab treatment outcome., Patients and Methods: We enrolled 23 patients with NSCLC and MPE between September 2010 and June 2012. Plasma VEGF levels were measured in 19 patients and pleural VEGF levels were measured in 22 patients., Results: Compared to patients with a low plasma VEGF level, patients with a high level exhibited significantly shorter overall survival (OS: 13.8 vs. 6.5 months, p=0.04), progression-free survival (PFS: 8.7 vs. 4.8 months, p<0.01), and period to re-accumulation of MPE (pPFS: 9.7 vs. 6.2 months, p=0.02). Compared to patients with a low VEGF level in pleural effusion, patients with a high VEGF level exhibited significantly shorter OS (19.6 vs. 6.9 months, p<0.01) and pPFS (9.6 vs. 6.7 months, p=0.04), although there was no significant difference in their PFS (6.6 vs. 5.9 months, p=0.18)., Conclusion: VEGF levels in the plasma and pleural effusion may predict the outcome of bevacizumab treatment in patients with NSCLC and MPE., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The aim of this study was to investigate the bond strength of dental porcelain and the preheated Zr-14Nb alloy, and compare this strength with that of titanium. White oxide layers, which were predominantly composed of monoclinic zirconia, were formed on the preheated sample groups, and exhibited a greater roughness than the control samples. At the metal-ceramic interface, a greater Nb diffusion range was observed than in the control samples. The bond strengths of the samples subjected to 20min preheating treatment were the lowest (33.6 ± 3.2 MPa), which may be ascribed to the formation of a brittle thick oxide layer under excessive heat treatment. The samples subjected to this heat treatment for 5 min exhibited the highest mean bond strength (43.7 ± 5.9 MPa), which was significantly higher than that of titanium (35.3 ± 3.5 MPa). Thus, the Zr-14Nb alloy is a promising candidate for fixed dental prosthesis, as long as the appropriate treatment conditions are adopted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Spin polarized electron beam is often used in material characterizations which relates to magnetism as well as in the high energy particle physics. The manipulation of the spin polarization toward the arbitrary direction is indispensable in such studies. In the present work, a novel multipole Wien filter is proposed as the three-dimensional spin manipulator, and a prototype 8-pole Wien filter is developed. It is applied to spin polarized low energy electron microscopy, and the variation of the magnetic contrast with managing the spin polarization is evaluated. It is confirmed that the novel multipole Wien filter can manipulate the spin polarization three-dimensionally.

After the disastrous incident of the Fukushima Daiichi Nuclear Power Station, various agricultural, livestock and fishery products have been inspected for radioactive contamination with cesium in Japan. In this study, radioactive cesium was measured in various edible parts of cattle to verify the current inspection method for cattle, in which the neck tissues are generally used as samples. Radioactive cesium concentration in the short plate, diaphragm, liver, lung, omasum, abomasum and small intestine were lower and sirloin, tenderloin, top round meat and tongue were higher than that in the neck. There was no significant difference between the other organs (heart, kidney, lumen and reticulum) and the neck. Ninety-five percent upper tolerance limits of the relative concentration to the neck were 1.88 for sirloin, 1.74 for tenderloin, 1.87 for top round and 1.45 for tongue. These results suggest that a safety factor of 2 is recommended for the radioactivity inspection of cattle to prevent a marketing of meat with higher cesium than the legal limit. Re-inspection should be conducted using another part of muscle, for example, top round, when suspicious levels of 50-100 Bq/kg are detected in the neck., (© 2013 Japanese Society of Animal Science.)

Materials with perpendicular magnetic anisotropy can reduce the threshold current density of the current-induced domain wall motion. Co/Ni multilayers show strong perpendicular magnetic anisotropy and therefore it has become a highly potential candidate of current-induced domain wall motion memories. However, the details of the mechanism which stabilizes the strong perpendicular magnetization in Co/Ni multilayers have not yet been understood. In the present work, the evolution of the magnetic domain structure of multilayers consisting of pairs of 2 or 3 monolayers (ML) of Ni and 1 ML of Co on W(110) was investigated during growth with spin-polarized low-energy electron microscopy. An interesting phenomenon, that the magnetic domain structure changed drastically during growth, was revealed. In the early stages of the growth the magnetization alternated between in-plane upon Co deposition and out-of-plane upon Ni deposition. The change of the magnetization direction occurred within a range of less than 0.2 ML during Ni or Co deposition, with break-up of the existing domains followed by growth of new domains. The Ni and Co thickness at which the magnetization direction switched shifted gradually with the number of Co/Ni pairs. Above 3-4 Co/Ni pairs it stayed out-of-plane. The results indicate clearly that the Co-Ni interfaces play the important role of enhancing the perpendicular magnetic anisotropy.

Magnetic domains in ultrathin films form domain patterns, which strongly depend on the magnetic anisotropy. The magnetic anisotropy in Co/Ni multilayers changes with the number of layers. We provide a model to simulate the experimentally observed domain patterns. The model assumes a layer-dependent magnetic anisotropy. With the anisotropy parameter estimated from experimental data, we reproduce the magnetic domain patterns.

