Yuji Taketani

Modulation of Endothelium-Dependent Flow-Mediated Dilatation of the Brachial Artery by Sex and Menstrual Cycle

BACKGROUND Estrogen has been reported to augment endothelium-dependent vasodilatation. The role of endogenous ovarian hormones in modulating endothelium-dependent vasodilatation, however, remains to be determined. The purpose of the present study was to investigate the effects of sex and menstrual cycle on endothelium-dependent flow-mediated vasodilatation. METHODS AND RESULTS Seventeen female volunteers 25.1 +/- 0.8 years old and 17 age-matched male volunteers were examined. We measured brachial artery diameters noninvasively using a 7.5-MHz ultrasound machine at rest, during reactive hyperemia, and after sublingual nitroglycerin administration. All female subjects were studied three times each, in three different phases of one menstrual cycle (M, menstrual phase; F, follicular phase; and L, luteal phase). Flow-mediated diameter (D) increase (%FMD; delta D/D x 100) in M, when serum estradiol level was low (121.9 +/- 12.5 pmol/L), was 11.22 +/- 0.58%, and the value was comparable to that in male subjects (10.60 +/- 0.75%). %FMD increased in F (18.20 +/- 0.81%, P < .01 versus M) and L (17.53 +/- 0.74%, P < .01 versus M), when serum estradiol level was high (F, 632.0 +/- 74.5 and L, 533.8 +/- 33.4 pmol/L, P < .01 versus M). Endothelium-independent vasodilatation by nitroglycerin increased in both F and L. However, the increment was smaller than that of %FMD. CONCLUSIONS Endothelium-dependent vasodilatation varies during the menstrual cycle. The endogenous estradiol may be involved in this menstrual cycle-related vasodilatation.

Expression profiling in ovarian clear cell carcinoma: Identification of hepatocyte nuclear factor-1β as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma

Of all of the epithelial ovarian cancers, clear cell carcinoma (CCC) of the ovary has the worst prognosis. We applied the oligonucleotide array technique to identify genes generally involved in CCC. Of the approximately 12,600 genes that were analyzed, 28 were expressed significantly differently between four CCC and seven non-CCC cell lines. Among 16 up-regulated genes in CCC, we further investigated a transcription factor, hepatocyte nuclear factor-1 beta (HNF-1 beta). We validated up-regulation of HNF-1 beta in CCC in terms of both mRNA and protein level using real-time quantitative reverse transcriptase-polymerase chain reaction and immunoblotting. Immunohistochemical analysis of 83 surgically resected ovarian cancers showed that almost all CCC specimens (21 of 22 cases) had nuclear staining for HNF-1 beta, whereas most non-CCC specimens (60 of 61 cases) showed no immunostaining or only focal and faint staining in the nucleus. Furthermore, we investigated the significance of HNF-1 beta expression in CCC using RNA interference. The reduction of HNF-1 beta expression by RNA interference induced apoptotic cell death in ovarian CCC cells, which was confirmed by terminal dUTP nick-end labeling and fluorescence-activated cell-sorting analyses. Our results suggest that HNF-1 beta is not only an excellent CCC-specific molecular marker but also a molecular target for therapy of ovarian CCC.

Altered Expression of Human Leukocyte Antigen G (HLA‐G) on Extravillous Trophoblasts in Preeclampsia: Immunohistological Demonstration With Anti‐HLA‐G Specific Antibody “87G” and Anti‐cytokeratin Antibody “CAM5.2”

PROBLEM: Human leukocyte antigen‐G (HLA‐G) is suggested to be at play in the materno‐fetal immune relationship during pregnancy. In the light of current concept that disruption of the materno‐fetal immune relationship could account for several complications of pregnancy, including preeclampsia, we asked whether the expression of HLA‐G protein on the trophoblasts is altered in preeclampsia.

Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis—a randomized, double-blind, multicenter, controlled trial

OBJECTIVE To compare the efficacy and safety of dienogest (DNG) with intranasal buserelin acetate (BA) in patients with endometriosis. DESIGN Phase III, randomized, double-blind, multicenter, controlled trial. SETTING Twenty-four study centers in Japan. PATIENT(S) Two hundred seventy-one patients with endometriosis. INTERVENTION(S) Dienogest (2 mg/day, orally) or BA (900 microg/day, intranasally) for 24 weeks. MAIN OUTCOME MEASURE(S) The pre- to posttreatment changes in the scores of five subjective symptoms during nonmenstruation (lower abdominal pain, lumbago, defecation pain, dyspareunia, and pain on internal examination) and two objective findings (induration in the pouch of Douglas and limited uterine mobility). RESULT(S) Dienogest reduced the scores of all symptoms and findings at the end of treatment, and the mean changes in the scores of all symptoms and findings except induration in the pouch of Douglas were comparable to those obtained with BA. Compared with BA, DNG was associated with irregular genital bleeding more frequently and with fewer hot flushes. The reduction in bone mineral density (BMD) during DNG treatment was significantly lower than that during BA treatment. CONCLUSION(S) DNG is as effective as intranasal BA in alleviating endometriosis, and causes less BMD loss.

