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Purpose To assess whether stepwise insulin treatment in addition to current oral antidiabetic drug (OAD) therapy is useful for achieving the Japan Diabetes Society glycemic target (HbA1c

Interactions between advanced glycation endproducts (AGE) and the receptor for AGE (RAGE) have been implicated in the development of diabetic vascular complications. RAGE has two N-glycosylation sites in and near the AGE-binding domain, and G82S mutation in the second N-glycosylation motif was recently reported in human. In this study, we examined whether de-N-glycosylation or G82S of RAGE affect its ability to bind AGE and cellular response to AGE. Recombinant wild-type, de-N-glycosylation and G82S RAGE proteins were produced in COS-7 cells, purified and assayed for ligand-binding abilities. De-N-glycosylation at N81 and G82S mutation decreased Kd for glycolaldehyde-derived AGE to three orders of magnitude lower levels compared with wild-type. AGE-induced upregulation of VEGF mRNA was significantly augmented in endothelial cell-derived ECV304 cells expressing de-N-glycosylated and G82S RAGE when compared with wild-type expressor. Exposure to low glucose resulted in the appearance of RAGE proteins of deglycosylated size in wild-type RAGE-expressing cells and significantly enhanced glycolaldehyde-derived AGE-induced VEGF mRNA expression. De-N-glycosylation or G82S mutation of RAGE increases affinity for AGE ligands, and may sensitize cells or conditions with it to AGE.

The formation and accumulation of advanced glycation endproducts (AGE) have been implicated in the development of diabetic vascular complications. Their biological responses are known to be mediated by the receptor for AGE (RAGE). Recently, AGE have been proposed to be derived not only from the classical Maillard reaction but also from other pathways of sugar autoxidation and metabolism. Here, we report the identification of glyceraldehydes (Gcer)- and glycolaldehyde (Gcol)-derived AGE as RAGE ligands and their presence in vivo. The apparent dissociation constants assessed by surface-plasmon resonance (SPR) analysis with purified human RAGE proteins were 360 nM for Gcer-AGE and 1.35 microM for Gcol-AGE. The radiolabeled-ligand binding assay with RAGE-expressing COS-7 cells revealed similar association kinetics. Competitive SPR assay with antibodies specific to the respective AGE fractions demonstrated abundant existence of both Gcer- and Gcol-AGE in RAGE affinity-purified proteins from human sera. The serum contents of Gcer- and Gcol-AGE in a diabetic patient were about twice as high as those in a healthy control. Functionally, Gcer- and Gcol-AGE upregulated the endothelial cell levels of mRNA for vascular endothelial growth factor (VEGF) and the secretion of its protein product into the culture media and DNA synthesis in a dose-dependent manner. Further, these endothelial responses were augmented by RAGE overexpression. The results suggest that RAGE engagement of Gcer- and Gcol-AGE may elicit angiogenesis through the induction of autocrine VEGF, thereby contributing to the development and progression of diabetic angiopathies.

We recently identified a naturally occurring soluble form of RAGE (the receptor for advanced glycation endproducts, receptor for AGE) in cultured human vascular cells, and named it endogenous secretory RAGE (esRAGE). esRAGE is generated by alternative RNA splicing and is able to capture AGE, and exerts protection against AGE-induced endothelial cell injury. In the present study, the presence of esRAGE in human circulation was demonstrated for the first time, and a highly sensitive and specific sandwich ELISA system for esRAGE was developed to see whether esRAGE could be related to an individual resistance to the development of diabetic vascular complications. Sera from 47 type 1 diabetic subjects without clinical nephropathy (urinary albumin excretion

The aim of this study was to compare mortality and incidence of end-stage renal disease (ESRD) in patients with type 1 (insulin-dependent) diabetes who had attended a diabetes center with those who had not. The cohort consisted of a total of 1430 patients diagnosed with Type 1 diabetes at 18 years or younger, and between 1965 and 1979. This population-based cohort in Japan was subdivided into two groups: patients who had visited a large diabetes center in Tokyo ( n =162) and those who had not ( n =1212). Mortality and incidence of ESRD were compared between the two subgroups as of January 1, 1990. Crude mortality was 1.95 per 1000 person-years (95% CI: 0.49–5.06) for those who had visited the center and 6.05 (4.86–7.41) for those who had not. A multivariate Cox proportional hazard model showed that the patients who had visited the center were three times less likely to die (hazard ratio: 0.31, 95% CI: 0.10–0.98) than those who had not. Crude incidence of ESRD was 1.32 (0.22–4.09) and 5.86 (4.65–7.26) for those who had visited the center and for those who had not, respectively. After adjusting for covariates, the patients who had visited the center were five times less likely to develop ESRD (hazard ratio: 0.19, 0.05–0.78) than those who had not. Education and treatment of type 1 diabetes with an integrated management system under specialists and a multidisciplinary team appears to be associated with a better prognosis.

