Okayama University Survey of the current situation of community-based medical facilities supported by part-time work by physicians

　We investigated the situation of how physicians at Okayama University support local medical institutions by serving as a part-time worker, and analyzed the difference between the five medical districts of Okayama prefecture and other prefectures. Many physicians (actual number of physicians, full-time equivalent number of physicians) served in the southeastern region of the Okayama prefecture (339, 82.2). On the other hand, fewer physicians (42, 11.4) served in Takahashi・Niimi in the northwestern region of Okayama. Many physicians also served in Hiroshima prefecture (193, 48.8), Hyogo prefecture (109, 26.7), and the four prefectures of Shikoku Island (81, 23.6). 　It has been clarified that many physicians at Okayama University are working on a part-time basis to support local and community medical institutions in the wide area of Okayama prefecture, Hiroshima prefecture, Hyogo prefecture and the four prefectures of Shikoku Island

Epidemiology of plasmid-mediated quinolone resistance in salmonella enterica serovar typhimurium isolates from food-producing animals in Japan

A total of 225 isolates of Salmonella enterica serovar Typhimurium from food-producing animals collected between 2003 and 2007 were examined for the prevalence of plasmid-mediated quinolone resistance (PMQR) determinants, namely qnrA, qnrB, qnrC, qnrD, qnrS, qepA and aac(6')Ib-cr, in Japan. Two isolates (0.8%) of S. Typhimurium DT104 from different dairy cows on a single farm in 2006 and 2007 were found to have qnrS1 on a plasmid of approximately 9.6-kbp. None of the S. Typhimurium isolates had qnrA, qnrB, qnrC, qnrD, qepA and acc(6')-Ib-cr. Currently in Japan, the prevalence of the PMQR genes among S. Typhimurium isolates from food animals may remain low or restricted. The PFGE profile of two S. Typhimurium DT104 isolates without qnrS1 on the farm in 2005 had an identical PFGE profile to those of two S. Typhimurium DT104 isolates with qnrS1. The PFGE analysis suggested that the already existing S. Typhimurium DT104 on the farm fortuitously acquired the qnrS1 plasmid

Outburst of LS V+44 17 Observed by MAXI and RXTE, and Discovery of a Dip Structure in the Pulse Profile

We report on the first observation of an X-ray outburst of a Be/X-ray binary pulsar LS V +44 17/RX J0440.9+4431, and the discovery of an absorption dip structure in the pulse profile. An outburst of this source was discovered by MAXI GSC in 2010 April. It was the first detection of the transient activity of LS V +44 17 since the source was identified as a Be/X-ray binary in 1997. From the data of the follow-up RXTE observation near the peak of the outburst, we found a narrow dip structure in its pulse profile which was clearer in the lower energy bands. The pulse-phase-averaged energy spectra in the 3$-$100 keV band can be fitted with a continuum model containing a power-law function with an exponential cutoff and a blackbody component, which are modified at low energy by an absorption component. A weak iron K$\alpha$ emission line is also detected in the spectra. From the pulse-phase-resolved spectroscopy we found that the absorption column density at the dip phase was much higher than those in the other phases. The dip was not seen in the subsequent RXTE observations at lower flux levels. These results suggest that the dip in the pulse profile originates from the eclipse of the radiation from the neutron star by the accretion column.Comment: 18 pages, 7 figures, accepted for publication in PAS

Long-term Monitoring of the Black Hole Binary GX 339-4 in the High/Soft State during the 2010 Outburst with MAXI/GSC

We present the results of monitoring the Galactic black hole candidate GX 339-4 with the Monitor of All-sky X-ray Image (MAXI) / Gas Slit Camera (GSC) in the high/soft state during the outburst in 2010. All the spectra throughout the 8-month period are well reproduced with a model consisting of multi-color disk (MCD) emission and its Comptonization component, whose fraction is <= 25% in the total flux. In spite of the flux variability over a factor of 3, the innermost disk radius is constant at R_in = 61 +/- 2 km for the inclination angle of i = 46 deg and the distance of d=8 kpc. This R_in value is consistent with those of the past measurements with Tenma in the high/soft state. Assuming that the disk extends to the innermost stable circular orbit of a non-spinning black hole, we estimate the black hole mass to be M = 6.8 +/- 0.2 M_sun for i = 46 deg and d = 8 kpc, which is consistent with that estimated from the Suzaku observation of the previous low/hard state. Further combined with the mass function, we obtain the mass constraint of 4.3 M_sun < M < 13.3 M_sun for the allowed range of d = 6-15 kpc and i < 60 deg. We also discuss the spin parameter of the black hole in GX 339-4 by applying relativistic accretion disk models to the Swift/XRT data.Comment: 9 pages, 8 figures, accepted for publication in PASJ (Suzaku+MAXI special issue

