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We theoretically investigate mechanisms of higher-order harmonic generation in solid-state materials under a high-intensity ac electric field. A new theoretical framework presented in this Letter holds the legitimacy of Bloch theorem even under the influence of the high-intensity electric field and provides an exact treatment of the diabatic processes of Bloch electrons. Utilizing this framework, we first discovered that the diabatic processes, namely, ac Zener tunneling and semimetallization of semiconductors, are key factors for nonperturbative mechanisms of HHG. These mechanisms are classified by the field intensity and could be understood by an extended simple man model based on an analogy between tunnel ionization in gaseous media and Zener tunneling in semiconductors. These conclusions would stimulate the universal understanding of HHG mechanisms in both atomic and solid cases., Comment: 14 pages, 4 figures

We theoretically investigated the dependence of higher-order harmonic generation (HHG) in solid-state materials on the ellipticity of the electric field. We found that in the multiphoton absorption and ac Zener regimes, the intensity of HHG monotonically decreases with increasing ellipticity of the incident electric field, while in the semimetal regime, the intensity reaches a maximum for finite values of ellipticity. Moreover, the characteristics of the polarization of the emitted HHG change depending on the field intensity; only parallel emissions with respect to the major axis exist in the multiphoton absorption and ac Zener regimes, while both parallel and perpendicular emissions exist in the semimetal regime. These peculiar characteristics of the semimetal regime can be understood on the basis of changes in the HHG mechanism and may be able to be identified in experiments utilizing solid-state materials such as narrow-gap semiconductors., Comment: 16 pages, 5 figures

The ratio of membrane/cytosolic protein kinase C (PKC) activity and the levels of c-fos and c-jun expressions in uterine endometrial fibroblasts were increased and reached peak levels with the administration of estradiol, but were partially diminished by the addition of progesterone. The response of c-fos was earlier than that of c-jun. Twelve-0-tetradecanoylphorbol-13-acetate (TPA) increased c-fos and c-jun expressions in endometrial fibroblasts as estradiol did, and pretreatment with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) reduced the estrogen-inducible c-fos and c-jun expressions. Therefore, it is suggested that oncogenes c-fos and c-jun in uterine stromal cells might be induced by estrogen partly via PKC, involving the interplay of the anti-estrogenic effect of progesterone, and there might be a cross talk between estrogen and PKC stimulants for c-fos and c-jun expressions.

By combining a tilted-pulse-intensity-front scheme using a LiNbO3 crystal and a chirped-pulse-beating method, we generated a narrowband intense terahertz (THz) pulse, which had a maximum electric field of more than 10 kV/cm at around 2 THz, a bandwidth of about 50 GHz,and frequency tunability from 0.5 to 2 THz. By performing THz-pump and near-infrared-probe experiments on GaAs quantum wells, we observed that the resonant excitation of the intraexcitonic 1s-2p transition induces a clear and large Autler-Townes splitting. Our time-resolved measurements show that the splitting energy observed in the rising edge region of electric field is larger than in the constant region. This result implies that the splitting energy depends on the time-averaged THz field over the excitonic dephasing time rather than that at the instant of the exciton creation by a probe pulse.

Staurosporine is a potent apoptosis inducer, but its mechanism remains to be clarified. We investigated the involvement of PTEN in staurosporine-induced apoptosis. Ishikawa cells, from an endometrial carcinoma cell line, expressed a high amount of PTEN mRNA but did not express the PTEN protein because of protein truncations. We isolated clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells by transfection. The obtained clones showed reduced proliferative activity and reduced anchorage-independent cell growth with the augmented p27(Kip1). These cell lines were sensitized to apoptosis by staurosporine. A low concentration of UCN-01 did not affect apoptosis, but a high concentration augmented apoptosis in the PTEN-expressing clone. Alpha-sphingosine and H-7 did not affect apoptosis in these cell lines. PI3K inhibition augmented staurosporine-induced apoptosis in the parental cell line, but not in the PTEN-expressing clone. In the clone, phosho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Staurosporine reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clone. These results suggest that inhibition of the PI3K/Akt/PKB signaling pathway might be associated with staurosporine-induced apoptosis in Ishikawa cells.