We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Early morning hypertension and a high heart rate are risk factors for cardiovascular disease. The DOHSAM study was designed to evaluate the effect of candesartan on early morning blood pressure (BP) and heart rate in hypertensives. We used a prospective, randomized, open-label design. Protocol 1: Patients with early morning BP more than 135/85 mmHg who were not on any antihypertensive drug or on candesartan were given amlodipine 2.5 mg/day (amlodipine group, n = 22) or added candesartan 4 mg/day (candesartan group, n = 36). Candesartan or amlodipine was added when BP did not fall lower than 135/85 mmHg. Protocol 2: Early morning hypertensives who were on other angiotensin receptor blockers (ARBs) (n = 50) such as valsartan, losartan, telmisartan and olmesartan were switched to candesartan. Early morning BP significantly decreased in the candesartan group compared with the amlodipine group 9 and 12 months after treatment. Switching other ARBs except for olmesartan to candesartan significantly decreased early morning systolic and diastolic BP 3, 6, 9 and 12 months after treatment. Heart rate in the office significantly decreased by switching to candesartan 6, 9 and 12 months after treatment. In conclusion, candesartan significantly decreased early morning hypertension more than amlodipine or other ARBs except olmesartan in early morning hypertensives.

Introduction: Lung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix., Patients and Methods: We measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non-small-cell lung cancer (NSCLC)., Results: This study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close association between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level < 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level ≥ 22 nmol BCE/L (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.36-2.99; log-rank P = .00037)., Conclusions: We have revealed that a high serum NTx level (> 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Vascular endothelial growth factor (VEGF) is involved in non-small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but little is known regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for NSCLC with MPE. Chemotherapy-naive non-SQ NSCLC patients with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. In the first cycle, the treated patients received only CP to prevent Bev-induced wound healing delayed after chest drainage. Subsequently, they received 2-6 cycles of CP with Bev. Patients who completed more than 4 cycles of CP and Bev without disease progression or severe toxicities continued to receive Bev alone as a maintenance therapy. The primary end point was overall response, although an increase in MPE was allowed in the first cycle. The VEGF levels in plasma and MPE were measured at baseline, and the VEGF levels in plasma were measured after 3 cycles of chemotherapy. Between September 2010 and June 2012, 23 patients were enrolled. The overall response rate was 60.8 %; the disease control rate was 87.0 %. Sixteen patients received maintenance therapy, following a median of 3 cycles. Median progression-free and overall survival times were 7.1 months (95 % confidence interval [CI], 5.6-9.4 months) and 11.7 months (95 % CI, 7.4-16.8 months), respectively. Most patients experienced severe hematological toxicities, including ≥grade 3 neutropenia; none experienced severe bleeding events. The MPE control rate improved on combining CP with Bev (CP, 78.3 %; CP with Bev, 91.3 %; P = 0.08). The median baseline VEGF level in MPE was 1798.6 (range 223.4-35,633.4) pg/mL. Plasma VEGF levels significantly decreased after 3 chemotherapy cycles (baseline, 513.6 ± 326.4 pg/mL, post-chemotherapy, 25.1 ± 14.1 pg/mL, P < 0.01). CP plus Bev was effective and tolerable in chemotherapy-naïve non-squamous NSCLC patients with MPE.

A combination of low-dose aspirin (ASA) and a phosphodiesterase inhibitor has been clinically tried for the secondary prevention of atherothrombotic diseases. The in vivo antithrombotic property of ibudilast (CAS 50847-11-5), a phosphodiesterase 4 (PDE4) inhibitor, was evaluated in a photochemically-induced guinea pig carotid artery thrombosis model in combination with low-dose ASA. The time required to decrease the carotid artery blood flow to the reading "zero" was defined as the time to occlusion (TTO) of the artery through thrombogenesis. Each independent use of ASA (300 mg/kg, p.o.) and ibudilast (3 and 10 mg/kg, p.o.) significantly prolonged the TTO, and ASA (300 mg/kg) significantly increased bleeding time (BT) and gastric mucosal injury. A selective PDE4 inhibitor rolipram (1 and 5 mg/kg, p.o.) tended to prolong the TTO without extending BT. ASA (100 mg/kg) plus ibudilast (3 mg/kg) and ASA (100 mg/kg) plus rolipram (5 mg/kg) markedly prolonged the TTO compared with each agent alone. Interestingly, ASA (100 mg/kg) plus ibudilast (3 mg/kg) caused a longer TTO than ASA (300 mg/kg) alone, without significant extension of BT and gastric mucosal injury as observed in ASA (300 mg/kg). These results indicate that the combination of low-dose ASA and ibudilast has a more potent antithrombotic effect than ASA alone without increasing bleeding tendency and gastric mucosal injury. The potent in vivo antithrombotic effect of this combination may be brought about by an action that is associated with PDE4 inhibition of ibudilast., (© Georg Thieme Verlag KG Stuttgart · New York.)

