Kitasato Institute for Life science

Minato-ku, Japan

Kitasato Institute for Life science

Minato-ku, Japan

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Oguri H.,Hokkaido University | Hiruma T.,Hokkaido University | Yamagishi Y.,Hokkaido University | Oikawa H.,Hokkaido University | And 4 more authors.
Journal of the American Chemical Society | Year: 2011

To access high-quality small-molecule libraries to screen lead candidates for neglected diseases exemplified by human African trypanosomiasis, we sought to develop a synthetic process that would produce collections of cyclic scaffolds relevant to an assortment of natural products exhibiting desirable biological activities. By extracting the common structural features among several sesquiterpenes, including artemisinin, anthecularin, and transtaganolides, we designed six types of scaffolds with systematic structural variations consisting of three types of stereochemical relationships on the sp 3 ring-junctions and two distinct arrays of tricyclic frameworks. A modular and stereodivergent assembly of dienynes exploiting a versatile manifold produced a series of cyclization precursors. Divergent cyclizations of the dienynes employing tandem ring-closing metathesis reactions overrode variant reactivities of the cyclization precursors, leading to the six canonical sets of the tricyclic scaffolds incorporating a diene group. Screenings of trypanosomal activities of the canonical sets, as well as regio- and stereoisomers of the tricyclic dienes, allowed generation of several antitrypanosomal agents defining the three-dimensional shape of the pharmacophore. The candidate tricyclic dienes were selected by primary screenings and further subjected to installation of a peroxide bridge, which generated artemisinin analogues that exhibited potent in vitro anti-trypanosomal activities comparable or even superior to those of artemisinin and the approved drugs, suramin and eflornithine. © 2011 American Chemical Society.


Takayama Y.,Kitasato University | Okamoto R.,Kitasato University | Sunakawa K.,Kitasato Institute for Life science
Journal of the Formosan Medical Association | Year: 2010

Background/Purpose: To evaluate the epidemiology, clinical features, and microbiological features (including antibiotic susceptibility) of infective endocarditis (IE) at Kitasato University Hospital, Japan. Methods: We retrospectively analyzed 153 patients (155 episodes) with definite IE according to the Duke criteria, who presented over a 17-year period. The minimum inhibitory concentrations of antibiotics for cultured causative microorganisms were also examined. Results: Viridans group streptococci were the most common pathogens (36.8%, 57 episodes), followed by Staphylococcus aureus [21.3%, 33 episodes, including 10 episodes due to methicillin-resistant S. aureus (MRSA)]. Thirty-nine of the 40 strains of viridans streptococci were fully susceptible to penicillin. Comparison of IE due to methicillin-sensitive S. aureus (MSSA) and MRSA showed that the latter had a higher mortality rate (34.8%, 8/23 vs. 70.0%, 7/10). Compared with MSSA, IE caused by MRSA was significantly more likely to be related to nosocomial infection (10/10, p < 0.001), hemodialysis (4/10, 40.0%, p = 0.005), and surgery or intravascular catheter insertion (8/10, 80.0%, p = 0.007). There was a significantly higher mortality rate in non-operated (15/43, 34.9%) than in operated (2/21, 9.5%) (p < 0.001) elderly patients. In 92/155 episodes (59.4%), antibiotics were given before blood cultures were obtained. Culture-negative IE occurred in 20.7% (19/92) of patients on antibiotics versus 6.3% (4/63) of those not on antibiotics (p = 0.02). Of 155 episodes of IE, 34 (21.9%) were fatal and staphylococcal had significantly higher mortality than streptococcal IE [(19/40, 47.5%) vs. (7/72, 9.7%); p < 0.001]. Conclusion: The most frequently isolated pathogens were viridans group streptococci, which differed from other recent studies. In the present study, no penicillin-resistant strains were detected and there was a higher mortality rate for IE caused by MRSA than MSSA. IE should be considered in MRSA patients with the following risk factors: nosocomial infection, hemodialysis, and surgery or intravascular catheter insertion. © 2010 Elsevier & Formosan Medical Association.