Co-expression of macrophage colony-stimulating factor (M-CSF) and its receptor (c-fms) is often found in ovarian epithelial carcinoma, suggesting the existence of autocrine regulation of cell growth by M-CSF. To block this autocrine loop, we have developed hammerhead ribozymes against c-fms mRNA. As target sites of the ribozyme, we chose the GUC sequence in codon 18 and codon 27 of c-fms mRNA. Two kinds of ribozymes were able to cleave an artificial c-fms RNA substrate in a cell-free system, although the ribozyme against codon 18 was much more efficient than that against codon 27. We next constructed an expression vector carrying a ribozyme sequence that targeted the GUC sequence in codon 18 of c-fms mRNA. It was introduced into TYK-nu cells that expressed M-CSF and its receptor. Its transfectant showed a reduced growth potential. The expression levels of c-fms protein and mRNA in the transfectant were clearly decreased with the expression of ribozyme RNA compared with that of an untransfected control or a transfectant with the vector without the ribozyme sequence. These results suggest that the ribozyme against GUC in codon 18 of c-fms mRNA is a promising tool for blocking the autocrine loop of M-CSF in ovarian epithelial carcinoma. Images Figure 2 Figure 3 Figure 5 Figure 6

A 32-year infertile Japanese woman suffered from endometrial cancer, which was treated with repeated endometrial curettage and medroxyprogesterone acetate for 6 months. The patient then became pregnant and was delivered of a live-born male infant at 37 weeks gestation by cesarean section for placenta previa. At cesarean section there were no abnormal findings in the uterine cavity or other pelvic organs.

Expression of DNA topoisomerase (Topo)-I-mRNA in various cancer cell lines was detected using the reverse transcription-polymerase chain reaction (RT-PCR) method. The cytoplasmic polyadenylated RNA isolated from cancer cell lines was reverse-transcribed and the complementary DNA was amplified by PCR primed with Topo-I specific primers. Fidelity of the amplified sequence was confirmed by restriction endonuclease digestion and Southern blot hybridization. The level of Topo-I mRNA was correlated positively with the cytotoxicity of a Topo-I inhibitor, a camptothecin derivative. This RT-PCR method may be applicable to the assessment of sensitivity of cells to Topo-I targeted drugs, especially when only small quantities of cell samples are available.

A number of cellular processes, including cell proliferation and differentiation, appear to be regulated by the phosphorylation of proteins on tyrosine residues (1,2). The level of tyrosine phosphorylation of intracellular protein substrates is determined by the balance of phosphorylation by tyrosine kinase and dephosphorylation by phosphotyrosine phosphatase (PTPase) activities. Recent studies have proposed a role for PTPase in counterbalancing the growth-promoting effects of tyrosine kinases (3-5). Because the enzymatic activity of PTPases far exceeds that of tyrosine kinases (6-8), the PTPases may play an important physiological role in regulating growth, differentiation and neoplastic transformation.

The anti-proliferative effects of interferon gamma (IFN-gamma) and CPT-11, a new derivative of camptothecin, both singly and in combination, on two human endometrial carcinoma cell lines, HHUA and ISHIKAWA, were examined in vitro. The HHUA cells were responsive dose-dependently to IFN-gamma, while the ISHIKAWA cells were unresponsive to IFN-gamma. Both cell lines were responsive dose-dependently to CPT-11. In both cell lines, IFN-gamma at clinically achievable concentrations (10 and 100 U ml-1 enhanced the anti-proliferative activity of CPT-11 in the range of concentrations where CPT-11 showed more than 10% cell growth inhibition. Sequential treatment with CPT-11 followed by incubation with IFN-gamma resulted in significant cell growth inhibition, but not vice versa. Flow cytometric studies indicated that the combined anti-proliferative effect did not correlate with cytokinetic alterations. Treatment with IFN-gamma did not change the extractable topoisomerase I activity of the HHUA and ISHIKAWA cells. The combination therapy of IFN-gamma and CPT-11 could provide a new approach against endometrial cancer.

The major presenting symptom of uterine arteriovenous fistulas is massive, torrential vaginal bleeding, the degree of which often leads to a shock state.A 35-year-old woman, gravida 3, para 2 presented with massive vaginal hemorrhage at the first menstruation six months after delivery. Uterine arteriovenous fistulas were diagnosed by color Doppler ultrasonography (US), dynamic computer tomography (CT), and conventional angiography. The patient underwent hysterectomy after bloodstream decrease by bilateral uterine artery embolization.The extent of uterine arteriovenous fistulas was diagnosed by color Doppler US, CT, and pelvic angiography, and this precise evaluation led to an adequate therapeutic strategy for uterine arteriovenous fistulas.

The present study was performed to identify the effects of medroxyprogesterone acetate (MPA) plus adjuvant chemotherapy on advanced epithelial ovarian carcinoma (FIGO Stage III/IV).A total of 50 patients were enrolled in this study. A relatively low dose of MPA (200 mg/day) after surgery was administered in combination with platinum-based chemotherapy and the treatment was continued for two years. Patients' backgrounds were also analyzed.Relapse-free survival (p0.05) and overall survival (p0.001) rates in FIGO Stage III/IV ovarian cancer patients with MPA combined chemotherapy were significantly longer than the control group. The effect was more prominent in the higher progesterone receptor expression group. The chemotherapy regimens (cyclophosphamide, doxorubicin and cisplatin vs paraplatin plus cyclophosphamide or paclitaxel) did not affect prognosis.MPA with platinum-based chemotherapy as an adjuvant therapy might improve the prognosis in FIGO Stage III/IV epithelial ovarian cancer cases. A randomized controlled study is still needed for further analyses.