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The electron-density distribution and the contribution to anomalous scattering factors for Fe ions in magnetite have been analyzed by X-ray resonant scattering at the pre-edge of Fe K absorption. Synchrotron X-ray experiments were carried out using a conventional four-circle diffractometer in the right-handed circular polarization. Difference-Fourier synthesis was applied with a difference in structure factors measured on and off the pre-edge (E(on) = 7.1082 keV, E(off) = 7.1051 keV). Electron-density peaks due to X-ray resonant scattering were clearly observed for both A and B sites. The real part of the anomalous scattering factor f' has been determined site-independently, based on the crystal-structure refinements, to minimize the squared residuals at the Fe K pre-edge. The f' values obtained at E(on) and E(off) are -7.063 and -6.682 for the A site and -6.971 and -6.709 for the B site, which are significantly smaller than the values of -6.206 and -5.844, respectively, estimated from the Kramers-Kronig transform. The f' values at E(on) are reasonably smaller than those at E(off). Our results using a symmetry-based consideration suggest that the origin of the pre-edge peak is Fe ions occupying both A and B sites, where p-d mixing is needed with hybridized electrons of Fe in both sites overlapping the neighbouring O atoms.

Bone metastasis is an important factor for determining the appropriate treatment for patients with lung cancer. The cross-linked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of the bone matrix. Urinary NTx is recognized as a useful marker of bone metastasis, but the application of serum NTx and its cutoff value for determining bone metastasis from lung cancer have not been characterized. We measured serum NTx by enzyme-linked immunosorbent assay of individuals who underwent staging during hospitalization for initial treatment of lung cancer in our department and compared the NTx levels with the presence of bone metastasis in staging. The study included 166 patients with lung cancer (128 men and 38 women), including 85 adenocarcinoma, 42 squamous cell carcinoma, 32 small-cell carcinoma, and 7 other cancer types. Bone metastasis was present in 73 cases. The average/median serum NTx of bone metastasis (+) and bone metastasis (-) was 27.8/23.8 and 17.1/16.5 nmol bone collagen equivalents/L, respectively. There was an intentional difference with P < 0.001. The cutoff value of the serum NTx level indicating bone metastasis from lung cancer was estimated using the receiver operating characteristics curve. The optimal cutoff value was found to be 22.0 (sensitivity: 61.6%, specificity: 89.2%). The results of univariate and multivariate analysis revealed that the serum NTx levels were significantly related to bone metastasis from lung cancer (P < 0.001). Measurement of serum NTx levels provides a simple diagnostic marker of bone metastasis from lung cancer.

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Clearance of apoptotic cells, so-called efferocytosis, by alveolar macrophages (AMs) is important for lung homeostasis and is impaired in pulmonary inflammatory diseases, such as chronic obstructive pulmonary disease and asthma. Carbocisteine, a mucoregulatory drug, corrects the contents of fucose in airway mucus and has anti-inflammatory properties in airway inflammation. Thus, we conducted the present study to better understand the anti-inflammatory properties of carbocisteine. First, we induced airway inflammation in mice with lipopolysaccharide intratracheally. Carbocisteine significantly decreased neutrophil numbers in bronchoalveolar lavage fluid at the resolution phase of inflammation, implying the promotion of neutrophil clearance. Then, we investigated whether carbocisteine would enhance the efferocytosis by AMs isolated from mice and found that this drug promoted not only the phagocytosis but also the binding of apoptotic cells to AMs in vitro. Furthermore, carbocisteine decreased the fucose residues stained with fluorescent fucose-binding lectin, Lens culinaris agglutinin, on the cell surface of AMs. We found here that removing fucose residues from cell surfaces of AMs by fucosidase markedly enhanced both the binding and phagocytosis of apoptotic cells. Finally, AMs from mice orally given carbocisteine also promoted both the binding and phagocytosis ex vivo similarly to in vitro. These results suggest that carbocisteine could promote the clearance of apoptotic cells by AMs in airway. In addition, the present findings suggest that the binding and phagocytosis of apoptotic cells may be modulated by fucose residues on the cell surface of AMs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In tetrapod limbs, an anteriormost digit has common traits of small, short and less-phalange morphology. In this study, we focused on three genes, Mkp3, Sef and Tsukushi (TSK), which have anterior-specific or anterior-prominent expression patterns in the developing limb bud at the autopod-forming stage. The anterior expression is not fixed in the period of limb development, but the expression domains of Mkp3, Sef and TSK change considerably from the distal domain to the anterior domain. This change in expression domains, anterior shift, of these genes involves maintenance of gene expression in the anterior side and downregulation in the posterior side. Manipulated overdose of fibroblast growth factor (FGF) in the presumptive digit 2 region of chick forelimb bud results in elongation of cartilage elements of digit 2, suggesting that attenuated FGF signaling, which Mkp3, Sef, and TSK negatively regulate, provides digit 2-specific traits of morphology. The anterior expression of Mkp3 and Sef but not TSK is conserved also in limb buds of the mouse and gecko, and the anterior shift of these genes, accumulation of their transcripts in the anterior side and appropriate regulation of strength of FGF signaling may control species-specific morphology of the anteriormost digit.