Jin L.,Public Health England | Orvell C.,University of Stockholm | Myers R.,Public Health England | Rota P.A.,Centers for Disease Control and Prevention | And 4 more authors.
Reviews in Medical Virology | Year: 2015

The WHO recently proposed an updated nomenclature for mumps virus (MuV). WHO currently recognizes 12 genotypes of MuV, assigned letters from A to N (excluding E and M), which are based on the nucleotide sequences of small hydrophobic (SH) and haemagglutinin-neuraminidase (HN) genes. A total of 66 MuV genomes are available in GenBank, representing eight of the 12 genotypes. To complete this dataset, whole genomes of seven isolates representing six genotypes (D, H, I, J, K and L) and one unclassified strain were sequenced. SH and HN genes of other representative strains were also sequenced. The degree of genetic divergence, predicted amino acid substitutions in the HN and fusion (F) proteins and geographic distributions of MuV strains were analysed based on the updated dataset. Nucleotide heterogeneity between genotypes reached 20% within the SH gene, with a maximum of 9% within the HN gene. The geographic and chronologic distributions of the 12 genotypes were summarised. This review contributes to our understanding of strain diversity for wild type MuV, and the results support the current WHO nomenclature. © 2014 John Wiley & Sons, Ltd.


Kashiwagi Y.,Tokyo Medical University | Maeda M.,Kitasato Institute for Life science | Kawashima H.,Tokyo Medical University | Nakayama T.,Kitasato Institute for Life science
Vaccine | Year: 2014

Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48. h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1β, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past. © 2014 Elsevier Ltd.


Nakayama T.,Kitasato Institute for Life science | Kumagai T.,Kumagai Pediatric Clinic | Ishii K.J.,Japan National Institute of Biomedical Innovation | Ishii K.J.,Osaka University | Ihara T.,National Mie Hospital
Vaccine | Year: 2012

IgG subclass antibody responses are not fully understood. Alum-adjuvanted H5N1whole virion inactivated vaccine (WIV), a genetically reassortant vaccine seed strain originating from H5N1/A/Vietnam/1194/2004 and PR-8, induced significantly stronger antibody responses in neutralizing antibodies in children. In this report, IgG subclass antibody responses were investigated, and most serum samples were positive for IgG1 antibody before immunization. A significant response (more than 4-fold increase) of IgG1 antibody was observed in 67/193 (34.7%) and that of gG4 antibodies in 42/193(21.8%). Children <4 years of age showed a significant increase in IgG subclass antibodies but those ≥4 years showed lower responses. Alum- adjuvanted H5N1WIV induced an efficient immune response in young children especially <4 years. © 2012 Elsevier Ltd.


Yoshida N.,Tachikawa Kyousai Hospital | Nakayama T.,Kitasato Institute for Life science
Intervirology | Year: 2010

Objective: Mumps virus is isolated in Vero cells and, recently, B95a cells have been reported to be susceptible to it. Currently circulating wild-type mumps virus strains (genotypes B, G, J and L) induced cytopathic effects in both Vero and B95a cells. On the other hand, the Hoshino vaccine strain (KO3) did not induce cytopathic effects in B95a cells. In this study, differences in fusion inducibility were investigated. Methods: Nucleotide sequences of the fusion (F) and hemagglutinin-neuraminidase (HN) protein regions were compared. The F and HN expression plasmids were constructed and fusion analysis was conducted, using recombinant F expression plasmids under the control of T7 RNA polymerase. Results: Extensive cell fusion was observed when B95a cells were transfected with the wild-type F expression plasmid as the F expression partner; 13-16 amino acid differences were observed in the F protein region between the KO3 and the wild types. F expression plasmids with leucine at position 383 of the F protein induced large cell fusion in B95a cells. Conclusion: Leucine at position 383 of the F protein of the wild types was the critical amino acid for fusion inducibility in B95a cells. Copyright © 2010 S. Karger AG, Basel.