A case of a primary uterine corpus lymphoma in a 75-year-old woman is described. Immunohistochemical studies showed diffuse large B-cell type one. Primary lymphoma of the uterine corpus is considered to be an unusual location for a common disease.

A postmenopausal 52-year-old Japanese woman with a 5-month history of a right labial tumor was referred to the Department of Obstetrics and Gynecology. The resected tumor had been diagnosed as a primary endodermal sinus tumor of the vulva with pT2N0M0 in 2001. Six courses of adjuvant chemotherapy using bleomycin, etoposide and cisplatin were administered. The patient was free of recurrence or metastasis 67 months after the initial treatment.

This study was performed to examine the effects of selective estrogen receptor modulators [tamoxifen (TAM) and toremifene (TOR)] and pure anti-estrogen, ICI-182780 (ICI, Faslodex) and soybean isoflavone, genistein (GE) on the expression of estrogen-stimulated c-fos/jun, ERalpha/beta and COX-1/2 in the uteri of ovarectomized mice. TAM, TOR, ICI and GE treatment significantly decreased the levels of estradiol (E2)-induced c-fos. ICI and GE treatment significantly decreased the levels of E2-induced c-jun and ERalpha expressions. High doses of TOR treatment significantly increased the E2-induced ERbeta expression. In contrast, ICI and GE treatment significantly decreased the levels of E,-induced COX-2 expression, thus suggesting that TOR and GE might prevent E2-related endometrial carcinogenesis.

An extremely rare case of a pseudomyxoma peritonei (PMP) and mucinous pyometral fluid, possibly arising from an ovarian borderline mucinous tumor is reported. A 68-year-old Japanese patient received an expolatory laparatomy under a working diagnosis of a PMP, left ovarian cystic tumor and an umbilical hernia. Surgery and platinum-based chemotherapy induced a 15-month disease-free condition.

This study was undertaken to examine the effects of dioxin (TCDD) and nutrition on cellular proliferation and dioxin- and estrogen-linked gene expression in ovarian cancer cell lines. Caov-3 and SK-OV-3 cells were incubated in a medium supplemented with 0.5-10% fetal bovine serum (FBS). Cell proliferation was assayed with an MTT assay. Dioxin- and estrogen-linked genes (AhR, ERalpha, ERbeta, CYP1A1 and ARNT) expressed were determined with the RT-PCR method. Caov-3 cells, but not SK-OV-3 cells, were proliferated with TCDD alone with increased AhR and ERa mRNA expressions when incubated in the low FBS concentration. CYP1A1 and ARNT mRNA expressions of SK-OV-3, but not that of Caov-3, were suppressed in the low FBS (under 1.0%) concentration. In the low FBS concentration medium with dioxin, AhR and ERa expression were increased with the proliferation of Caov-3 cells; CYP1A1 and ARNT were stable. Each ovarian cancer cell line may have its own distinct responsiveness to dioxin depending on the nutritional state.

The placenta is a major source of leptin in the fetomaternal circulation, although its physiological role remains to be clarified. Leptin in the fetomaternal circulation is proposed to be a marker of acute stress in the fetus, and the fetus suffering from pre-eclampsia would be under chronic stress. In 16 pre-eclamptic placentas, the expressions of leptin, hypoxia-inducible factor 1alpha (HIF1alpha) and leptin receptor mRNAs were analyzed by semi-quantitative reverse-transcriptase-polymerase chain reaction and compared with clinical data. The co-expressions of leptin and the isoforms of the leptin receptor were observed in all the pre-eclamptic placentas. Leptin mRNA was significantly augmented in the pre-eclamptic placentas, although the level in fetal plasma was not high. The level of the expression of leptin mRNA was correlated with the placental HIF1alpha mRNA level and fetal body weight, but not with the levels of the leptin receptor isoforms in the pre-eclamptic placentas. This observation may suggest that autocrine/paracrine regulation of leptin exists in the human placenta and is upregulated in the pre-eclamptic placenta.

This study was performed to examine the inhibitory effects of soybean isoflavones on estrogen-stimulated gene expression of the uteri in ovarectomized mice. Especially when compared with the inhibitory effect of genistein and daidzein as aglycosides described in our previous report, subcutaneous administration of the glycoside genistin significantly decreased the levels of estradiol-17beta (E2)-induced expressions of c-jun, interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha mRNAs (p0.005, p0.05 and p0.05, respectively) and seemingly proteins in the mice uteri, whereas the glycoside daidzin weakly inhibited E2-stimulated expressions of c-fos and IL-1alpha. Both genistin and daidzin seemed to have a weaker inhibitory effect than that of genistein and daidzein on the expression of estrogen-stimulated genes. It is suggested that those glycosides are naturally derived and generally absorbed from plant foods and might prevent E2-related endometrial carcinogenesis.

