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We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P, Prophylactic use of entecavir reduced HBV‐related hepatitis and mortality in HBsAg‐positive DLBCL treated with R‐chemotherapy. The 4‐year overall survival rate in HBsAg‐positive DLBCL patients receiving prophylactic entecavir was similar to that in HBsAg‐negative DLBCL.

The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in high‐risk DLBCL patients having an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. As induction chemotherapy, 6 cycles of R‐CHOP‐14 (arm A) or 3 cycles of R‐CHOP‐14 followed by 3 cycles of CHASER (arm B) were planned, and patients who responded proceeded to HDCT with LEED and ASCT. The primary endpoint was 2‐y progression‐free survival (PFS), and the main secondary endpoints included overall survival, overall response rate, and adverse events (AEs). In total, 71 patients were enrolled. With a median follow‐up of 40.3 mo, 2‐y PFS in arms A and B were 68.6% (95% confidence interval [CI], 50.5%‐81.2%) and 66.7% (95% CI: 48.8%‐79.5%), respectively. Overall survival at 2 y in arms A and B was 74.3% (95% CI: 56.4%‐85.7%) and 83.3% (95% CI: 66.6%‐92.1%). Overall response rates were 82.9% in arm A and 69.4% in arm B. During induction chemotherapy, 45.7% and 75.0% of patients in arms A and B, respectively, had grade ≥ 3 non‐hematologic toxicities. One patient in arm A and 6 in arm B discontinued induction chemotherapy due to AEs. In conclusion, R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations (UMIN‐CTR, UMIN000003823)., The efficiency of upfront consolidation with high‐dose chemotherapy/autologous stem‐cell transplantation (HDCT/ASCT) for newly diagnosed high‐risk diffuse large B‐cell lymphoma (DLBCL) may be influenced by induction chemotherapy. To select better induction chemotherapy regimens for HDCT/ASCT, a randomized phase II study was conducted in patients with high‐risk DLBCL who had an age‐adjusted International Prognostic Index (aaIPI) score of 2 or 3. R‐CHOP‐14 showed higher 2‐y PFS and less toxicity compared with R‐CHOP‐14/CHASER in patients with high‐risk DLBCL, suggesting the former to be a more promising induction regimen for further investigations.

ファイル公開：2021-04-01

We managed perioperative hemostasis for a 72-year-old man with hemophilia A and low inhibitor titers (3 BU/mL), who underwent osteosynthesis for supracondylar fracture of the left humerus. He was treated perioperatively using the combination of high doses of factor VIII (FVIII) with recombinant human Factor VIII Fc fusion protein (rFVIIIFc), followed by emicizumab. On the day of surgery (day 0), he was administered bolus infusion of 150 IU/kg rFVIIIFc, followed by continuous infusion at a dose of 4 IU/kg/h. Emicizumab, 3 mg/kg, was injected subcutaneously once a week, on days 5, 12, 19, and 26. Inhibitors were detected on day 6 at a titer of 4 BU/mL and FVIII:C decreased to below assay sensitivity limits on day 10. The rate of increase in inhibitor titers was high, with inhibitors increasing to 343.4 BU/mL on day 14. The transition of thrombin production by thrombin generation assay (TGA) showed temporary decrease in thrombin production on day 7, although it was restored by day 10, i.e., five days after commencement of emicizumab therapy. Rotational thromboelastometry displayed consistent results with TGA, showing that clotting time was prolonged and the alpha angle decreased to less than measurable levels on day 6, although they were improved by day 10. There were no bleeding-related events or other adverse events throughout the perioperative period. In conclusion, emicizumab was effective for the management of perioperative hemostasis after development of an anamnestic response in a patient with hemophilia A with inhibitors. Combination therapy with high doses of FVIII followed by emicizumab could be a workable alternative for patients with hemophilia A with inhibitors.

This study examines what “memory elements” are connected, and how and when preschoolers use those elements to understand nature. Nature and how preschoolers understand it are relevant to elementary school subjects, such as Living Environment Science and Natural Science. Relying on White’s theory of memory elements （1988）, this paper analyzes two case studies in which preschoolers brought various concepts of nature into their cognition and extracted relevant memory elements. The analysis clarifies how preschoolers cognize nature in and through their experiences. Findings from the study suggest that preschoolers’ original cognition settles into proto-experience when the obtained memory elements, such as images, motor skills, and episodes are enhanced by preschoolers’ relations with others, narratives of the situation, and their own emotional preference. The results also suggest the possibility that preschoolers’ improved cognition of nature helps them become capable of dealing with elementary school subjects as the structuring of their memory elements, and parts of their memory elements are verbalized and words are muttered, perhaps in the form of self-talk, and the memory elements are transformed into strings, propositions, and intellectual skills.

Background Congenital antithrombin (AT) deficiency, which arises from various SERPINC1 defects, is an autosomal-dominant thrombophilic disorder associated with a high risk of recurrent venous thromboembolism. Patients/methods We investigated SERPINC1 defects in Japanese patients with congenital AT deficiency who developed venous thromboembolism or had a family history of deep vein thrombosis. We analyzed the full DNA sequences of SERPINC1 exons and exon-intron junctions by PCR-mediated direct sequencing. If no mutation was found, multiplex ligation-dependent probe amplification (MLPA) was conducted for the relative quantification of the copy number of all exons in SERPINC1. If splice-site mutations were detected, mRNA splicing abnormalities were further investigated using an in vitro cell-based exontrap assay. Results We identified 19 different SERPINC1 abnormalities, including 8 novel mutations, in 21 Japanese patients with AT deficiency. These abnormalities were distributed as follows: 9 missense mutations (42.9%), 3 nonsense mutations (14.3%), 1 splice-site mutation (4.8%), 2 small insertions (9.5%), 2 deletion mutations (9.5%) and 4 large deletions (19.0%). Cases with large deletions of SERPINC1 included Alu-mediated gene rearrangements and non-Alu-mediated complex gene rearrangements; the latter could conceivably be explained using the fork stalling and template switching (FoSTeS) model. Conclusions We identified a variety of SERPINC1 defects in Japanese patients with AT deficiency. The SERPINC1 mutations detected in patients with type I AT deficiency included single nucleotide missense or nonsense mutations, small intragenic insertions or deletions, and large genomic structural deletions. Large deletions of SERPINC1 were caused by various recurrent or non-recurrent complex genomic rearrangement mutations.