Anomalous step contrast in low energy electron microscopy (LEEM) images observed during Pb deposition on a W(110) surface is discussed. The steps are dark on the clean surface, and become bright by Pb deposition at about 200 °C. The contrast reversal is related to the presence of a two-dimensional (2D) Pb gas on the surface and its atomic density distribution. Upon further deposition the steps become dark again and show an anomalous intensity profile. This change is attributed to the 2D crystallization process.

Current treatments for patients with Crohn's disease (CD) are based on recent advances in elucidating the pathophysiology of the disease. A satisfactory therapeutic strategy has not been well established. A new sphingosine 1-phosphate (S1P) receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), has been developed for immunomodulation in autoimmune diseases and organ transplantation. We aimed to evaluate the efficacy and potency of KRP-203 on the treatment of chronic colitis in an interleukin (IL)-10 gene-deficient (IL-10(-/-)) mouse model. KRP-203 agonistic activity on S1P receptor was assessed in vitro. KRP-203 was administered for 1 or 4 weeks to IL-10(-/-) mice with clinical signs of colitis. The histological appearance of the colon and the numbers, phenotype, and cytokine production of lymphocytes were compared with a control group. KRP-203 treatment was effective in preventing body weight loss in the IL-10(-/-) colitis model. One-week administration resulted in the sequestration of circulating lymphocytes within the secondary lymphoid tissues. After 4 weeks of treatment, highly significant reductions were observed in number of CD4(+) T cell and B220(+) B cell subpopulations in the lamina propria of the colon and peripheral blood. KRP-203 obviously inhibited the production of interferon-gamma, IL-12, and tumor necrosis factor-alpha by the colonic lymphocytes, but had no influence on IL-4 production. KRP-203 significantly inhibits ongoing IL-10(-/-) colitis in part through decreasing the infiltration of lymphocytes at inflammatory sites and by blocking T-helper 1 cytokine production in the colonic mucosa. Therefore, the possibility arises that KRP-203 plays a potential role in control of chronic colitis.

The critical phase competition between different spin-orbital-ordered states has been investigated for the DyVO3 single crystal. As temperature is lowered, the compound exhibits a reentrant spin and orbital ordering (SO and OO) transition: C-->G-->C type for SO and G-->C-->G type for OO. It was found that a magnetic field also drives the phase transition from C to G for OO and concomitantly from G to C for SO, the latter of which is coupled with the metamagnetic transition of the Dy 4f moments. The mechanism of this novel magnetic-field-induced orbital switching is discussed.

Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the treatment of rat experimental autoimmune myocarditis. KRP-203 significantly attenuated the inflammation area, heart weight/body weight ratio, and left ventricular function. Immunohistochemical analysis and RT-PCR revealed that KRP-203 significantly decreased the infiltration of macrophages and CD4 T cells in the myocardium and the expression of inflammatory cytokines. Flow cytometric analysis revealed that treatment with KRP-203 effectively reduced the number of peripheral CD4 and CD8 T cells but not that of B cells and granulocytes. Further, late KRP-203 treatment was effective even against established EAM. These results demonstrate the therapeutic potential of KRP-203 for the treatment of human myocarditis and provide new insights into the pathogenesis of this disease.

Spectroscopic photoemission and low energy electron microscope (SPELEEM) improved its performance after installation at BL17SU/SPring-8, where a multipolarization-mode undulator is employed to produce circularly and linearly polarized soft x rays. This undulator enables us to study the domain structures of ferromagnetic and antiferromagnetic materials by x-ray magnetic circular dichroism and x-ray magnetic linear dichroism. SPELEEM is used to study light elements (C, N, and O), 3d transition-metal elements and 4f rare earth elements, utilizing a wide range of photon energies. The two cylindrical mirrors adopted in front of SPELEEM ensure an illumination area of 14 x 14 microm(2) on the samples. The lateral resolution of a secondary electron photoemission electron microscope image is estimated to be better than 85 nm, whereas the energy resolution of the instrument is better than 0.4 eV.