Since insulin-like growth factors (IGFs) are known to play critical roles in the development of cancers, we examined the expression of the mRNA and protein of IGF-binding protein (IGFBP) and cognate receptors to assess their possible involvement in gynecological malignancy. The specimens were obtained from 46 endometrial, 32 cervical, and 20 ovarian cancers, and 28 normal endometrium. In endometrial cancers, IGFBP-1, -2, -3 and IGF-1 receptor (IGF-1R) mRNAs were detected in 8.7, 89.1, 95.6, and 91.3% of tumors, respectively, and the corresponding proteins in 54.3, 54.3, 95.6, and 91.3% of tumors, respectively. Clinical staging was significantly related to the expression of IGFBP-1 and -2 proteins. In ovarian cancers, their mRNAs were detected in 10.0, 90.0, 95.0, and 100.0%, and proteins in 15.9, 50.0, 90.0, and 80.0%. In cervical cancers, their mRNAs were detected in 6.3, 90.6, 96.8, and 87.5%, and proteins in 44.4, 18.8, 84.4, and 87.5%. IGF-1R was highly expressed in all specimens. The abnormally balanced co-expression of IGFBPs and high levels of IGF-R in gynecological cancers suggest that IGF signals might be involved in the growth of these tumors.

The preload index (PLI) has been shown to increase in the recipient fetus of twin-twin transfusion syndrome in the presence of uterine contractions. The objective of this study was to determine whether there are changes in PLI in the presence of uterine contractions in normal fetuses.Inferior vena cava blood flow was measured using Doppler sonography in 45 normal fetuses at 18-41 weeks' gestation in the presence of uterine contractions and during quiescence and the PLI was compared between groups.There was a highly significant difference (P0.0001) between the mean +/- SD PLI in fetuses in the absence (0.235 +/- 0.07) and in the presence (0.534 +/- 0.183) of uterine contractions.Uterine contractions appear to increase fetal preload conditions in normal pregnancy.

Angiogenesis is essential for development, growth and advancement of solid tumors. During angiogenesis, ETS-1 is strongly expressed in vascular endothelial cells and the adjacent interstitial cells, while the inhibition of ETS-1 expression leads to suppression of angiogenesis. This prompted us to study the clinical implications of ETS-1 in relation to angiogenesis in uterine endometrial cancers.Sixty patients underwent resection for uterine endometrial cancers. From the tissues of 60 uterine endometrial cancers, the levels of ets-1 mRNA, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF) and interleukin (IL)-8 were determined by competitive RT-PCR using recombinant RNA and enzyme immunoassay, and the localization and counts of microvessel were determined by immunohistochemistry.There was a significant correlation between microvessel count and ets-1 gene expression levels in uterine endometrial cancers. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. The level of ets-1 mRNA tended to increase with increasing disease stage. Furthermore, the level of ets-1 mRNA correlated with levels of VEGF in well-differentiated adenocarcinomas (G1) and of bFGF in moderately differentiated adenocarcinomas (G2) and poorly differentiated adenocarcinomas (G3).ETS-1 is a possible angiogenic mediator in uterine endometrial cancers.

A herbal complex consisting of Hoelen, Angelicae radix, Scutellariae radix and Glycyrrhizae radix suppressed cell viability and telomerase activity in hormone-refractory and chemo-resistant cancer cell lines, namely poorly differentiated uterine endometrial cancer cell line AN3 CA, adriamycin-resistant breast cancer cell line MCF7/ADR and cisplatin-resistant ovarian cancer cell line A2780. Furthermore, the herbal complex suppressed the expression of the full length of human telomerase reverse transcriptase (hTERT), which is related to telomerase activity. This indicates that the herbal complex can suppress the tumor growth of chemoendocrine resistant cancers, at least in part via suppression of telomerase activity associated with down-regulated hTERT.

Ginsenoside-Rb2 derived from ginseng inhibited invasiveness to the basement membrane of endometrial cancer cell lines Ishikawa. HHUA and HEC-1-A cells. These cells dominantly expressed matrix metalloproteinase (MMP)-2 (gelatinase A) among MMPs by zymography. Ginsenoside-Rb2 suppressed the expression and activity of MMP-2, but did not alter the expression of tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in the cells. Therefore, ginsenoside-Rb2 might inhibit invasiveness to the basement membrane via MMP-2 suppression in some endometrial cancers, and can be used as a medicine for inhibition of secondary spreading of uterine endometrial cancers.