Background Circulating interferon-γ (IFN-γ) concentration may be sustained at a high level regardless of the initiation of antiretroviral therapy (ART) in some patients with HIV-1 infection. In the present study, we examined the clinical characteristics of HIV-1-infected patients with high levels of plasma IFN-γ. Methods The study subjects were patients infected with HIV-1 who were either naïve to ART with CD4+ cell count > 200 cells/μL (n = 12), or had achieved viral suppression after ART for over a year (n = 188). The levels of plasma IFN-γ and interleukin-6 (IL-6) were measured by the enzyme-linked immunosorbent assay. Patients were divided into high IFN-γ and low IFN-γ groups based on a cutoff level of 5 pg/mL. Results The high IFN-γ group included 41 patients (21%). Compared to the patients on ART with low IFN-γ levels, those on ART in the high IFN-γ group were more likely to be younger than 50 years of age (P = 0.0051) and less likely to have dyslipidemia (P = 0.0476) or to be on a protease inhibitor (P = 0.0449). There was no significant difference between groups in the median increase of CD4+ cell counts from the initiation of ART for up to 3 years. However, after 4 years, the increase in CD4+ cell counts was significantly lower in the high IFN-γ group compared with that in the low IFN-γ group. There were no such significant differences between patients with low and high (> 2 pg/mL) levels of plasma IL-6. Conclusion We concluded that HIV-1-infected patients with high levels of circulating IFN-γ did not have a higher rate of comorbidities related to immune activation. However, they exhibited lower CD4+ cell count recovery after 4 years of being on ART. This deficit could be a consequence of persistent immune activation. Electronic supplementary material The online version of this article (10.1186/s12879-018-3643-2) contains supplementary material, which is available to authorized users.

Background Hemophilia A (HA) is an X‐linked recessive bleeding disorder caused by pathogenic variants of the coagulation factor VIII gene (F8). Half of the patients with severe HA have a recurrent inversion in the X chromosome, that is, F8 intron 22 or intron 1 inversion. Here, we characterized an abnormal F8 due to atypical complex X chromosome rearrangements in a Japanese patient with severe HA. Methods Recurrent F8 inversions were tested with inverse shifting‐PCR. The genomic structure was investigated using PCR‐based direct sequencing or quantitative PCR. Results The proband's X chromosome had a 119.5 kb insertion, a reverse duplex of an extragenic sequence on the F8 telomere region into the F8 intron 1 with two breakpoints. The telomeric breakpoint was a joining from the F8 intron 1 to the inverted FUNDC2 via a two‐base microhomology, and the centromeric breakpoint was a recombination between F8 intron 1 homologous sequences. The rearrangement mechanism was suggested as a multi‐step rearrangement with template switching such as fork stalling and template switching (FoSTeS)/microhomology‐mediated break‐induced replication (MMBIR) and/or homologous sequence‐associated recombination during a sister chromatid formation. Conclusion We identified the aberrant X chromosome with a split F8 due to a multi‐step rearrangement in a patient with severe HA., Hemophilia A (HA) is an X‐linked recessive bleeding disorder caused by mutations in the coagulation factor VIII gene (F8). We identified the aberrant chromosome X with a split F8 due to a multi‐step rearrangement in a severe HA patient. The rearrangement mechanism was suggested as a multi‐step rearrangement with template switching such as FoSTeS/MMBIR and/or homologous sequence associating recombination during a sister chromatid formation.

Introduction Antithrombin resistance (ATR) prothrombinemia is an inherited thrombophilic disorder caused by missense mutations in prothrombin gene (F2) at Arg596 of the sodium-binding region. Previously, prothrombin mutants Yukuhashi (Arg596Leu), Belgrade (Arg596Gln), and Padua 2 (Arg596Trp) were reported as ATR-prothrombins possessing a risk of familial venous thrombosis. To identify additional F2 mutations causing the ATR-phenotype, we investigated the coagulant properties of recombinant prothrombins mutated at amino acid residues within the sodium-binding region by single nucleotide substitutions (Thr540, Arg541, Glu592, and Lys599). Materials and methods We constructed expression vectors of prothrombin mutants, established stably transfected HEK293 cells, and isolated the recombinant prothrombin proteins. We evaluated procoagulant activity and ATR-phenotypes of those mutants in reconstituted plasma by mixing with prothrombin deficient plasma. Results The secreted quantity of all prothrombin mutants was the same as that of the wild-type prothrombin. Procoagulant activity of each mutant varied from 1.7% to 79.5% in a one-stage clotting assay and from 2.0% to 104.5% in a two-stage chromogenic assay. Most prothrombin mutants tested presented with a severe ATR-phenotype. To estimate the thrombosis risk of these mutations, we determined the residual clotting activity (RCA) after 30 min inactivation with antithrombin. RCA scores, normalized to the wild-type, revealed that prothrombin mutants Lys599Arg (5.35) and Glu592Gln (4.71) had high scores, which were comparable with prothrombins Yukuhashi (4.36) and Belgrade (5.19). Conclusions Mutation of prothrombin at the sodium-binding site caused ATR-phenotypes. Of those tested, Lys599Arg and Glu592Gln may possess a thrombosis risk as large as the known pathogenic prothrombins Yukuhashi and Belgrade.