A Spectral Study of the Black Hole Candidate XTE J1752-223 in the High/Soft State with MAXI, Suzaku and Swift

We report on the X-ray spectral analysis of the black hole candidate XTE\ J1752--223 in the 2009--2010 outburst, utilizing data obtained with the MAXI/Gas Slit Camera (GSC), the Swift/XRT, and Suzaku, which work complementarily. As already reported by Nakahira et al. (2010) MAXI monitored the source continuously throughout the entire outburst for about eight months. All the MAXI/GSC energy spectra in the high/soft state lasting for 2 months are well represented by a multi-color disk plus power-law model. The innermost disk temperature changed from $\sim$0.7 keV to $\sim$0.4 keV and the disk flux decreased by an order of magnitude. Nevertheless, the innermost radius is constant at $\sim$41 $D_{3.5}(\cos{\it i})^{-1/2}$ km, where $D_{3.5}$ is the source distance in units of 3.5 kpc and $i$ the inclination. The multi-color disk parameters obtained with the MAXI/GSC are consistent with those with the Swift/XRT and Suzaku. The Suzaku data also suggests a possibility that the disk emission is slightly Comptonized, which could account for broad iron-K features reported previously. Assuming that the obtained innermost radius represents the innermost stable circular orbit for a non-rotating black hole, we estimate the mass of the black hole to be 5.51$\pm$0.28 $M_{\odot}$ $D_{3.5}(\cos{\it i})^{-1/2}$, where the correction for the stress-free inner boundary condition and color hardening factor of 1.7 are taken into account. If the inclination is less than 49$^{\circ}$ as suggested from the radio monitoring of transient jets and the soft-to-hard transition in 2010 April occurred at 1--4% of Eddignton luminosity, the fitting of the Suzaku spectra with a relativistic accretion-disk model derives constraints on the mass and the distance to be 3.1--55 $M_{\odot}$ and 2.3--22 {\rm kpc}, respectively. This confirms that the compact object in XTE J1752--223 is a black hole.Comment: 12 pages including 7 figures and 4 tables, accepted for publication in PAS

Expression and Function of Inducible Costimulator on Peripheral Blood CD4 ؉ T Cells in Behçet&apos;s Patients with Uveitis: A New Activity Marker?