Telomerase is an excellent target molecule for cancer therapy, though any effective agents have never been developed in human subjects. We designed a variety of hammerhead ribozymes against human telomerase RNA (hTR) and hTERT mRNA and studied their possibility as a tool for cancer therapy. To search promising target site of hTR, the catalytic actiuity of 3 kinds of hammerhead ribozymes was studied in cell-free system. They showed equivalent catalytic activity, but only 36-ribozyme, which was designed to cleave the template region of hTR, revealed telomerase inhibitory activity in an endometrial carcinoma cell line. Among hTERT-mRNA-targeted ribozymes, the ribozyme to cleave 13 nucleotides downstream from the 5'-end of hTERT mRNA (13-ribozyme) exhibited the strongest telomerase-inhibitory activity, and the ribozyme to cleave 59 nucleotides upstream from the poly(A) tail showed clear activity. Stable transfection studies confirmed that the 36-ribozyme as well as the 13-ribozyme suppressed telomerase. These observations suggest that the template region of hTR and 5'end of hTERT mRNA are promising target sites for ribozymes to reduce telomerase activity.

To characterize serial findings of the middle cerebral artery (MCA) and umbilical artery (UA) flow patterns, their relationship to each other, and neonatal outcomes in growth-restricted fetuses.Serial pulsatility indices (PIs) from MCA and UA Doppler waveforms were measured in 41 growth-restricted fetuses until Cesarean delivery. We found three patterns, as follows: phase 1 (n = 27), UA PIMCA PI (no brain-sparing effect); phase 2 (n = 11), UA PIMCA PI (brain-sparing effect); phase 3 (n = 3), both PIs elevated with the absence of end-diastolic flow or presence of reverse end-diastolic flow, which was designated as the 'breakdown of the brain-sparing effect'. Umbilical cord blood gas data at delivery were compared between each group.Age at delivery and body weights were significantly different for each phase. The mean body weights in all phases were significantly diminished from Japanese standard body weights, indicating growth restriction. The phase 3 pH and base excess were significantly different from those of the other two phases.Growth-restricted fetuses which suffered from the state of breakdown of the brain-sparing effect were delivered early with severe growth restriction and mild metabolic acidosis. The change from decreased to increased MCA PI along with increasing UA PI may predict a severely growth-restricted infant.

The frequency and the antibacterial sensitivity of Streptococcus pneumoniae strains isolated from 6 key hospitals (in 5 areas) and 1 otorhinolaryngology clinic in Gifu Prefecture from February to March, 1999, were investigated with several antibiotics. A total of 128 strains of Streptococcus pneumoniae were isolated throughout the study: 47 strains (36.7%) of penicillin-susceptible S. pneumoniae (PSSP), 51 strains (39.8%) of penicillin-intermediate S. pneumoniae (PISP), and 30 strains (23.4%) of penicillin-resistant S. pneumoniae (PRSP); the resistant bacteria being relatively prominent. In these hospitals, PSSP was isolated by 38.8% in all the key hospitals and by 30% in the otolaryngology clinic with almost no discernible difference. PISP was isolated by 63.3%, higher in the otolaryngology clinic and PRSP by 28.6%, higher in the key hospitals conversely. The MIC90s in PISP and PRSP were determined with the antibiotics. In result, only cefditoren (CDTR) showed favorable antibacterial activities with the MIC90 of 0.78 microgram/ml among penicillins or oral cephems. The MIC90s of carbapenems such as imipenem (IPM), meropenem (MEPM), and panipenem (PAPM) were less than 0.39 microgram/ml; particularly, PAPM showed the highest antibacterial activities. Among new quinolones such as tosufloxacin (TFLX), levofloxacin (LVFX), sparfloxacin (SPFX), and ciprofloxacin (CPFX), TFLX showed the highest antibacterial activities with the MIC90 of 0.39 microgram/ml. Other agents showed very low antibacterial activities as the MIC90s were 25 micrograms/ml in minocycline (MINO) and more than 100 micrograms/ml in clarithromycin (CAM) and clindamycin (CLDM).

7-Hydroxystaurosporine (UCN-01) is a novel antitumor agent as well as a potent inhibitor of a variety of protein kinases with a preference to protein kinase C. Because an intimate interaction exists between PKC signaling and the ER signaling pathways, sex steroid agonists/antagonists might modulate the cytotoxicity of UCN-01.Effects of sex steroid agonists and antagonists on the UCN-01 cytotoxicity were analyzed by MTT assay in MCF-7/WT and MCF-7/ADR, a multiple drug resistance phenotype lacking ER and PR.MCF-7/ADR is 23-fold more resistant to UCN-01 than MCF-7. In MCF-7/WT, danazol and mifepristone enhanced the cytotoxicity of UCN-01, while these agents did not exert any significant effects on it in MCF-7/ADR.These results suggest that danazol or mifepristone might enhance the antitumor activity of UCN-01 in hormone-dependent cancer cells by interacting with PR.