Background & Aims HBV reactivation is a risk in patients receiving anti-CD20 antibodies for the treatment of lymphoma. The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitivity HBsAg assay to guide preemptive antiviral treatment in patients with lymphoma and resolved HBV infections using prospectively stored samples from an HBV DNA monitoring study. Methods HBV reactivation (defined as HBV DNA levels of ≥11 IU/ml) was confirmed in 22 of 252 patients. A conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/ml) and an ultra-high sensitivity HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/ml) were performed at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. Results Baseline HBsAg was detected using ICT-CLEIA in 4 patients; in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the 5 patients undetectable by ICT-CLEIA, HBV reactivation resolved spontaneously in 2 patients. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/ml, HBV DNA detected but below the level of quantification, and HBsAg detected by ICT-CLEIA at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p Conclusions A novel ICT-CLEIA HBsAg assay is an alternative method to diagnose HBV reactivation. Clinical trial number UMIN000001299. Lay summary Hepatitis B virus can be reactivated in lymphoma patients receiving anti-CD20 antibodies such as rituximab. Currently, reactivation requires the monitoring of HBV DNA, but monitoring of the surface antigen (HBsAg) could provide a relatively inexpensive, quick and easy alternative. We assessed the performance of an ultra-high sensitivity HBsAg assay and showed that it could be effective for the diagnosis and monitoring of HBV reactivation.

Introduction Hemophilia B is an X-linked recessive bleeding disorder caused by coagulation factor IX (FIX) gene (F9) mutations. Several F9 synonymous mutations have been known to cause hemophilia B; however, the deleterious mechanisms underlying the development of hemophilia B have not been completely understood. To elucidate the molecular pathogenesis causing hemophilia B, we investigated the synonymous F9 mutation: c.87A>G, p.(Thr29=). Materials and methods The influence of F9 c.87A>G on mRNA splicing was analyzed by exon-trap assay and in silico prediction. We prepared FIX expression vectors using mutant F9 cDNA and transfected HepG2 cells to investigate intracellular transport and extracellular secretion of FIX. Intracellular kinetics of the expressed FIX was examined by treatment with the proteasome inhibitor MG132. Results Exon-trap analysis revealed that F9 c.87A>G resulted in almost (99.1%) aberrant splicing (r.83_88del). In silico analysis predicted that F9 c.87A>G influenced the splicing pattern by generating an available aberrant 5′ splice site. The aberrant F9 mRNA (r.83_88del) was translated to a mutant FIX p.Cys28_Val30delinsPhe with an in-frame mutation at the signal peptide cleavage site. Simultaneously, a small amount (0.9%) of mutant F9 r.87A>G translating into WT FIX p.Thr29 = was also observed. The mutant FIX was abnormally retained in the endoplasmic reticulum (ER) and was not extracellularly secreted. It appeared to be intracellularly degraded via proteasome-dependent degradation machinery. Conclusion F9 c.87A>G was found to cause abnormal mRNA splicing, r.83_88del, and produce the mutant FIX p.Cys28_Val30delinsPhe. The mutant FIX is an abnormal protein with extracellular secretory defects and is intracellularly eliminated via proteasome-dependent ER-associated degradation.

Kathoey (male-to-female transgender) sex workers (KSW) in Thailand are at high risk for sexually transmitted infections; however, few qualitative studies have been conducted to understand the sociocultural context of engaging in HIV risk behaviors. A total of 24 participants were purposively sampled in Bangkok based on KSW work venues and substance use. Results revealed the importance of participants' understanding of the self in relation to establishing economic independence through sex work, which could then be used to re-establish support from family, who often have not accepted a son's gender transition. Participants linked being kathoey to a belief in fate but did not view engagement in sex work in the same way. Different sex work venues exposed KSW to different risky situations. HIV prevention programs for kathoey must address the importance of economic security and its relation to social support and gender transition within a cultural- and work-environment-specific framework.

BACKGROUND There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of

Introduction Antithrombin resistance (ATR) is a novel thrombotic risk in abnormal prothrombins. A manual ATR assay using Oxyuranus scutellatus (Ox) venom as a prothrombin activator was established for detecting antithrombin-resistant prothrombin. However, this assay was limited because of Ox snake venom availability and its throughput capacity. Here, we have improved the ATR assay using bovine factors Xa and Va (FXa/Va) as prothrombin activators and have optimised assay conditions for an automated instrument (ACL TOP 500). Methods Diluted plasma was incubated with a prothrombin activator mix (phospholipids, CaCl2 , and bovine FXa/Va), followed by inactivation with antithrombin for 10, 20 and 30 minutes. We added a chromogenic substrate S-2238, and assessed changes in absorbance/min at 405 nm. We also adapted assay conditions for ACL TOP 500. Results Optimum conditions for FXa/Va treatment were 6.25% phospholipids, 5 mM CaCL2 , 0.01 μg/mL FXa and 0.1 μg/mL FVa. ATR assay kinetics with the FXa/Va activator was comparable with that with the Ox activator in heterozygous reconstituted plasma with the recombinant wild-type or antithrombin-resistant prothrombin. Using ACL TOP 500, optimum conditions for the FXa/Va treatment were 10.0% phospholipids, 5 mM CaCl2 , 0.02 μg/mL FXa and 0.2 μg/mL FVa. The automated ATR assay with the FXa/Va activator demonstrated good detectability for antithrombin-resistant prothrombin in plasma from a heterozygous carrier with prothrombin Yukuhashi or Belgrade. Conclusion We optimised the ATR assay with the FXa/Va activator and adapted the assay for ACL TOP 500; the assay showed the ability to clearly detect antithrombin-resistant prothrombin in manual and automated procedures.