PURPOSE. Inducible costimulator (ICOS) is an important costimulatory molecule involved in T-cell activation. In this study, the role of ICOS in the pathogenesis of uveitis in Behçet&apos;s disease (BD) was investigated. METHODS. Peripheral blood mononuclear cells (PBMCs) were obtained from BD patients with uveitis in the active or remission phase and in healthy subjects. Total RNA was isolated from PMBCs, and mRNA expression was analyzed on an oligonucleotide microarray. ICOS expression on CD4 ϩ T cells was determined by flow cytometry, and the functional costimulatory effect of ICOS/B7RP-1 interaction was assessed on stimulation with concanavalin A (conA) or IRBP in the presence or absence of anti-ICOS mAb. RESULTS. As the result of microarray analysis, ICOS in PBMCs showed the greatest difference in expression in BD patients with uveitis compared with healthy control subjects. ICOS expression on CD4 ϩ T cells in BD patients with uveitis was significantly higher than that in healthy individuals, both before and after conA stimulation. Among the BD patients, ICOS expression on CD4 ϩ T cells was significantly higher in those with active uveitis than in those with remitted uveitis. Blockade of ICOS/B7-related protein-1 (B7RP-1) interaction by anti-ICOS mAb significantly decreased IFN-␥, IL-17, and TNF-␣ production by PBMCs when stimulated with conA or IRBP in BD with active uveitis. CONCLUSIONS. High ICOS expression in BD patients with uveitis contributed to the upregulation of IFN-␥, IL-17, and TNF-␣ production, suggesting that abnormal ICOS costimulation may play an immunopathologic role in the pathogenesis of uveitis in BD. (Invest Ophthalmol Vis Sci. 2010;51:5099 -5104) DOI: 10.1167/iovs.10-5286 E ndogenous uveitis such as Behçet&apos;s disease (BD), VogtKoyanagi-Harada syndrome, sympathetic ophthalmia, birdshot retinochoroidopathy, and sarcoidosis is a potentially blinding disease in humans and is responsible for 10% to 15% of the acquired blindness in Japan. 1 Although endogenous uveitis covers a spectrum of clinical entities, all forms are believed to share immunohistologic similarities characterized by the infiltration of mainly T cells. Behçet&apos;s disease (BD) is a systemic inflammatory disease characterized by oral and genital ulcers as well as ocular, cutaneous, arthritic, vascular, and neurologic lesions. 3-5 An increasing number of reports indicate that aberrant cellular immunity, such as pathogenic CD4 ϩ T-cell[b]-mediated autoimmunity via the Th1/Th17 pathway, plays a key role in the pathophysiological process in BD with uveitis, 6 -10 although the mechanisms of ocular inflammation in BD remain largely unknown. During recent years, the understanding of immunologic mechanisms involved in uveitis has advanced greatly through investigations of experimental autoimmune uveoretinitis (EAU), an animal model of human uveitis that can be induced by immunization of susceptible animals with interphotoreceptor retinoid-binding protein (IRBP) or with an eye-specific retinal antigen or by adoptive transfer of CD4 ϩ T cells specific for retinal antigens. 11 EAU resembles certain human uveitic conditions in various aspects 14,15 Although CD28 regulation has substantial effects on immunity, its function appears to reside predominantly in the control of primary, but not secondary, immune responses in various autoimmune diseases. 16 -18 The CD28 homolog inducible costimulator (ICOS) has recently been identified as a novel member of the CD28 costimulator family and is expressed by activated T cells in both humans and mice. To identify new genes that may cause or contribute to the disease process of ocular BD, we used cDNA microarrays that provide the expression profile of more than 54,000 genes, some of which are immune-related, whereas others are involved in the cell cycle, cell growth, intracellular signaling, cellular adhesion, and transport, and we compared the expression profiles of healthy individuals and patients. One of the genes found to be upregulated in patients with ocular BD is ICOS, an activation marker expressed on activated T cells that binds B7RP-1-expressing monocytes. The engagement of ICOS with B7RP-1 along with an appropriate antigen provide a positive signal that promotes T-cell differentiation, cytokine secretion, and effector function in the absence of CD28. ϩ T cells and B7RP-1 expressed on infiltrating APCs are upregulated directly after disease onset. 30 Therefore, we speculated that in active BD, pathogenic CD4 ϩ T cells that infiltrate the eye express ICOS in the inflamed eye and would be an appropriate target for the treatment of human ocular BD. Moreover, we have demonstrated that blockade of the ICOS/ B7RP-1 costimulatory pathway inhibits ocular inflammation in the effector phase of murine EAU. 30 Therefore, to investigate the role of ICOS in the pathogenesis of ocular BD, we assessed its expression on peripheral blood CD4 ϩ T cells and functional roles in patients with ocular BD. The results suggest that upregulation of ICOS is associated with the pathogenesis of uveitis in BD. MATERIALS AND METHODS PBMC Samples Thirty-five patients with BD (27 men and 8 women, mean age; 37.8 Ϯ 11.1 years) were enrolled in the study Heparinized blood samples were obtained from patients and healthy individuals, and PBMCs were isolated within 2 hours by density gradient centrifugation. The PBMCs were washed twice and resuspended at 1 ϫ 10 6 cells/mL in complete medium (RPMI 1640 supplemented with 10% fetal calf serum, 1 mM L-glutamine, 100 U/mL penicillin, and 100 g /mL streptomycin). Cell suspension was dispensed in 24-well plates (Falcon; BD Biosciences, Mountain View, CA) at 1 mL/well and incubated with or without concanavalin A (ConA; 10 g/mL) for 12 hours. Analysis of Gene Expression with cDNA Array Gene expression profile of human PBMCs was analyzed by microarray, as described previously. 