Background: We demonstrate the long-term effectiveness of KRP-203 treatment in combination with a subtherapeutic dose of cyclosporine A (CsA) on rat renal allografts., Methods: We tested the effect of KRP-203 in combination with CsA using a rat skin allograft model. The Pharmacokinetic interaction between CsA and KRP-203 was evaluated. The selectivity of KRP-203 for sphingosine-1-phosphate (S1P)1 and S1P3 receptors were investigated in vitro. Heart rate alteration following bolus injection of phosphorylated KRP-203 (KRP-203-P) or FTY720 (FTY720-P) was also monitored in rats. Finally, the long-term effectiveness of KRP-203 in conjunction with a low dose of CsA was investigated in a rat renal transplantation model., Results: Administration of KRP-203 with CsA prolonged skin allograft survival. KRP-203 and CsA had no effect on the pharmacokinetics of the other. While FTY720-P activated both S1P1 and S1P3 receptors, KRP-203-P selectively activated S1P1, but not the S1P3 receptor (EC50:>1000 nM). Compared to FTY720-P, a tenfold higher dose of KRP-203-P was necessary to induce transient bradycardia. With a low dose of CsA (1 mg/kg/day), KRP-203 (0.3 mg/kg/day) significantly prolonged renal allograft survival (P<0.05, survival time: 9.8 days (CsA) vs. >27.4 days (CsA+KRP)). Although a higher dose of CsA (3 mg/kg/day) alone kept recipients alive, this caused severe renal graft dysfunction. Use of KRP-203 (3 mg/kg/day) in conjunction with CsA markedly improved graft function (P<0.05, creatinine clearance: 0.41+/-0.25 ml/min [CsA] vs. 1.15+/-0.16 ml/min [CsA+KRP])., Conclusions: The selectivity of KRP-203 for S1P1 reduces the risk of bradycardia, and the combination therapy of KRP-203 with CsA represents a safe and effective strategy for use in renal transplantation.

Background: Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity., Methods: Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically., Results: Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft., Conclusions: Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

T cell-mediated immune responses play a critical role in a variety of liver injuries including autoimmune hepatitis. Injection of concanavalin A (Con A) into mice mimics the histological and pathological phenotype of T cell-mediated hepatitis. Recent advances in host immune control of organ transplantation include the development of sphingosine-1-phosphate (S1P) receptor agonists such as FTY720, which alter lymphocyte homing but do not suppress host general immunity. Herein we examined the effect of the new S1P receptor agonist KRP-203 on the Con A-induced liver damage model. In normal liver lymphocytes of BALB/c mice, both FTY720 and KRP203 promoted lymphocyte sequestering from the liver to secondary lymph nodes and significantly reduced the number of liver lymphocytes (p<0.05). Based on this observation, KRP203 was employed in the Con A-induced hepatitis model. KRP203 markedly reduced the number of CD4(+) lymphocytes that infiltrate Con A-treated liver (p<0.05) and successfully reduced serum transaminase elevation (p=0.017), therefore protecting mice from Con A-induced liver injury. Interestingly this homing modulation less occurs in natural hepatic T cell homing through the chemokine receptor, CXCR4. Therefore, S1P receptor agonists preferentially target CXCR4(+)CD4(+) peripheral blood T lymphocytes and suppress the occurrence of Con A-induced hepatitis, suggesting their therapeutic usefulness against T cell-mediated hepatic injury.

Background: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation., Methods and Results: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720., Conclusions: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.

To find more effective and less toxic immunosuppressive strategies in long-term treatment for organ transplantation patients, we examined the effects on rat heart allograft survival of a novel sphigosine-1-phosphate receptor agonist, KRP-203, combined with a subtherapeutic dose of cyclosporine (CsA). Rat heart transplantation was performed across a major histocompatibility complex-incompatible (DA to LEW) rat combination. KRP-203 alone showed little or no effect on heart allograft survival. In contrast, KRP-203 combined with a subtherapeutic dose of CsA led to prolonged allograft survival. Histologic analyses showed that the combination completely suppressed acute rejection, as characterized by allograft vasculopathy, mononuclear cell infiltration, and myocardial necrosis in the heart allografts. RT-PCR analysis showed that the allografts treated with CsA or KRP-203 alone showed no suppression of IL-10, IFN-gamma, and TNF-alpha mRNA expression, but when combined with a subtherapeutic dose of CsA it completely suppressed their mRNA expressions. Furthermore, the combination treatment reduced donor-specific antibody production. KRP-203 combined with a subtherapeutic dose of CsA synergistically prolonged rat heart allograft survival. The combination of CsA with KRP-203 may provide an option to prevent allograft rejection and reduce adverse effects.