A lithium test assembly used for lithium-free surface flow experiments at 300 °C for 1200 h at Osaka University was analyzed metallographically to verify the design of the lithium target of the International Fusion Materials Irradiation Facility (IFMIF). Certain irregularities such as traces of high-speed lithium flow at a maximum velocity of 15 m/s were observed at the tip of the nozzle. Mottled unevenness with numerous microcracks a few microns deep was detected at the inlet of the nozzle, the velocity ratio of which was 0.1–0.4 as compared with the nozzle tip. A thin, altered layer developed on the surface of these regions because of carbide formation. It is believed that the microcracks were nucleated by thermal transients at the start or stop of operations of the lithium loop. These slight irregularities could be the result of exfoliation of the altered layer because of the high-speed lithium flow caused by the increased hardness of the altered layer as compared with that of the base metal. The metallurgical analysis proved for the first time that carbon control in lithium is also important for corrosion and erosion protection of the IFMIF components.

Severity of corrosion damage in automobiles depends on use environments and parts. Corrosion life prediction is a key technology for the optimum selection of materials. The Fe–Ag type Atmospheric Corrosion Monitor (ACM) sensor has been the object of many studies from this viewpoint. In the present study, ACMs were installed on various parts of a monitoring test vehicle and the corrosivity of the environments of those parts was evaluated. To simulate different use environments, pure water and salt water were sprayed on the right and left halves of the vehicle body. The corrosion behavior in each part was characterized by the output of the ACM sensor against atmospheric parameters and driving history. Corrosion of test coupons (cold-rolled steel, Zn-coated steel) was also measured at the same positions. The corrosion rates of these exposure test specimens showed a good correlation with the average daily charge calculated from the sensor output. These results demonstrated the possibility of corrosion life prediction and materials selection based on ACM monitoring results. It was concluded that ACM monitoring is applicable to corrosivity evaluation of automotive environments, including both specific parts of automobiles and automobile use environments.

Light and electron microscopic studies that we have published in the past have reported many aspects of the reproductive process in Armadillidium vulgare with particular emphasis on the reconstruction of female genitalia. Together this body of work provides an almost complete, albeit fragmented picture of these processes and include many data on sperm storage and sperm translocation. Females of A. vulgare have a pair of cuticular genitalia in the lumen of the oviduct. For insemination, these genitalia can receive the copulatory organs of males formed by the elongated tips of the first two pleon endopods. During transitions between reproductive (parturial) and non-reproductive (normal, non-parturial) moult cycles the genitalia undergo intriguing structural changes resulting in two types of genitalia. Throughout their reproductive lifetime, either type is reconstructed after each moult depending on the reproductive phase of the female. In this review, we integrate the events that occur during a reproductive...

Background An effective and coordinated process of transitioning adolescents with bleeding disorders from pediatric to adult medical care is essential for maintaining continuity of care and establishing a lifelong medical support system. Barriers to transition among people with a bleeding disorder (PWBD) at the University of California San Francisco (UCSF) are currently unknown. Objective The purpose of this study is to collect and evaluate data on potential demographic, clinical and socioeconomic determinants of the length of time to transition among PWBD at UCSF. Methods A retrospective chart review of 60 patients with bleeding disorders born between 1982 and 1996 was conducted to collect baseline demographic, clinical and socioeconomic data. The data was analyzed using a two-tailed t-test to determine factors associated with length of time to transition. Results Of the 60 total patients included in this analysis, 15 were lost to follow-up. The average length of time to transition for the 45 patients who completed transition into adult care was 1.31 years, and the average age at transition was 22 years old. We analyzed various determinants of length of time to transition that fell into five categories: demographics, socioeconomic status, disease severity, level of independence and adherence to recommended care. Females trended toward a longer average time to transition of 1.93 years compared to 1.13 years for males (p=0.08). One variable had a statistically significant correlation to length of time to transition. Patients prescribed a factor product had a significantly shorter time to transition of 0.85 years compared to 2.13 years for patients not prescribed a factor product (p=0.0009). Of the 45 patients who completed transition into adult care, 62% were prescribed a factor product. Conclusions Our study demonstrated that prescription of a factor product, which is likely an indicator of a greater disease severity, is correlated with time to transition. Our univariate analysis did not indicate that demographics, socioeconomic status, level of independence or adherence to recommended care related to length of time to transition. The results of this study are preliminary and further analysis is required to better understand the barriers to transition that exist among PWBD at UCSF. Disclosures Lesh: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: International Nursing Advisory Board 2017. Tobase:Partners: Consultancy, Honoraria.