37 Briefly, total RNA was isolated from pooled PBMCs obtained from seven patients with BD and active uveitis by an extraction method (Isogen Nippon Gene, Tokyo, Japan), and portions (2 g) of the preparation were subjected to amplification of mRNA with T7 RNA polymerase. Biotin-labeled cRNA (10 g) synthesized from the amplified RNA was subjected to hybridization with the Human Whole Genome Bioarray chip (Amersham Biosciences, Piscataway, NJ) that contains oligonucleotides corresponding to a total of approximately 55,585 human genes. Detection and digitization of hybridization signals were performed (G2565; Agilent Technologies, San Diego, CA) and analyzed (CodeLink Expression Analysis software version 4.0; Amersham Biosciences). The microarray data of various costimulatory molecules are summarized in Reagents FITC-conjugated anti-human CD4 (L3T4) was purchased from eBioscience (San Diego, CA), and anti-human ICOS (DX29) from BD PharMingen (San Diego, CA). ConA was obtained from Vector Laboratories (Burlingame, CA). Preparation of IRBP Fresh swine IRBP was purified according to the method described by Fukai et al. Immunofluorescence and Flow Cytometry The results of ICOS gene expression obtained from microarray were confirmed by flow cytometry. PMBCs were isolated by density gradient centrifugation of heparinized blood samples obtained from patients and healthy individuals. Each PBMC sample was divided into two aliquots: one for direct flow cytometry analysis of ICOS expression and the other for flow cytometry analysis after activation with conA at 10 g/mL for 12 hours. ICOS analysis was performed by using the following procedures: A cocktail of FITC-conjugated anti-CD4 and PE-conjugated anti-ICOS was added to the PBMCs. After the cells were washed with PBS, the stained cells (live-gated based on forward-and sidescatter profiles and propidium iodide exclusion) were passed through a flow cytometer (FACSCalibur; BD Biosciences, San Jose, CA) and the results analyzed (CellQuest program; BD Biosciences). ICOS expression on human CD4 ϩ T cells was calculated by gating for the CD4 ϩ T cell population, and 10,000 cells were analyzed in each experiment. Cytokine Assay Purified PBMCs (5 ϫ 10 5 /well) from BD patients with active uveitis were cultured in 96-well microtiter plates, with or without stimulation with conA (3 g/mL) or IRBP (10 g/mL) plus anti-ICOS mAb (10 g/mL) or control IgG at 37°C for 48 hours. The unstimulated PBMCs served as negative control samples. After stimulation, cell-free supernatants were collected at 48 hours and assayed for IFN-␥, TNF-␣, IL-2, and IL-6 by cytometric bead array (CBA) kits (BD PharMingen) and IL-17 by ELISA (Human IL-17 Quantikine ELISA kit; R&amp;D Systems, Minneapolis, MN), according to the manufacturers&apos; instructions. The minimum levels detected by CBA kits in either the culture supernatant or serum/plasma were 2.6 pg/mL for IL-2, 3.0 pg/mL for IL-6, 7.1 pg/mL for IFN-␥, and 2.8 pg/mL for TNF-␣; the minimum level in the IL-17 ELISA was 7.8 pg/mL. In a preliminary study, serial concentrations of conA (1, 3, 5, and 10 g/mL) or IRBP (1, 5, and 10 g/mL) were used in the assays. The results showed that optimal concentrations of cytokines were obtained at a concentration of 3 g/mL for conA and 10 g/mL for IRBP, as previously described. Statistical Analysis Data were analyzed (JMP 5; SAS Institute, Inc., Cary, NC) and the results expressed as the mean Ϯ SD. Statistical analysis was performed by using a paired or unpaired t-test. P Ͻ 0.05 was considered significant. RESULTS Analysis of Microarray Results in BD Patients with Active Uveitis To identify the genes involved in the pathogenesis of ocular BD, we compared phosphorescent images of the arrays hybridized with cDNA probes generated from RNA preparations from BD patients with active uveitis and healthy individuals. The array membrane that we used contained 360 positive bacterial controls and 384 negative controls. All positive controls were detected on the microarray. No signals were observed for the negative spots, indicating that the hybridization was highly specific. The DNA screening can evaluate more than 54,000 genes for a single sample. Among these genes, we focused on the immune-related ones, especially those of costimulatory molecules. Among the seven genes of costimulatory molecules, ICOS showed the greatest difference in expression in BD patients with active uveitis compared with that in healthy control subjects ICOS Expression on CD4 ؉ T Cells of BD Patients with Uveitis Flow cytometry was performed to confirm the results of gene array analysis. ICOS expression (median fluorescence intensity [MFI] of ICOS on CD4 ϩ T cells; Comparison of ICOS Expression on CD4 ؉ T Cells in BD Patients with Active or Inactive Uveitis Next, we compared ICOS expression on CD4 ϩ T cells in BD patients with active or inactive uveitis. ICOS expression (MFI of ICOS on CD4 ϩ T cells, Cytokine Production Stimulated with ConA and Uveitogenic Antigen To determine whether ICOS has functional costimulatory activity, we first measured the amounts of pathogenic Th1 and Th17 cytokines (IFN-␥, IL-17, TNF-␣, IL-6, and IL-2) produced by nonspecific stimulation (conA) of PBMCs obtained from BD patients with active uveitis. When ICOS costimulation was blocked with anti-ICOS mAb, the amounts of IFN-␥, IL-17, and TNF-␣ (Figs. 3A-C) produced by PBMCs were both significantly reduced. Since PBMCs from BD patients are known to be sensitized to the two most uveitogenic retina-specific antigens, S-antigen and IRBP, 1 we then examined the amounts of pathogenic Th1 and Th17 cytokines produced by stimulation with swine IRBP protein as the specific antigen. DISCUSSION The precise pathogenesis of uveitis associated with BD is unknown. Accumulated data obtained from animal models such as EAU suggest that Th1 and Th17 cells have major roles IOVS, October 2010, Vol. 51, No. 10 New Activity Marker for Ocular Behçet&apos;s Disease 5101 Downloaded from iovs.arvojournals.org on 06/30/2019 in its pathogenesis. We have previously shown that blockade of the ICOS ϩ costimulatory pathway has an ameliorating effect during the effector phase of EAU, by suppressing the expansion and effector function of pathogenic Th1 cells. In conclusion, our data provide additional evidence of the potential utility of ICOS expression on CD4 ϩ T cells as a marker of disease activity and as a promising therapeutic target for ocular BD via its inhibition of Th1 and Th17 cytokines. As the population studied was small and heterogeneous, further studies are needed to confirm the findings