Folate and methionine are important nutrients in the "one-carbon" metabolism that is closely associated with DNA synthesis and DNA methylation. Genetic variation in these pathways may change susceptibility to cancer development. We have previously reported associations between lymphoma risk and germline polymorphisms in genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase (MTR A2756G), finding the genotype other than the MTHFR 677CC/1298AA to confer a half-risk compared to the MTHFR 677CC/1298AA and a 3-fold higher risk with the MTR GG genotype than the AA/AG genotypes. To confirm the association and explore the histological difference, we extended the previous case series. A case-control study was conducted in Japan with a total of 372 lymphoma cases and 500 noncancer controls examined for genotypes. The relative risks were estimated by unconditional logistic regression analysis. In overall analyses, the age-sex adjusted odds ratio (OR) for the subjects harboring MTHFR 677T or 1298C alleles relative to 677CC/1298AA genotype was 0.58 (95% confidence interval: 0.41-0.83, P = 0.002). The MTR GG genotype showed an OR of 1.75 (0.87-3.52, P = 0.114). These findings were validated in separate analyses of the 273 new incident cases. Subgroup analyses according to histological subtype [diffuse large B-cell lymphoma (DLB), follicular lymphoma (FL), low-grade lymphoma of mucosa associated lymphoid tissue (MALT), and others] illustrated similar associations with certain exceptions for FL and MALT. Our data showed an association between the MTHFR polymorphisms and malignant lymphoma risk for all histological subtypes, although the extent of contribution of these polymorphisms may differ somewhat with histological subtype. Lack of association with MTR polymorphism was also confirmed., (2004 Wiley-Liss, Inc.)

APE1 (apurinic/apyrimidinic endonuclease 1) and XRCC1 (X-ray cross-complementing group 1) are DNA repair proteins that play important roles in the base excision repair (BER) pathway. Polymorphisms in their encoding genes are associated with altered DNA repair capacity and thus may impact on cancer risk. In the present case-control study with 178 Japanese incident lung cancer cases and 449 age- and sex-matched controls, we investigated the gene-environment interaction among APE1 Asp148Glu, XRCC1 Arg399Gln and smoking habit in lung cancer risk. The results were analyzed by using conditional logistic regression models, adjusted for age, sex and smoking status. The adjusted odds ratio for the current smokers with APE1 148Asp/Asp, Asp/Glu and Glu/Glu genotype as compared with the never smokers with the Asp/Asp genotype were 3.01 (95% CI 1.39-6.51, P = 0.005), 2.73 (95% CI 1.29-5.77, P = 0.008) and 7.33 (95% CI 2.93-18.3, P < 0.001), respectively. The gene-environment interaction between current smoking and APE1 148Glu/Glu genotype was statistically significant (OR 3.59, 95% CI 1.28-10.1, P = 0.015). When APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms were evaluated together, the adjusted odds ratios for the current smokers with 0-1, 2 and 3-4 of APE1 148Glu or XRCC1 399Gln alleles as compared with never smokers with the 0 of these alleles were 2.96 (95% CI 1.57-5.58, P = 0.001), 3.86 (95% CI 1.85-8.05, P < 0.001) and 6.01 (95% CI 2.25-16.1, P < 0.001), respectively. The gene-environment interaction between current smoking and three or more APE1 148Glu or XRCC1 399Gln alleles was statistically significant (OR 2.44, 95% CI 1.00-9.22, P = 0.049). The OR for the gene-environment interaction of Glu/Glu genotype of APE1 codon 148 with heavy smoking was 1.04 (95% CI 0.38-2.90, P = 0.936) and that with light smoking was 2.67 (95% CI 1.00-7.68, P = 0.049). These results suggest that APE1 Asp148Glu and XRCC1 Arg399Gln polymorphisms might modify the risk of lung cancer attributable to cigarette smoking exposure.

Cultured epidermal autografting has been employed in a variety of clinical treatments including vitiligo management. In this study, we successfully treated 2 patients with vitiligo using a short-pulsed CO2 laser and by grafting the autologous cultured epidermis. Small pieces of uninvolved skin (2 x 1 cm) were taken for cultivation from a pudendal or axillary area and were expanded into 2 pieces of epidermal sheets 100 cm. Before grafting, the lesions were abraded superficially using a short-pulsed CO2 laser with a computerized pattern generator. After successful grafting, repigmentation was visible within 1 to 2 months. One year after grafting, the skin color was almost the same as that of the surrounding normal skin. Thus, the combination of short-pulsed CO2 laser resurfacing and cultured epidermal grafting is a powerful option for treating an asymmetric and wide vitiliginous lesion.

IL-5 stimulation of CD38-activated murine splenic B cells induces mu-gamma1 CSR at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent mu-gamma1 CSR. Although some of the postreceptor signaling events initiated by IL-5 in activated B cells have been characterized, the involvement of Stat in IL-5 signaling has not been thoroughly evaluated. In this study, we examined the activation of Stat5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells by IL-5. The role of Stat5a and Stat5b in IL-5-induced mu-gamma1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a(-/-) and Stat5b(-/-) mice. Expression levels of CD38-induced germline gamma1 transcripts and AID in Stat5a(-/-) and Stat5b(-/-) B cells upon IL-5 stimulation were comparable to those of wild-type B cells. The impaired mu-gamma1 CSR by Stat5b(-/-) B cells, but not by Stat5a(-/-) B cells, was rescued in part by IL-4, as the addition of IL-4 to the culture of CD38- and IL-5-stimulated B cells induced mu-gamma1 CSR leading to IgG1 production. Analysis of cell division cycle number of wild-type B cells revealed that mu-gamma1 CSR was observed after five or six cell divisions. Stat5a(-/-) and Stat5b(-/-) B cells showed similar cell division cycles, but they did not undergo mu-gamma1 CSR. Our data support the notion that both Stat5a and Stat5b are essential for IL-5-dependent mu;-gamma1 CSR and Ig secretion; however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.