金沢大学大学院医学部医学系研究科, As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies conducted in this lab revealed advanced glycation endproducts (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes, and the receptor for AGE (RAGE) as the major genetic factor that responds to them. AGE fractions that caused the vascular derangement were proven to be RAGE ligands. When made diabetic, RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice. They showed marked amelioration of diabetic nephropathy. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)+ RNA, we came across a novel splice variant coding for a soluble RAGE protein, and named it endogenous secretory RAGE (esRAGE). esRAGE was able to capture AGE ligands and neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE–RAGE system should thus be regarded as a candidate molecular target for overcoming this life- and quality of life (QOL)-threatening disease.

The mid- I 990s saw some important developments in the Japanese government's approach to gender issues, as conservative politicians started to realize that greater gender equality could help to revive a moribund economy and a steadily falling birth rate. In this paper I trace those developments, focusing on the role of the Council for Gender Equality (Danjo Kyodo Sankakushingikai), created by government ordinance in 1994 and upgraded by an Act of the Diet in 1997.The 'Vision of Gender Equality', which the Council submitted to then-prime minister Hashimoto Ryataro in 1996, bore fruit in the Basic Law for a Gender-Equal Society, finally passed in 1999. But while the government has shown some genuine concern over gender issues, this has always had to struggle against competing discourses of traditional values and fiscal rectitude. So far, the new receptiveness to feminist arguments has yet to be matched by funding for reforms in important areas like nursing care, child-rearing and pensions that are needed if women are to participate fully in society

Targeted suicide gene therapy for Epstein-Barr virus (EBV)-associated neoplasms was attempted by using EBV-based plasmid vectors coupled with hemagglutinating virus of Japan (HVJ)-liposome in vitro. Expression of EBV nuclear antigen (EBNA)1 is a common feature of the neoplasms associated with EBV. When various leukemic cell lines were transduced with a vector carrying a marker gene and EBV replication origin of plasmid (oriP), the marker gene product was exclusively detected in cells expressing EBNA1. Transduction of herpes simplex virus (HSV)-1 thymidine kinase (Tk) gene resulted in a marked reduction in viable cell number by ganciclovir (GCV) specifically in EBNA1 positive cells. The results demonstrate that this virus-free system may be applicable to gene therapy of EBV-associated neoplasms.

Using a database of patients with type 1 (n = 1675) and type 2 (n = 2259) diabetes diagnosed before the age of 30 years at the Diabetes Center, Tokyo Women's Medical University (TWMU), in which such Japanese patients have been registered at the time of first visit since the 1960s, we performed a hospital-based study over the last 40 years to clarify time-course changes in clinical features of type 1 and type 2 diabetes diagnosed before the age of 30 years. Type 2 diabetes had a male dominancy, while there has been a female dominancy in patients with type 1 diabetes as in previous reports of Japanese childhood-onset type 1 diabetes. Such dominances had been continued over the last 40 years. The number of patients with type 2 diabetes and with a past history of obesity increased with time. The age at which type 2 diabetes was diagnosed was suggested to have been getting lower with time, whereas that of type 1 diabetes has been higher with time. There was no marked difference in family history of diabetes in the first-degree relatives of patients with type 2 diabetes, regardless of the presence or absence of a past history of obesity. More female patients with type 2 diabetes diagnosed before the age of 15 years had mothers with type 2 diabetes compared to corresponding male patients.

List of figures List of tables Preface Notes on Editors PART ONE: RE-CONCEPTUALIZING THE KNOWLEDGE ECONOMY, GENDER AND REGULATION Introduction: Theorizing the Gendering of the New Economy: Comparative Approaches S.Walby Gender and the Conceptualization of the Knowledge Economy in Comparison K.Shire PART TWO: COMPARATIVE REGULATION Comparative Livelihood Security Systems from a Gender Perspective, with a Focus on Japan M.Osawa Varieties of Gender Regimes and Regulating Gender Equality at Work in the Global Context I.Lenz Similar Outcomes, Different Paths: The Cross-National Transfer of Gendered Regulations of Employment G.S.Roberts PART THREE: GENDERING NEW EMPLOYMENT FORMS Self-Employment in Comparative Perspective: General Trends and the Case of New Media K.Gottschall & D.Kroos Living and Working in the New Economy: New Opportunities and Old Social Divisions in the Cases of the New Media and Carework D.Perrons Are Care Workers Knowledge Workers? M.Nishikawa & K.Tanaka Who Gets to be a Knowledge Worker? The Case of UK Call Centres S.Durbin Restructuring Gendered Flexibility in Organizations: A Comparative Analysis of Call Centres in Germany U.Holtgrewe Appendix I Bibliography