Hepatitis B virus (HBV) surface antigen (HBsAg)-positive patients treated with anti-B-cell lymphoma therapy are at high risk of HBV reactivation; indeed, the incidence is as high as 60-80% without antiviral prophylaxis. Hepatitis caused by HBV reactivation usually leads to discontinuation of chemotherapy, which in itself may be fatal. Therefore, several guidelines recommend antiviral prophylaxis for HBsAg-positive patients treated with chemotherapy. However, there is limited evidence regarding the clinical impact of antiviral prophylaxis on HBV reactivation and subsequent hepatitis and long-term outcome, particularly in patients treated with rituximab (R)-containing regimens. To answer these questions, we conducted a nationwide multicenter retrospective analysis for HBsAg-positive patients with diffuse large B-cell lymphoma (DLBCL) treated with R-chemotherapy. Data were collected from HBsAg-positive patients with DLBCL who received R-CHOP or R-THP-COP regimens as an initial chemotherapy (regardless of steroid use) at 29 participating institutions between January 2004 and December 2014. Key exclusion criteria were as follows: seropositive for HCV or HIV; alanine transaminase (ALT) levels ≥ 100 U/L at the time of diagnosis; and a history of decompensated cirrhosis or hepatocellular carcinoma. Medical data were also obtained for HBsAg-negative DLBCL patients (controls), regardless of anti-HBc or anti-HBs seropositivity; these patients were diagnosed within 2 month (before and after 1 month) of the diagnosis date of each HBsAg-positive patient. Hepatitis was defined as an absolute serum ALT level of ≥ 100 U/L. HBV reactivation-related hepatitis was defined as hepatitis accompanied by an absolute serum HBV DNA level of ≥ 3.3 Log IU/mL or an absolute increase of ≥ 2 Log compared with the baseline value. Statistical analysis was performed at the Japanese Data Center for Hematopoietic Cell Transplantation using Stata software Version 13.1 and EZR 1.35. The study was registered at UMIN (ID: 000025574). A total of 394 patients were eligible: 116 (29.4%) were HBsAg-positive and 278 (70.6%) were HBsAg-negative. The baseline characteristics of the two cohorts were similar; exceptions was HBV status (Table). R-CHOP was the most common regimen (n=337, 85.5%), followed by R-THP-COP (n=57, 14.5%). For HBsAg-positive patients with detectable and quantifiable HBV DNA (n=65, 56.0%), the median baseline HBV DNA level was 2.9 Log IU/mL (interquartile range, 2.0-3.7). HBsAg-positive patients were divided into three groups based on prophylactic nucleoside analogue (NA) therapy: no prophylactic therapy (non-NA, n=9), prophylactic therapy with lamivudine (LAM, n=20), and prophylactic therapy with entecavir (ETV, n=87). Of the HBsAg-negative patients, 64 (23.0%) were seropositive for anti-HBc or anti-HBs. The median follow-up time for HBsAg-positive and HBsAg-negative patients was 4.3 years and 4.5 years, respectively. The 4-year cumulative incidence of hepatitis in HBsAg-positive and HBsAg-negative patients was 21.1% (95% confidence interval (CI): 14.1-28.9%) and 14.6% (95% CI: 10.7-19.2%), respectively (p=0.081). Importantly, the 4-year cumulative incidence of HBV reactivation-related hepatitis was higher in HBsAg-positive patients than in HBsAg-negative patients (8.0% (95% CI: 3.9-14.0%) vs. 0.4% (95% CI: 0.0-2.0%, respectively; p Prophylactic use of entecavir reduced the incidence of HBV reactivation-related hepatitis and reduced mortality associated with HBV reactivation-related hepatitis in HBsAg-positive patients with DLBCL treated with R-chemotherapy. Disclosures Maruyama: Abbvie: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Amgen Astellas BioPharma: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Solasia Pharma: Research Funding; AstraZeneca: Research Funding; Asahi Kasei Pharma: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Zenyaku Kogyo: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka: Research Funding; Dai-ichi-Sankyo: Honoraria. Yamamoto:Bristol-Myers Squibb: Honoraria. Igarashi:Eisai Co Ltd.: Research Funding; Celltrion Inc.: Research Funding; Zenyaku-Kogyo Co.Ltd.: Research Funding; Sanofi K.K.: Research Funding. Izutsu:Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Amgen: Research Funding; Gilead Sciences: Honoraria; Solasia: Research Funding; Sanofi: Research Funding; Otsuka: Honoraria; Mundhi: Honoraria; Kyowa Hakko Kirin: Honoraria; Abbvie: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Symbio: Research Funding; Celltrion: Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; MSD: Honoraria; Celgene: Consultancy, Research Funding; Bristol- Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Uchida:Nippon Shinyaku: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Meiji Seika Pharma: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Teijin: Honoraria; Novartis: Honoraria; Janssen Pharma: Honoraria; Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria. Tsukamoto:Chugai: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Kyowa-Kirin: Research Funding. Nosaka:Celgene Co. LTD.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Eisai Co. Ltd.,: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Bristol-Myers Squibb: Honoraria. Ueda:Rikaken Co. Ltd.: Research Funding; Medical and Biological laboratories Co. Ltd.: Research Funding; Chugai Pharmaceutical Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Honoraria, Research Funding; Terumo Co.: Consultancy; Ono Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Mundipharma K.K.: Consultancy. Mizokami:Sysmex Corporation: Honoraria; Gilead Sciences: Honoraria. Kusumoto:Bristol-Myers Squibb: Honoraria, Research Funding; Chugai Pharmaceutical Co. Ltd: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding.

The development of herpes zoster is associated with reduced varicella zoster virus (VZV)-specific cell-mediated immune (CMI) reactions. In this study, VZV-specific CMI reactions in 42 anti-VZV-IgG antibody-positive adults infected with HIV-1 were evaluated by measuring the IFN-γ production levels in whole blood in response to stimulation with ultraviolet light-inactivated live attenuated VZV vaccine. The median VZV-specific IFN-γ production level in all patients was 63 pg/ml. Antiretroviral therapy (ART)-naive patients with an AIDS-defining illness (HIV classification category C) had significantly lower IFN-γ production than ART-naive patients in categories A and B and patients receiving ART (P=0.0194 and P=0.0046, respectively). IFN-γ production increased significantly in patients within 1 month of the onset of recurrent VZV disease and at more than 1 year from onset, compared with patients who had never had recurrent VZV disease (P=0.0396 and P=0.0484, respectively). In multivariate analyses, category C and history of recurrent VZV disease were significant factors affecting IFN-γ production. Levels of IFN-γ were measured before and after ART in seven ART-naive patients with no history of recurrent VZV disease, and no significant changes were observed. The results indicate that VZV-specific CMI reactions were reduced in patients with an AIDS-defining illness and enhanced in patients with a history of recurrent VZV disease, but not enhanced by ART alone. Vaccination may be necessary to inhibit the development of herpes zoster in patients receiving ART; this IFN-γ releasing assay is one useful method for evaluating VZV-specific CMI reactions in clinical settings.

The reproductive cycle of female Tylos granuliferus was investigated in laboratory conditions. We focused our experiments on female copulative timing for effective insemination and on female sexual receptivity for reproduction. We used females who were isolated from males along with delayed copulation. The female reproductive cycle of T. granuliferus is related to the parturial moult cycle. Females copulate soon after shedding the posterior half of their body cuticle through anterior shedding with a shedding interval of 2 days. Copulation ends just before oviposition. The optimum timing for copulation is within a few days after completion of the parturial moult. Oviposition immediately follows insemination. Without copulation, females do not oviposit their eggs. Pre-copulatory mate guarding by males and sperm storage by females for future broods do not appear to occur in this species. Isolated females have a sexual receptive period of 12 days during the early stages of the reproductive cycle and cannot pr...