Screening group B Streptococcus (GBS) in the vagina of pregnant women and measuring serum level of its type-specific antibody would be useful for cost-benefit of the prevention against GBS infection.The subjects included a total of 1,150 pregnant women who consented to the study. Serotypes of GBS detected were classified with antiserum. Serum type-specific antibody titers were measured by a bacterial agglutination method.Of a total of 1,150 pregnant women, 250 cases (21.7%) had GBS in the vagina. The turn of GBS serotype occurrence was types VI (NT6) (27. 2%), VIII (JM9) (25.2%), III (11.2%), Ia (8.8%), and Ib (8.0%). None or low type-specific antibody titer was 41.0% of Ia, 20.0% of Ib, 22. 0% of II, 15.0% of III, 65.0% of VI, and 69.0% of VIII incarriers. Noneonatal GBS infection occurred under the empirically treatment.The measurement of serum type-specific antibody against GBS would be informative for the cost-benefit treatment of the vaginal GBS in pregnant women.

Serum platelet-derived endothelial cell growth factor (PD-ECGF) in patients with uterine cervical cancers revealed a significantly positive correlation with clinical stage and tumor size and with the advancement indicators lymph node metastasis, parametrial involvement, and vessel permeation in both squamous cell carcinomas and adenocarcinomas. The prognosis of the patients with high serum PD-ECGF was extremely poor, whereas the 36-month survival rate of the other patients with low serum PD-ECGF was 81.3% in squamous cell carcinomas and 80.0% in adenocarcinomas. Our data indicate that serum PD-ECGF levels reflect the status of advancement of uterine cervical cancers and thus may be recognized as a novel tumor marker for both squamous cell carcinomas and adenocarcinomas of the uterine cervix.

There was a significant correlation between microvessel counts and interleukin (IL)-8 levels and between infiltrated macrophage counts and IL-8 levels in uterine cervical cancers. Immunohistochemical staining revealed that the localization of IL-8 was similar to that of CD68 for macrophages. The prognosis of the 20 patients with high IL-8 (1000 pg/mg protein) in uterine cervical cancers was extremely poor, whereas the 24-month survival rate of the other 60 patients with low IL-8 (1000 pg/mg protein) was 67%. Therefore, this indicates that IL-8 might be a prognostic indicator as an angiogenic factor supplied from macrophages within and around the tumor.

In addition to its hypophysiotropic action, gonadotropin-releasing hormone (GnRH) can modify activity in extrapituitary organs and peripheral tumors. GnRH analogs are the preferred treatment for advanced and even metastatic or recurring carcinomas in vivo and in vitro. Hormone-responsive tumors undergo apoptosis with the appropriate stimulus; GnRH-induced tumor growth arrest may result from stimulated apoptotic cell death. The sensitivity of tumors and normal tissue to GnRH is strongly associated with the possession of receptors for GnRH as well as other hormonal control. Despite the lack of a precise apoptotic signaling cascade through GnRH receptors, biochemical events observed within a plasma membrane appear to constitute the most convincing evidence that the membrane event is primarily stimulated during cell activation by GnRH. GnRH receptors in tumors differ from those in pituitary gonadotrophs in some aspects, in particular with regard to the transmembrane signaling cascade. The intramembranous phenomena that occur independently of the contribution of other organelles upon tumoral GnRH receptor engagement include (i) activation of phosphotyrosine phosphatase and loss of phosphotyrosine from the endogenous membrane protein and (ii) phosphoinositide and perhaps sphingomyelin cleavage producing lipid-originated second messengers. GnRH has also been demonstrated to increase Fas ligand expression within plasma membrane, which is known to promote apoptotic cell death through attack on Fas-positive cells within tumors. The Fas-Fas ligand complex might, at least in part, account for the antiproliferative action of the hormone. An understanding of the relationship between the extracellular (hormonal) stimuli that leads to cell death and the intracellular events regulating growth arrest on GnRH action may fundamentally help clarify the therapeutic approach to all hormone-dependent carcinomas that respond to stimuli that lead to apoptosis. In this chapter, we review the recent literature and the results of our studies on GnRH-induced membrane events and summarize what is currently known about this promising antiproliferative function.