This chapter explores the development of livelihood security systems since the early 1980s in major industrialized countries with a particular focus on Japan. As Esping-Andersen mentions in his ‘Preface to the Japanese edition’ of The Three Worlds of Welfare Capitalism (1990), Japan is a difficult case to classify, to the extent that it has served as a touchstone for his typology. The Japanese welfare state, as of 1980, exhibited the lowest expenditure among OECD countries, and was of a ‘liberalistic’ nature in the sense that its ‘highly selective’ social policy offered insufficient family support, and that its low degree of ‘de-commodification’ compelled the individual to participate in the labour market. Meanwhile, the division of its social insurance schemes by occupation and social stratification (due to disparity created by the size of the enterprise, etc.) demonstrated its more ‘conservative’ nature.

The aim of this study was to compare mortality and incidence of end-stage renal disease (ESRD) in patients with type 1 (insulin-dependent) diabetes who had attended a diabetes center with those who had not. The cohort consisted of a total of 1430 patients diagnosed with Type 1 diabetes at 18 years or younger, and between 1965 and 1979. This population-based cohort in Japan was subdivided into two groups: patients who had visited a large diabetes center in Tokyo (n=162) and those who had not (n=1212). Mortality and incidence of ESRD were compared between the two subgroups as of January 1, 1990. Crude mortality was 1.95 per 1000 person-years (95% CI: 0.49-5.06) for those who had visited the center and 6.05 (4.86-7.41) for those who had not. A multivariate Cox proportional hazard model showed that the patients who had visited the center were three times less likely to die (hazard ratio: 0.31, 95% CI: 0.10-0.98) than those who had not. Crude incidence of ESRD was 1.32 (0.22-4.09) and 5.86 (4.65-7.26) for those who had visited the center and for those who had not, respectively. After adjusting for covariates, the patients who had visited the center were five times less likely to develop ESRD (hazard ratio: 0.19, 0.05-0.78) than those who had not. Education and treatment of type 1 diabetes with an integrated management system under specialists and a multidisciplinary team appears to be associated with a better prognosis.

Objective To examine the impact of add-on sitagliptin therapy on glucose, endogenous insulin and glucagon concentrations in Japanese patients with type 2 diabetes under insulin therapy.

Advanced glycation end products (AGEs) and receptor for AGE (RAGE)-mediated mechanism has been implicated in the pathogenesis of the vascular derangements.1–3 Yonekura et al recently identified a novel splice variant of RAGE that would serve as a decoy receptor, and named it endogenous secretory RAGE (esRAGE).4 esRAGE is secreted from expresser cells exemplified by vascular endothelial cells and is able to captures RAGE ligands extracellularly, thereby protecting cells from AGE-induced injury.4 Recently, we reported that type 1 diabetic patients with high serum esRAGE levels were resistant to developing early retinal complications than those with low esRAGE levels.5 Moreover, plasma esRAGE is found to be a novel biomarker and a potential protective factor in metabolic syndrome and atherosclerosis.6 It is thus expected that esRAGE plays a protective role in the development of diabetic vascular complications. The balance or imbalance between RAGE ligand and esRAGE levels may be a …

We show here a novel non-viral strategy to transduce human cells by using an EBV-based vector system. The EBV-based vectors, the plasmid vectors carrying EBV oriP (origin for plasmid replication) and EBNA (EBV nuclear antigen) 1 gene from EBV genome, were combined with 2 gene delivery systems, i.e., cationic liposome and HVJ-liposome. By both methods, EBV-based vectors could be more efficiently transfected into HeLa cells than non-EBV, conventional plasmid vectors. When human primary fibroblasts were transfected, EBV-based vectors coupled with cationic liposome but HVJ-liposome resulted in successful gene transduction, while human bone marrow cells were transduced with both HVJ-liposome- and cationic liposome-EBV vectors. These results suggest the potential applications of the EBV-based vector system for gene therapy.