Dall's porpoise (Phocoenoides dalli) is a small toothed cetacean, widely inhabiting the North Pacific Ocean and adjacent seas, between about 30 and 62°N; however, only limited studies of its ecology have been made in nearshore areas. A cetacean sighting survey lasting 60 days was conducted during the 2012 summer cruise of the T/S Oshoro Maru (Hokkaido University, Japan) in the North Pacific Ocean and Bering Sea. Based on this data, the distribution of Dall's porpoises and the factors controlling it in the pelagic habitat were investigated. A total of 808 individual Dall's porpoises in 166 groups were sighted during a total of 469.6 hr and 4946.6 nm observations. The cruise consisted of three legs and the average porpoise group size was significantly larger in Leg 1. The sightings were concentrated at water depths of less than 1000 m and near eastern Aleutian passes. Sighting clusters were found on the 200 m isobath of the southeastern Bering Sea continental slope. There was a peak in sightings where the sea surface temperature (SST) was relatively cold, between 5 and 7°C. Although similar track routes were taken in Leg 1 and Leg 3, the number of sightings per unit effort was larger in Leg 1. This difference may have arisen from the significant rise in SST as the season progressed. Relatively large group size found in this study might relate with prey abundance along the Aleutian Islands.

High human herpesvirus 8 (HHV-8) seroprevalence has been reported in men who have sex with men (MSM) and are infected with HIV-1. However, it is unclear when they become infected with HHV-8. Thus, we conducted cross-sectional and longitudinal investigations of HHV-8 seroprevalence in HIV-1-infected individuals in Osaka, Japan.Plasma was collected from 121 individuals infected with HIV-1 and the anti-HHV-8 antibody titer was measured using an enzyme-linked immunosorbent assay with whole virus lysate. Subjects were classified into those with and without a past medical history of HHV-8-associated disease; the latter group was then classified into 3 subgroups based on the assumed route of HIV-1 infection: blood products, homosexual contact, and other routes. HHV-8 seroprevalence was compared among the groups and measured again approximately 3 years after the baseline measurement. The relationship between HHV-8 seropositivity and possible associated factors was also investigated.All 15 subjects with HHV-8-associated disease were seropositive, and all 11 subjects in the blood product group were seronegative. In the MSM group, 25 (30%) of 79 subjects were HHV-8 seropositive and, in the non-MSM group, 1 (6%) of 16 subjects was (p 0.0001). In the longitudinal investigation, seroconversion was observed in 10 (19%) of 52 subjects in the MSM group who were seronegative at baseline. A correlation was observed between seroconversion and symptomatic syphilis (p = 0.0432).HHV-8 seropositivity and seroconversion rates were high in HIV-1-infected MSM, suggesting that, currently, HHV-8 is an epidemic pathogen in this population.

The structures of two mutants (H192A and Y246F) of a mannuronate-specific alginate lyase, A1-III, from Sphingomonas species A1 complexed with a tetrasaccharide substrate [4-deoxy-L-erythro-hex-4-ene-pyranosyluronate-(mannuronate)(2)-mannuronic acid] were determined by X-ray crystallography at around 2.2 A resolution together with the apo form of the H192A mutant. The final models of the complex forms, which comprised two monomers (of 353 amino-acid residues each), 268-287 water molecules and two tetrasaccharide substrates, had R factors of around 0.17. A large conformational change occurred in the position of the lid loop (residues 64-85) in holo H192A and Y246F compared with that in apo H192A. The lid loop migrated about 14 A from an open form to a closed form to interact with the bound tetrasaccharide and a catalytic residue. The tetrasaccharide was bound in the active cleft at subsites -3 to +1 as a substrate form in which the glycosidic linkage to be cleaved existed between subsites -1 and +1. In particular, the O(η) atom of Tyr68 in the closed lid loop forms a hydrogen bond to the side chain of a presumed catalytic residue, O(η) of Tyr246, which acts both as an acid and a base catalyst in a syn mechanism.

This paper aims to determine via responses to three questionnaire surveys how sexuality education programs are conducted at junior high schools in Japan. Study 1 examined the practice of sexuality education in schools, Study 2 investigated junior high school students' (age 12–13 and 14–15 years) knowledge of sexuality, and Study 3 examined parents'/guardians' views on sexuality education. For Study 1, 703 principals of 5158 junior high schools returned an original questionnaire (13.6% recovery rate), and for Studies 2 and 3, 9492 students and 5374 parents returned questionnaires (86.2% and 60.3% recovery rate, respectively). In Study 1, an average of 9.19 hours of instruction was allocated to sexuality education over three grades. In Study 2, the average correct response rate was as low as 34.5% for boys and 39.4% for girls, with many answering ‘I don't know.’ Approximately one-half of the boys indicated there was nothing in particular they wanted to know about sex and no-one they wanted to consult. In St...

We investigated the susceptibility of Streptococcus pneumoniae isolated from 8 hospitals in Chiba prefecture during 2012-2013. We further checked the serotype of S. pneumoniae derived from invasive pneumococcal disease (IPD). We tested for antimicrobial susceptibility in 256 clinical isolates (137 isolates from children, 119 isolates from adults) for 25 drugs. In MIC50 and MIC90, there were very little differences between children and adults, but there were 3 isolates from adults which were resistant to levofloxacin. The most major serotypes were 15A and 3 in IPD. Additionally there was no isolation of the type contained in the 7-valent pneumococcal conjugate vaccine in children, so it seems that the vaccination is very effective for children. Furthermore, in contrast with our preceding report, a decreasing was seen in PCG resistant proportion of S. pneumoniae. The maximum PCG-MIC was 2 μg/mL.