The injectable cephalosporin cefpirome (CPR) was launched in Japan in 1993. It has widely been used in the various infectious diseases. We therefore studied the clinical and bacteriological efficacy of CPR against infections caused by Bacteroides species, Prevotella species and Porphyromonas species frequently isolated from the obstetric and gynecologic infections. Thirteen institutions were involved in this study which ran from March 1994 to January 1999. The administration dosage of CPR was 2 to 4 gram per day administered by drip infusion or intravenous infusion. The duration of treatment was from 3 to 15 days. The evaluations were performed before and after the treatment. CPR was administered to 194 patients with obstetric and gynecologic infections, and 146 of 194 cases were acceptable for the evaluation of drug efficacy. Bacteroides species were identified in 102 patients. Clinical efficacy in 146 cases was excellent in 12 patients, good in 110, fair in 9 and poor in 15 patients. The eradication rate for Bacteroides species could be in 37 cases out of 54 evaluable cases; Prevotella species in 38 out of 49; and Porphyromonas species in 5 out of 5. The overall assessment of bacteriological efficacy was "eradicated" in 91 cases out of 133 (68.4%). Adverse reactions including abnormal findings in laboratory tests were seen in 8 patients (4.76%). Based on these results, CPR promises efficacy and safety in the treatment of obstetric and gynecologic infections due to Bacteroides species.

The in vivo efficacy of levofloxacin (LVFX), one of the most standard new quinolone antimicrobial agents, in the different treatment schedules of Chlamydia trachomatis uterine cervicitis in women was evaluated. Cervical C. trachomatis was detected by polymerase chain reaction. LVFX at a dosage of 300 mg t.i.d. for 5, 7 and 14 days was orally administered to 18, 33 and 35 Japanese patients, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rate in 5-, 7- or 14-day cases was 44.4, 87.9 or 88.6%, respectively. The recurrence rate of 5-, 7- or 14-day cases was 50.0, 0 or 0%, respectively. Seven-day treatment with LVFX is adequate for and effective in C. trachomatis uterine cervicitis.

An investigation was carried out to determine the therapeutic effect of levofloxacin (LVFX) once-a-day oral therapy at the dose of 200 mg/day for 7 days on uterine cervicitis, in comparison with LVFX twice-a-day oral therapy at the dose of 200 mg/day for 7 days. Of the 102 patients enrolled in the study, 90 were subjected to the analysis. The efficacy rate on uterine cervicitis of the once-a-day therapy and twice-a-day therapy groups according to the evaluation of the Drug Efficacy Evaluation Committee were 72.0% (36/50) and 82.5% (33/40), respectively. The efficacy rate on uterine chlamydial cervicitis of the once-a-day therapy and twice-a-day therapy groups according to the evaluation of the Drug Efficacy Evaluation Committee were 88.0% (22/25) and 85.7% (18/21), respectively. Safety was evaluated as "safe" in 88 of the 90 assessable patients (97.8%). Side effects were seen in two cases, which belong to the once-a-day therapy group; mild candidiasis and mild breast distension sense. As the antimicrobial treatment started, the levels of the inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8) in the cervical mucus, decreased. It is suggested that IL-6 and IL-8 can be useful indicators of the antimicrobial treatment in the uterine cervicitis. These results suggested that the LVFX once-a-day therapy can be useful on uterine cervicitis.

A 34-year-old woman with secondary amenorrhea is reported. She had a 30-day regular cycle menstruation from 12 to 24 years old. Her hormonal examination showed hypogonadotropic, secondary ovarian functional defect, and hyperprolactinemia. Her chromosomal arrangement was 46, XX, 13ph+ which is the elongation of 13p.

To evaluate in vivo efficacy of macrolides; erythromycin (EM) and clarithromycin (CAM), in the different treatment schedules of Chlamydia trachomatis uterine cervicitis im women. Cervical C. trachomatis was detected by the polymerase chain reaction. EM was orally administered to 8, 15 and 18 Japanese patients, at a dosage of 600 mg, t.i.d. for 5, 7 and 14 days, respectively. CAM was orally administered to 10, 26 and 19 Japanese patients at a dosage of 400 mg, b.i.d. for 5, 7 and 14 days, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rates after 5, 7 or 14 days of treatment with EM were 1/8, 8/15 or 13/18, respectively. The recurrence rates after 5, 7 or 14 days of treatment with EM were 1/1, 3/8 or 2/13, respectively. On the other hand, the eradication rates after 5, 7 or 14 days of treatment with CAM were 5/10, 26/26 or 19/19, respectively. The recurrence rates after 5, 7 or 14 days of treatment with CAM were 3/5, 0/26 or 0/19, respectively. A 7-day treatment with CAM would be adequate and effective for C. trachomatis uterine cervicitis.