Treatment of node-positive endometrial cancer with complete node dissection, chemotherapy and radiation therapy

We assessed the therapeutic significance of systematic aortic and pelvic lymphadenectomy followed by adjuvant therapy in node-positive endometrial carcinoma. Among 173 stage I-III patients, 30 (17%) had positive nodes: ten in the pelvic region alone (group P) and 20 in the aortic region alone or in both regions (group A). The adjuvant therapy was administered as follows: subjects in group P received 50 Gy pelvic radiation, including three post-surgical T3 (pT3) patients who received either one or three cycles of cisplatin-based chemotherapy before radiation. Subjects in group A were given three cycles of chemotherapy followed by 50 Gy pelvic and 50 Gy extended field periaortic radiation using a four-field or conformational technique. Five-year survival was 95% for 143 patients with negative nodes and 84% for 30 patients with positive nodes (100% for group P and 75% for group A). In group A, 5-year survival was 38% for eight patients with both pT3 and histology other than endometrioid type G1, and 91% for the remaining 12 patients. Either way, both group P and group A patients had a better prognosis than previously reported. In summary, aortic and pelvic lymphadenectomy and subsequent chemotherapy and radiation therapy based on node status seem to improve the survival of endometrial cancer patients with positive nodes.

Evidence for an Elevation in Serum Interleukin-2 and Tumor Necrosis Factor-α Levels Before the Clinical Manifestations of Preeclampsia

PROBLEM: The purpose of this study is to clarify whether the disruption of immune regulation occurs in early pregnancy before the clinical manifestations of preeclampsia.

Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood

PROBLEM: To better understand the role of human leukocyte antigen (HLA)‐G in regulating the T helper (Th)1/Th2 cytokine balance, one of key conditions in determining the fate of pregnancy, we asked whether the presence of HLA‐G protein altered the release of cytokines from both decidual mononuclear cells and peripheral blood mononuclear cells (PBMCs).
 METHOD OF STUDY: The amounts of cytokines released from decidual mononuclear cells and PBMCs were compared in the presence or absence of HLA‐G‐expressing cells.
 RESULTS: When cocultured with HLA‐G‐expressing cells, the amounts of tumor necrosis factor‐α and interferon‐γ released from decidual mononuclear cells and PBMCs were decreased, while the amounts of interleukin (IL)‐4 from PBMCs was increased, with IL‐4 release from decidual mononuclear cells being unchanged.
 CONCLUSIONS: Upon contact with HLA‐G, decidual mononuclear cells, and PBMCs as well, modulate their ability to release cytokines in a way that may shift the Th1/Th2 balance towards relative Th2 dominance, suggesting a role for HLA‐G in maintaining pregnancy.

Assessment of metastases to aortic and pelvic lymph nodes in epithelial ovarian carcinoma. A proposal for essential sites for lymph node biopsy.

In staging epithelial ovarian carcinoma, it is necessary to assess the presence of lymph node metastases. However, the essential sites of selective lymph node biopsy have yet to be determined.

Visualization of mitotic radial glial lineage cells in the developing rat brain by Cdc2 kinase-phosphorylated vimentin

Although accumulating data reveal patterns of proliferation, migration, and differentiation of neuronal lineage cells in the developing brain, gliogenesis in the brain has not been well elucidated. In the rat brain, vimentin is selectively expressed in radial glia and in their progeny, not in oligodendrocytes or neurons from embryonic day 15 (E15) until postnatal day 15 (P15). Here we examined mitotic radial glial lineage cells in the rat brain E17–P7, using the monoclonal antibody 4A4, which recognizes vimentin phosphorylated by a mitosis‐specific kinase, cdc2 kinase. In the neocortex, mainly radial glia in the ventricular zone, but not their progeny, underwent cell division. In contrast, not only radial glia but also various types of radial glial progeny including Bergmann glia continued to proliferate in the cerebellum. Radial glia in the neocortex divided horizontally, obliquely, and vertically against the ventricular surface. The percentage of the vertical division increased with progress in the stage of development, concurrently with the decrease of the population of horizontal divisions. Thus, the monoclonal antibody 4A4 provides an useful tool to label mitotic glia in the developing brain and revealed different patterns of gliogenesis in the neocortex and cerebellum. A possibility is discussed that the dynamics of mitotic orientation observed here may be related to the change of the pattern of gliogenesis during development. GLIA 23:191–199, 1998.

Long-term use of dienogest for the treatment of endometriosis

Aim:  To investigate the safety and efficacy of 52 weeks of dienogest treatment in patients with endometriosis.