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Kawakami K.,Nagasaki Kawatana Medical Center | Ohkusa Y.,National Institute of Infectious Disease | Kuroki R.,Nagasaki Kawatana Medical Center | Tanaka T.,Nagasaki Kawatana Medical Center | And 5 more authors.
Vaccine | Year: 2010

To determine the clinical efficacy and cost-saving effect of pneumococcal polysaccharide vaccine (PPV) against community-acquired pneumonia (CAP), an open-label, randomized clinical trial was conducted involving 786 Japanese subjects older than 65 years of age receiving a routine influenza vaccine during the 2-year period. Study subjects were randomly assigned to either a PPV group (n= 394) or to a non-PPV group (n= 392). The incidence, admission and the medical cost for all-cause pneumonia were compared between these two groups. PPV vaccination significantly reduced the incidence of admission for all-cause pneumonia for subjects older than 75 years of age (41.5%, P= 0.039) and for those who had difficulty walking (62.7%, P= 0.005), but not for all study subjects older than 65 years of age (P= 0.183), for the 2-year period. The Kaplan-Meier survival curves for subjects who had difficulty walking free from all-cause pneumonia demonstrated a significant difference (P= 0.0146) between the two groups. PPV vaccination significantly reduced medical costs for all study subjects during the first year period (P= 0.027). Our present data demonstrated that PPV was effective for all-cause pneumonia for study subjects older than 75 years of age, although the effect was not significant for all study subjects older than 65 years of age. © 2010 Elsevier Ltd. Source

Matsubara T.,Osaka University | Ikeda F.,Osaka University | Hata K.,Osaka University | Nakanishi M.,Osaka University | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2010

A tyrosine kinase, c-Src, that plays an indispensable role in ruffled border formation and bone resorption is constitutively active in osteoclasts. However, to date, the molecular mechanism underlying increased c-Src activity in osteoclasts is unknown. To address this, we first examined the expression levels and subcellular localization of Csk, a negative regulatory kinase for c-Src. We found that the expression level of Csk in osteoclasts was comparable with that of other tissues. However, in osteoclasts, Csk was hardly localized in lipid rafts, where c-Src is highly expressed. Interestingly, expression of Cbp, which recruits Csk into lipid rafts through physical interaction with Csk, was very low in osteoclasts compared with other tissues. To understand the importance of Cbp in osteoclasts, we introduced Cbp into osteoclasts using an adenovirus gene delivery system. Introduction of Cbp stimulated recruitment of Csk into lipid rafts and suppressed c-Src activity in a dose-dependent manner. Furthermore, introduction of Cbp markedly inhibited formation of actin rings and bone-resorbing activity in osteoclasts. In addition, treatment with RANKL and overexpression of TRAF6 or NFAT2 inhibited Cbp expression in the osteoclastogenic cell line RAW264.7 along with osteoclastic differentiation. NFAT2 overexpression also inhibited Cbp expression in spleen macrophages. Collectively, our results indicate that reduction in Cbp expression is responsible for maintaining high c-Src activity in osteoclasts. These findings contribute to an understanding of the unique regulatory system for c-Src in osteoclasts. © 2010 American Society for Bone and Mineral Research. Source

Murakami H.,Research Institute for Microbial Diseases | Wang Y.,Research Institute for Microbial Diseases | Hasuwa H.,Osaka University | Maeda Y.,Research Institute for Microbial Diseases | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Glycosylphosphatidylinositol (GPI) is a complex glycolipid that serves as a membrane anchor for many cell-surface proteins, such as Thy-1 and CD48. GPI-anchored proteins (GPI-APs) play important roles in many biological processes, such as signal transduction and cell-cell interaction, through their association with lipid rafts. Fatty acid remodeling of GPI-APs in the Golgi apparatus is required for their efficient association with lipid rafts, i.e., the unsaturated fatty acid at the sn-2 position of the PI moiety is exchanged for the saturated fatty acid by PGAP2 and PGAP3. To investigate the immunological role of the fatty acid remodeling of GPI-APs, we generated a Pgap3 knockout mouse. In this mouse, GPI-APs are expressed on the cell surface without fatty acid remodeling, and fail to associate with lipid rafts. Male Pgap3 knockout mice were born alive at a ratio lower than expected from Mendel's law, whereas the number of female mice followed Mendel's law. All mice exhibited growth retardation and abnormal reflexes such as limb grasping. We focused T cell function in these mice and found that T cell development in the absence of Pgap3 was normal. However, the response of T cells was enhanced in Pgap3 knockout mice in both in vitro and in vivo studies, including alloreactive response, antigen-specific immune response, and experimental autoimmune encephalomyelitis. Cross-linking of Thy-1 in wild-type cells inhibited the signal transduced by the T cell receptor (TCR), whereas cross-linking of Thy-1 in Pgap3 knockout cells enhanced the TCR signal. These results suggest that GPI-APs localized in lipid rafts may modulate signaling through the TCR. © 2011 Elsevier Inc. Source

Hirata H.,Rakuno Gakuen University | Kawai S.,Dokkyo Medical University | Maeda M.,Rakuno Gakuen University | Jinnai M.,Rakuno Gakuen University | And 6 more authors.
American Journal of Tropical Medicine and Hygiene | Year: 2011

We demonstrate here the identification and phylogenetic characterization of Babesia microti (B. microti)-like parasite detected from a splenectomized Japanese macaque (Macaca fuscata fuscata) at a facility for laboratory animal science. On Day 133 after splenectomy, intra-erythrocytic parasites were found on light microscopic examination, and the level of parasitemia reached 0.3% on blood smear. Molecular characterization of the parasite using nested-polymerization chain reactions targeting the 18S rRNA, β-tubulin, and subunit 7 (eta) of the chaperonin-containing t-complex polypeptide 1 (CCT7) genes were identified as a B. microti -like parasite, designated the Japanese Macaque Babesia -1 (JM-1). Copyright © 2011 by The American Society of Tropical Medicine and Hygiene. Source

Kishimoto I.,Japan National Cardiovascular Center Research Institute | Takeuch Y.,National Hospital Organization Toneyama Hospital | Maed H.,National Hospital Organization Toneyama Hospital | Kidoy H.,Research Institute for Microbial Diseases | And 7 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice.We examined the effect of ANP on tumormetastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells. Source

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