In IFMIF/EVEDA, tasks for lithium target system consist of 5 validation tasks (LF1-5) and a design task (LF6), and are shared by Japan and Europe. Japan is covering LF1, LF2, LF4, LF5 and LF6, and JAEA as an Implementing Agency is organizing these tasks. Japanese universities contribute these tasks. The purpose of LF1 task is to construct and operate EVEDA Li test loop (ELTL) with diagnostics and purification systems for the validation of Li target facility. ELTL will be constructed at the end of February in 2011 and the operation will be started at the summer in 2011. LF2 and LF4 are basic research for the diagnostics and purification system, respectively. And LF2 and LF4 have also contributed the construction of the ELTL (LF1). LF5 is focusing on the remote handling for the replacement of the target assembly. Major deliverable of LF6 is finally engineering design report, which is assembled with all validation tasks, and this activity will be gradually enhanced to the end of IFMIF/EVEDA.

The simultaneous implantation of 10 keV C+ and 3.0 keV D 2 + into tungsten was carried out at elevated temperatures to establish the retention mechanism of energetic deuterium and carbon. Thermal desorption spectroscopy showed that the deuterium retention obviously decreased as the implantation temperature increased. All the desorption stages disappeared when the implantation was performed at 673 K, indicating no deuterium trapping as C–D bonds was processed in this temperature. The results of X-ray photoelectron spectroscopy and glow discharge-optical emission spectroscopy showed that a mixed carbon layer had been formed during the implantation, resulting from the carbon deposition and accumulation near the surface of tungsten during the implantation. The carbon layer would enhance the chemical sputtering with deuterium and reduce the deuterium retention, as the implantation temperature increases. During discussion, a simple retention mechanism has been proposed, which shows the importance of implantation temperature.

Tungsten (W) coatings were prepared using vacuum plasma spraying (VPS) technology and then the chemical states and retention behaviors of deuterium in VPS-W coatings were analyzed by X-ray photoelectron spectroscopy (XPS) and thermal desorption spectroscopy (TDS). The results showed that chemical reacted oxygen (W–O bonds) and chemisorbed oxygen (O–O bonds) existed both on the surface and interior of tungsten coatings. Oxygen was chemically sputtered during D 2 + implantation. Two deuterium desorption stages at the temperature ranges around 300–700 K and 800–1150 K were observed for tungsten coatings. The retention behavior of deuterium in tungsten coatings was greatly different from that of bulk tungsten, which was related to the existence of oxygen.

The ion fluence dependence of deuterium retention in SS-316 during oxidation at a temperature of 673 K was studied to evaluate the dynamics of deuterium retention in the oxide layer of SS-316. The correlation between the chemical state of stainless steel and deuterium retention was evaluated using XPS and TDS. It was found that the major deuterium desorption temperatures were located at around 660 K and 935 K, which correspond to the desorption of deuterium trapped as hydroxide. The deuterium retention increased with increasing deuterium ion fluence, since the deuterium retention as hydroxide increased significantly. However, retention saturated at an ion fluence of ∼2.5 × 1021 D+ m−2. The XPS result showed that FeOOD was formed on the surface, although pure Fe also remained in the oxide layer. These facts indicate the nature of the oxide layer have a key role in deuterium trapping behavior.

Background & Aims Little is known about the pathogenic mechanisms of functional dyspepsia. We investigated the role of microRNAs (miRNAs) in gastric motility disorders associated with Helicobacter pylori infection. Methods Male C57BL/6 mice were infected with H pylori . After long-term infection, gastric emptying was examined and compared with that of uninfected mice (controls). The miRNA expression profile was analyzed by miRNA microarray and quantitative reverse-transcriptase polymerase chain reaction. The results obtained from the animal study were confirmed by in vitro experiments. Results Gastric emptying was significantly accelerated in mice after chronic infection with H pylori. Histologic examination showed that the muscular layers of the stomachs of H pylori -infected mice were significantly thickened. The miRNA expression profile revealed that the muscle-specific miRNAs miR-1 and miR-133 were significantly down-regulated in the stomachs after long-term infection with H pylori . However, expression of histone deacetylase 4 and serum response factor, which are reported target genes of miR-1 and miR-133 , increased. Down-regulation of miR-1 and miR-133 and increased cell proliferation were observed in C2C12 mouse myoblast cells after coculture with H pylori . Conclusions Chronic infection with H pylori down-regulates expression of muscle-specific miRNAs and up-regulates expression of histone deacetylase 4 and serum response factor. These might cause hyperplasia in the muscular layer of the stomach and dysfunction in gastric emptying. These findings provide insight into the molecular pathogenesis of gastric motility disorders, including functional dyspepsia.

The anti-prion protein (PrP) monoclonal antibody T2 has previously been prepared using PrP-knockout mice immunized with mouse recombinant PrP residues 121-231, however its interaction mechanism to PrP antigen has not been cleared. Here we identified and characterized the epitope of T2 antibody. The competitive ELISA with 20-mer synthetic peptides derived from PrP121-231 showed that T2 antibody had no affinity for these peptides. The analysis with deletion mutants of PrP revealed that 10 amino acids in the N terminus and 66 amino acids in the C terminus of PrP121-231 were necessary for reactivity with T2. Two far regions are necessary for complete affinity of the T2 antibody for PrP; either region alone is not sufficient to retain the affinity. The epitope recognized by T2 antibody is discontinuous and conformational. We examined the effect of disulfide bond and salt bridges. Alkylation of cysteine residues in C terminus of PrP121-231, which breaks a disulfide bond and disrupts the structure, had diminished the reactivity. Mutations induced in the PrP121-231 to break the disulfide bond or salt bridges, markedly had reduced the reactivity with T2 antibody. It suggests that T2 antibody recognized the structure maintained by the disulfide bond and salt bridges.