Prevotella bivia is common in pelvic inflammatory diseases. Parenteral antimicrobial agents have been widely used against those infections. We investigated the bactericidal activities of three cephalosporins, i.e. cefluprenam (CFLP), ceftazidime (CAZ) and cefotaxime (CTX) and of two other antimicrobial agents, i.e. clindamycin (CLDM) and imipenem (IPM) against P. bivia. We also investigated the in vitro morphological changes induced by these agents in P. bivia. Cephalosporins exhibited bactericidal activities against P. bivia and induced time- and concentration-dependent morphological changes in P. bivia (filamentation). CLDM and IPM also had bactericidal activities, but induced different morphologic alterations: formation of spheroblasts and lysis. These results confirm the fact that each antimicrobial agent has characteristic aspects.

The effects of the extension of transit times on qualitative and quantitative bacterial culture after clinical sampling were investigated with the clinical samples, using the bacterial flora from the cancer portion inside the uterine cervix in 25 patients with the uterine cervical cancer. In the qualitative bacterial study, the strains of both aerobic and anaerobic bacteria detected were rather preserved for 6 hours after clinical sampling and decreased in a time-dependent manner in the samples of more than 6 hours after clinical sampling. In particular, number of anaerobic bacterial species detected remarkably decreased in the samples of more than 12 hours after clinical sampling. Therefore, prompt bacterial culture after clinical sampling, possibly within 6 hours after clinical sampling, may be crucial in order to detect most probable pathogenic anaerobic bacteria, particularly when anaerobic infection is suspected. In the quantitative bacterial study, the quantity of bacteria detected were rather preserved for 3 hours after clinical sampling and decreased in a time-dependent manner in the samples of more than 3 hours after clinical sampling. Therefore, quantitative bacterial culture should be performed within 3 hours after clinical sampling.

The platelet-derived endothelial cell growth factor (PD-ECGF) level was significantly (P0.05) increased in 8 of 40 metastatic lymph node lesions of uterine cervical cancers. The prognosis of the eight patients with high PD-ECGF (10,000 pg/mg protein) in metastatic lymph node lesions was extremely poor. On the other hand, the 24-month survival rate of the 32 patients with low PD-ECGF (10,000 pg/mg protein) in metastatic lymph node lesions was 75%. This indicates that PD-ECGF may contribute to the advancement of metastatic lesions, and that the PD-ECGF level in metastatic lesions may be a prognostic indicator.

Escherichia coli is one of the most common aerobic bacteria in pelvic inflammatory diseases. Oral cephalosporins have been widely used against those infections. We investigated in vitro morphologic changes induced on E. coli by a new oral cephalosporin, E1100, and its bactericidal activity on this organism. Morphologic changes were observed by electron microscopy. E1100 induced morphologic changes (filamentation) and exerted a bactericidal activity on E. coli. The filamentation induced by E1100 was time and concentration dependent.

An investigation was carried out to determine the therapeutic effect of panipenem/betamipron (PAPM/BP), a injectable carbapenem antimicrobial agent, on infections in pregnant women during perinatal period. Of the 41 patients enrolled in the study, 34 were subjected to the analysis, with 1 exemption because of protocol violations (regimen), 3 because of uncertain evidence symptoms of infection, and 3 because of failure to undergo laboratory tests. PAPM/BP was administered by intravenous drip infusion at doses of 0.5 g twice or three times a day daily for periods of 3 to 14 days. The efficacy rate according to the evaluation of the Drug Efficacy Evaluation Committee and the attending physicians was 79.4% (27/34), with 49 of the 61 clinical isolates (80.3%) being eradicated. Safety was evaluated as "safe" in 39 of the 41 assessable patients (94.1%). Mild headache and nausea were experienced by 1 patient (2.4%) as adverse drug reactions, but the symptoms disappeared after the completion of treatment. Slight elevations of GOT, GPT and LDH in laboratory tests were observed in 1 patient (2.4%), but these values returned to normal after the completion of treatment. These results suggested that PAPM/BP may be a useful drug in the treatment of bacterial infections during the perinatal period. To firmly establish its safety, however, further clinical and pharmacokinetic studies are needed in larger populations.

We conducted a multi-site late phase II trial of oral etoposide administered for 21 consecutive days in patients with cervical cancer in cooperation with 32 institutes. Fifty mg/body of oral etoposide was administered daily for 21 consecutive days. Treatment cycles were to be repeated at 4- to 5-week intervals. Eighty patients were enrolled and 70 patients were evaluated. The overall response rate (95% CI), including one complete response patient and 18 partial response patients, was 27.1% (19/70). The most commonly observed toxicity was myelosuppression such as leukopenia, neutropenia, hemoglobin decrease and thrombocytopenia. Other adverse effects were gastrointestinal toxicities such as anorexia, nausea, stomatitis and vomiting, as well as fatigue and alopecia. These adverse effects were well tolerated and controlled with medications. From these results we concluded oral etoposide administered for 21 consecutive days was an effective drug against cervical cancer.