Sakata M.,Kitasato Institute Research Center for Biologicals | Sakata M.,Japan National Institute of Infectious Diseases | Nakayama T.,Kitasato Institute for Life science
Vaccine | Year: 2011

Wild-type rubella viruses grow well at 39 °C (non-temperature sensitivity: non- ts), while vaccine strains do not (temperature sensitivity: ts). Histidine at position 1042 of the p150 region of the KRT vaccine strain was found to be responsible for ts, while wild-type viruses had tyrosine at position 1042 (Vaccine 27; 234-42, 2009). The point-mutated virus (Y1042H) based on the wild-type unexpectedly showed little reduction in growth at 39 °C. In this report, several recombinant viruses were characterized, and point-mutated Y1042H together with the p90 region of KRT significantly reduced virus growth, compared to the parental wild-type virus. There was one amino acid difference at position 1497 of the helicase domain in the p90 region. Double mutation involving both positions 1042 and 1497 markedly reduced virus growth at 39 °C, but single substitution at 1497 did not. The other vaccine strain (TO-336vac) was investigated, and serine at position 1159 of the protease domain in p150 was a crucial amino acid for ts and non- ts characteristics among four amino acid substitutions between TO-336vac and the wild-type. Our results suggest that protease and helicase domains in non-structural protein were consistent with ts phenotype, possibly related to the attenuation process of wild-type viruses. © 2010 Elsevier Ltd.


Nakayama T.,Kitasato Institute for Life science
Journal of Infection and Chemotherapy | Year: 2013

The concept of immunization was started in Japan in 1849 when Jenner's cowpox vaccine seed was introduced, and the current immunization law was stipulated in 1948. There have been two turning points for amendments to the immunization law: the compensation remedy for vaccine-associated adverse events in 1976, and the concept of private vaccination in 1994. In 1992, the regional Court of Tokyo, not the Supreme Court, decided the governmental responsibility on vaccine-associated adverse events, which caused the stagnation of vaccine development. In 2010, many universal vaccines became available as the recommended vaccines, but several vaccines, including mumps, zoster, hepatitis B, and rota vaccines, are still voluntary vaccines, not universal routine applications. In this report, immunization strategies and vaccine development are reviewed for each vaccine item and future vaccine concerns are discussed. © 2013 The Author(s).


The humoral and cellular immune responses of adaptive immunity are induced following immunization with effective vaccines. They induce functional cytokines and chemokines through the binding of vaccine components or adjuvants to innate immune receptors. Alum-adjuvanted vaccines induce local inflammatory nodules at injection sites, and the systemic and local production of the inflammatory cytokines, IL-1β, IL-6, and TNF-α, has been reported to occur three hours after vaccinations. Furthermore, G-CSF levels increase at injection sites. Neutrophils initially migrate and neutrophil extracellular traps (NETs) then develop, which stimulate damage-associated molecular patterns (DAMPs), inducing inflammatory cytokines production. Approximately 10–15% of recipients of simultaneous immunizations with multiple vaccines develop febrile reactions, and have higher G-CSF levels. Innate immune responses following vaccinations are discussed herein. © 2016 Elsevier Ltd


Nakayama T.,Kitasato Institute for Life science
Nihon rinsho. Japanese journal of clinical medicine | Year: 2011

Routine measles immunization was implemented in 1978 and rubella immunization in 1977. Measles outbreak was observed in 2001 and approximately 10 cases of congenital rubella syndrome in regional outbreaks in 2004. Thus, measles and rubella combined vaccine (MR) was recommended for children aged one year and just before the entry of primary school. Measles outbreak in young teenager and adults was noted in 2007/08. Additional MR catch-up campaign was started for teenagers of 13 and 18 years (MR III and IV) in 2008. After 2008, all cases with measles should be registered and the number of measles reduced to 457 cases in 2010 (3.58 cases per million), just on the edge of measles elimination. To realize the goal by 2012, we should promote vaccine coverage of MR III and IV.

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