Temperature dependence of oxide layer formation on hydrogen isotope retention in stainless steel type 316 was studied by TDS and XPS. The shape of TDS spectrum was clearly changed by the oxide formation temperature. The chemical states of iron, chromium and oxygen were also evaluated by XPS. The surface oxide layer was composed of iron and oxygen and the contribution of chromium was quite low. The ratio of oxide layer on stainless steel increased as increasing the annealing temperature. The deuterium retention trapped by the oxide layer, which corresponded to the desorption temperature of 600-800 K, was governed by the ratio of oxide layer, especially iron hydroxide. All of the iron was not oxidized and the saturation ratio of iron oxide to pure iron existed in the stainless steel. It was concluded that the saturation of deuterium retention trapped by the oxide layer was controlled by the amount of iron oxide in the oxide layer.

Deuterium ion implantation experiments into Li2TiO3 and TiO2 were performed with various ion fluences to elucidate the role of lithium on deuterium retention behavior in Li2TiO3. The experimental results showed that there were four deuterium trapping states in TiO2; two of them were interacted near the surface and the others were deuterium trapped by E’-center and bound to oxygen with forming TiO-D bond in bulk. For Li2TiO3, there were five trapping states; four of them were the same as those in TiO2 and the other was that bound to oxygen with forming LiO-D bond. The implanted deuterium was preferentially trapped by E’-center with forming hydroxide. LiOD phase was formed as increasing ion fluence. The retention of deuterium trapped by E’-center for Li2TiO3 was less than that for TiO2, indicating that the migration of lithium via irradiation defects during implantation refrains the deuterium retention in Li2TiO3.

To elucidate the C+ implantation effect on deuterium retention in tungsten, simultaneous C+ and D 2 + implantation was performed on tungsten. Deuterium desorption behavior for simultaneously implanted tungsten was compared with that the sequentially implanted tungsten. It was found that deuterium retention for the simultaneous case was lower than that for the sequential one, indicating that the sputtering of carbon and deuterium trapped by carbon would prevent the deuterium trapping. In addition, deuterium retention decreased with increasing C+/D+ ratio and deuterium trapping by carbon was not observed for high C+/D+ ratio. These facts indicate that the number of available traps in tungsten produced by simultaneous ion implantation would mainly control the deuterium retention in tungsten. However, for low C+/D+ ratios, deuterium trapping by carbon would be one of major trapping states.

A 37-year-old woman was diagnosed as having chronic adult T-cell leukemia (ATL) of the skin by a skin biopsy and human T-cell leukemia virus type-1 serology at our hospital in August 1992. The skin lesions of ATL were improved by treatment with psoralen ultraviolet ray A. She complained of severe pain in her bilateral forearms, hands and ankles, and X-ray examination in July 1999 revealed multiple punched-out lesions of the extremities. Serum levels of parathyroid hormone-related peptide, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha and total serum receptor activator of nuclear factor kappaB ligand were not elevated. However, serum levels of IL-6, CCL2 monocyte chemoattractant protein-1 (MCP-1), CCL3 [macrophage inflammatory protein-1alpha (MIP-1alpha)] and CCL4 (MIP-1beta) were markedly elevated. Here, we have discussed the possible mechanism underlying the onset of the osteolytic lesions.

To assess the effect of pre-germinated brown rice on metabolism of glucose and lipids, blood parameters of glucose and lipids were measured before and after 3 months of intake of test rice, which was mixed with Pre-germinated brown rice (PGBR) and white rice in a ratio of 1:1, in patients with diabetes mellitus type 2 (DM). Glycosylated hemoglobin A1c (HbA1c) was significantly decreased from 6.40+-0.23% to 6.23+-0.19 after 3 months of intake of PGBR. The fasting plasma glucose level was not changed by intake of PGBR, but serum insulin level and HOMA-IR were decreased slightly. As the decrease of LDL-cholesterol (LDL-c) and the increase of HDL-cholesterol (HDL-c) were slightly observed after 3 months of intake of PGBR, the LDL-c/HDL-c ratio was decreased significantly from 2.03+-0.13 to 1.83+-0.12. These changes were significantly larger in the high PGBR in take group than in the low PGBR in take group. These results suggested that the PGBR intake might have potentialities as one of therapeutic methods for diabetes mellitus type 2 and also be useful in the treatment of hypercholesterolemia.

Epoxyeicosatrienoic acids (EETs), including 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET, are produced by cytochrome P450 (P450) such as CYP2C8 and 2C9; and they are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. Particular interest in the epoxygenase reaction has developed because of the potent biological activities (modulation of vascular tone and anti-inflammatory activity, etc.) attributed to EETs. We focused on a new biological function of EETs and DHETs, which induce vascular endothelial growth factor (VEGF) and erythropoietin (EPO) under hypoxia. Human hepatoma cells, Hep3B, and human umbilical artery endothelial cells (HUAEC) were used in this study. An inhibitor of phospholipase A2, methyl arachidonyl fluorophosphonate (MAFP), and inhibitors of P450s inhibited the VEGF and EPO induction of HUAEC and Hep3B, respectively, under hypoxia. Overexpression of CYP2C8 in Hep3B induced EPO and VEGF under hypoxia. Sulfaphenazole, an inhibitor of CYP2C8/2C9 suppressed luciferase promoter activity with the hypoxia response element (HRE) of VEGF in HUAEC. Exogenous 11,12-EET and 14,15-DHET induced reporter activity in HUAEC and Hep3B cells concomitant with increased levels of hypoxia-inducible factor-1α (HIF-1α), which is a key factor in the hypoxia response, but 11,12-DHET and 14,15-EET did not. These results suggested that EETs and DHETs play an important role in the hypoxia response of cells. Keywords:: cytochrome P450, epoxyeicosatrienoic acid (EET), hypoxia-inducible factor (HIF), dihydroxyeicosatrienoic acid (DHET), vascular endothelial growth factor (VEGF)