The present survey was conducted to obtain answers to some basic questions regarding the use of intracanal medications, root canal filling methods, and the intracanal breakage of instruments. A letter was sent to 300 endodontists listed in the 1995-1996 membership roster of the American Association of Endodontists. Eighty-five replies were received. Calcium hydroxide as an intracanal medication was used by 91.7% of the responding endodontists. With regard to the root canal filling technique, 52.9% used the lateral condensation method. When intracanal breakage occurred, 95.3% of the respondents informed the patient. The results of this survey provide useful information for the education of undergraduate dental students.

CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induces proliferation, IL-5 receptor alpha chain expression and tyrosine phosphorylation of Bruton's tyrosine kinase. Furthermore, stimulation of splenic B cells with IL-5 together with CS/2 induces Blimp-1 expression and differentiation into Ig-producing cells. Here we examined the role of IL-5 in IgG1 and IgA production by B cells isolated from the spleen and peritoneal cavity. CD38 recognized by CS/2 was expressed in the follicular mantle B cells surrounding the germinal center, sIgD+ splenic B cells and peritoneal B cells. IL-5 induced IgG1 production in splenic sIgD+ B cells stimulated with CS/2, while it was ineffective to induce IgA production. Among the various cytokines tested, only IL-5 had a synergistic effect on IgG1 production with CS/2. IL-5 could induce the generation of S micro-Sgamma1 reciprocal recombination DNA products in CS/2-stimulated B cells. IL-4 was ineffective to induce either micro-gamma1 switch recombination or IgG1 secretion with CS/2, demonstrating that IL-5 promotes both micro-gamma1 switch recombination and IgG1 secretion in an IL-4-independent manner. The peritoneal B-2 cells exhibited both IgG1 and IgA production in response to IL-5 plus CS/2, while B-1 cells produced IgG1. These results imply that the pattern of differentiation to Ig-producing cells seen with peritoneal B cells is not identical to the pattern seen with splenic B cells and that peritoneal B-2 cells contain precursors of IgA-producing cells responding to IL-5 plus CS/2.

We determined the inhibitory activities of gatifloxacin against Staphylococcus aureus topoisomerase IV, Escherichia coli DNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 for S. aureus, r = 0.972 for E. coli, and r = 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 microg/ml for S. aureus topoisomerase IV; IC50 = 0.109 microg/ml for E. coli DNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50 = 265 microg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones against S. aureus topoisomerase IV and those against E. coli DNA gyrase (r = 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50 of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that for S. aureus topoisomerase IV and that for E. coli DNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.

CD38 ligation on mouse B cells by CS/2, an anti-mouse CD38 mAb, induced proliferation, interleukin 5 (IL-5) receptor alpha chain expression, and tyrosine phosphorylation of Bruton tyrosine kinase (Btk) from wild-type, but not from X chromosome-linked, immunodeficient mice. B cells from fyn-deficient (Fyn-/-) and lyn-deficient (Lyn-/-) mice showed an impaired response to mAb CS/2 for proliferation and IL-5 receptor alpha chain expression, and B cells from fyn/lyn double-deficient (Fyn/Lyn-/-) mice did not respond at all to mAb CS/2. The Btk activation by CD38 ligation was observed in B cells from Fyn-/- mice, and it was severely impaired in B cells from Lyn-/- and Fyn/Lyn-/- mice. CD38 expression on B cells from three mutant strains was comparable to that on control B cells. We infer from these results that both Fyn and Lyn are required and that their signals are synergistic for B cell triggering after CD38 ligation. Lyn is upstream of Btk activation in the CD38 signaling. Stimulation of B cells with IL-5 together with CD38 ligation induces not only IgM but also IgG1 secretion. Analysis of the synergistic effects of IL-5 and CD38 ligation on IgG1 secretion revealed the impaired IgG1 secretion of B cells from Lyn-/- and Fyn/Lyn-/- mice. These data imply that Lyn is involved in B cell triggering by CD38 ligation plus IL-5 for isotype switching.

We experienced a case of mediastinal lipoma, which is considered to be relatively rare disease. A 3-year-old girl was referred to Gifu University hospital because of fever and an abnormal shadow on her chest X-ray. The chest X-ray clearly showed a well-delineated tumor shadow which seemed to oppress the diaphragm and the right atrium in the right lower lung area. A computed tomogram (CT) of the chest showed a homogeneous mass localized on the right diaphragm and adjoining the right anterior chest wall and heart. The mass showed a fat density measuring about -100 HU. Magnetic resonance imaging (MRI) showed a high-intensity mass which was almost the same level as the subcutaneous fat on both the T1-weighted and T2-weighted images. Thoracotomy was performed and a fatty tumor was found. It arose from the right side of the pericardium and adjoined the diaphragm, the anterior chest wall, and the thymus. There was no adhesion between the tumor and the surrounding organs. It was resected easily and its contents were yellowish and homogeneous. The patient made an uneventful recovery and was discharged 10 days after the operation. Light microscopy showed a lipoma consisting of mature adipose tissue and no malignancy was found.