A Large X-ray Flare from a Single Weak-lined T Tauri Star TWA-7 Detected with MAXI GSC

We present a large X-ray flare from a nearby weak-lined T Tauri star TWA-7 detected with the Gas Slit Camera (GSC) on the Monitor of All-sky X-ray Image (MAXI). The GSC captured X-ray flaring from TWA-7 with a flux of $3\times10^{-9}$ ergs cm$^{-2}$ s$^{-1}$ in 2--20 keV band during the scan transit starting at UT 2010-09-07 18:24:30.The estimated X-ray luminosity at the scan in the energy band is 3$\times10^{32}$ ergs s$^{-1}$,indicating that the event is among the largest X-ray flares fromT Tauri stars.Since MAXI GSC monitors a target only during a scan transit of about a minute per 92 min orbital cycle, the luminosity at the flare peak might have been higher than that detected. At the scan transit, we observed a high X-ray-to-bolometric luminosity ratio, log $L_{\rm X}/L_{\rm bol}$ = $-0.1^{+0.2}_{-0.3}$; i.e., the X-ray luminosity is comparable to the bolometric luminosity. Since TWA-7 has neither an accreting disk nor a binary companion, the observed event implies that none of those are essential to generate such big flares in T Tauri stars.Comment: 4 pages, 2 figures, 1 table accepted for publication in PAS