Differential scanning calorimetry (DSC) and X-ray diffraction studies on (DMPA)/poly(L-lysine) systems are reported. DSC studies revealed that addition of poly(L-lysine) to DMPA bilayers raises the gel to liquid-crystalline phase transition of the systems, and that this effect depends on the molecular weight of the poly(L-lysine). Small-angle X-ray diffraction measurements showed that, in the liquid-crystalline phase, the lamellar spacing of a DMPA/short-poly(L-lysine) (approximately 4000 mol. wt.) system is shorter than that of a DMPA/long-poly(L-lysine) (approximately 22000 mol. wt.). In this connection wide-angle X-ray diffraction measurements indicate that the long-poly(L-lysine) adopts a beta-sheet conformation on the DMPA bilayers in both the gel and the liquid-crystalline phases, but the short-poly(L-lysine) adopts this conformation only on gel phase DMPA bilayers. We found that the spacings of the hydrocarbon chain packing in a DMPA bilayer in the gel phase increases with temperature, while the spacing between neighbouring polypeptide chains in long-poly(L-lysine) in the beta-sheet conformation remains almost constant. These observations indicate that the positively charged lysine residues are structurally independent of the negatively charged head groups of the phospholipid. On the basis of the present results we propose a model to explain the elementary behaviour of extrinsic membrane proteins in biomembranes.

Mouse CD38 has been implicated in the regulation of both B-cell proliferation and protection of B cells from irradiation-induced apoptosis. CD38 ligation on B cells by CS/2, an anti-mouse CD38 monoclonal antibody, induced proliferation, IgM secretion, and tyrosine phosphorylation of Bruton tyrosine kinase in B cells from wild-type mice. B cells from X chromosome-linked immunodeficient mice did not respond at all to anti-CD38 antibody, although CD38 expression on these B cells was comparable to that on wild-type B cells. We infer from these results that Bruton tyrosine kinase activation is involved in B-cell triggering after cross-linkage of CD38. Analysis of the synergistic effects of various cytokines with CD38 ligation on B-cell activation revealed that interleukin 5 (IL-5) showed the most potent effect on B-cell proliferation, Blimp1 gene expression, and IgM production. These synergistic effects were not seen with B cells from X chromosome-linked immunodeficient mice. Flow cytometry analysis revealed that CD38 ligation increased surface expression of the IL-5-receptor alpha chain on B cells. These data indicate that CD38 ligation increases IL-5 receptor alpha expression and synergizes with IL-5 to enhance Blimp1 expression and IgM synthesis.

Two kinds of calcium-dimyristoylphosphatidic acid (DMPA) complexes at acidic and neutral pH conditions were prepared in the following ways. The complex at pH 4 was obtained by adding Ca2+ to DMPA dispersion in pure water. On the other hand, the complex at pH 7.4 was obtained by adding Ca2+ to DMPA dispersion in the presence of NaOH. The stoichiometries of Ca2+ ion to DMPA molecule are 0.5-0.67 and approximately 1 for the complexes at pH 4 and 7.4, respectively. Static x-ray diffraction shows that the hydrocarbon chains of the Ca(2+)-DMPA complex at pH 4 at 20 degrees C are more tightly packed than those of the complex at pH 7.4 at 20 degrees C. Furthermore, the complex at pH 4 at 20 degrees C gives rise to several reflections that might be related to the ordered arrangement of the Ca2+ ions. These results indicate that the structure of the complex at pH 4 is crystalline-like. In the differential scanning calorimetry (DSC) thermogram, the complex at pH 7.4 undergoes no phase transition in a temperature range between 30 and 80 degrees C. On the other hand, in the DSC thermogram for the complex at pH 4, a peak appears at 65.8 degrees C in the first heating scan. In the successive second heating scan, a transition peak appears at 63.5 degrees C. In connection with the DSC results, the structural changes associated with these phase transitions were studied with temperature-scan x-ray diffraction. In the first heating scan, although a peak appears at 65.80C in the DSC thermogram, the hydrocarbon chain packing gradually converts from an orthorhombic lattice to a hexagonal lattice near 52 degree C, and successively the chain melting phase transition occurs near 670C. In the second heating scan, the hydrocarbon chains are packed in a hexagonal lattice over the whole temperature range and the chain melting phase transition occurs near 63.5 degree C. Therefore,the Ca2+-DMPA complex at pH 4 has a metastable state. The metastable state transforms to a stable state by maintaining the complex at pH 4 for about 90 h at 200C.