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Aims: Up to 10% of pregnant women have preterm birth that might be refractory to current therapy. Infections and asphyxia related to preterm birth are the causes of death in the majority of neonates and therefore represent an urgent clinical need. Methods: The present article reviews the English language literature for preclinical and clinical trials and promising molecular targets on preterm labor. Results: Preterm birth is a complex heterogeneous condition. There is no current treatment for the fetal membranes once they have ruptured; therefore, essentially any treatment has to be preventative to quiesce preterm labor and prevent any spread of infection to the fetus. Modulating the pro-inflammatory process-mediated cytokine network may present a new paradigm for preterm labor treatment. There are many reports on the role of β-adrenergic agonists (betamimetics), magnesium sulfate, progesterone, oxytocin antagonist, calcium channel blocker or the Kunitz inhibitor bikunin in the treatment of preterm labor. In the present review, we have focused on the preclinical and clinical anticytokine therapy for preterm labor. The preclinical and clinical trials with bikunin reducing preterm labor exacerbations have raised the importance of usefulness and safety considerations related to this novel therapy. Conclusion: Anticytokine therapy is ready for the clinic.

The purpose of this study is to evaluate an isometric exercise (Hand-Grip test) as a method to predict pregnancy-induced hypertension (PIH). One hundred and twenty-five pregnant women were given the Hand-Grip (HG) test before the 15th gestational week. The Hand-Grip test was rated positive when the systolic blood pressure increased 15 mmHg or more during isometric exercise or decreased 14 mmHg or more immediately after isometric exercise. As a result, the Hand-Grip test had the highest sensitivity (81.8%) and specificity (68.4%) for predicting PIH, compared to other risk factors. The positive predictive value was 20% (second highest among risk factors, the actual incidence of hypertension was 8.8%), and the negative predictive value was 97.5% (highest). In conclusion, by use of a very simple Hand-Grip test early in gestation, we are able to predict PIH with the highest sensitivity.

The detection of an ovarian mass during pregnancy is often a diagnostic challenge. We describe 2 cases of ovarian endometrioma during pregnancy with marked mural nodules on the cyst wall. The sonographic and MR imaging findings mimicked ovarian cancer. Surgical intervention may still be inevitable to exclude the possibility of malignancy.

Objective Our prospective studies in Japan have found an increased ovarian cancer incidence in women with ovarian endometrioma (standardized incidence ratio, 8.95; 95% confidence intervals, 4.12–5.3). The risk increased with increasing age at ovarian endometrioma diagnosis. The goal of this study was to define the risk factor(s) of ovarian cancer development in a Japanese population with ovarian endometrioma. We also analyzed whether the predisposition toward ovarian cancer is limited to endometrioid and clear cell carcinoma. Study design A total of 6398 participants at 212 participating hospitals in Shizuoka, Japan, were enrolled in the Shizuoka Cohort Study on Endometriosis and Ovarian Cancer (SCSEOC) Trial, which had prospective and retrospective components. The follow-up period was up to 17 years (median, 12.8 years). The risks of development of ovarian cancer were assessed in 6398 women with ultrasonographically diagnosed ovarian endometriomas. Cox proportional-hazards regression function was used to estimate impact in terms of risk factors and possible development of ovarian cancer. Results The prospective study demonstrated that 46 (0.72%) of 6398 women developed histologically proven ovarian cancer and were operated upon during follow-up. Clear cell carcinoma (39%) and endometrioid adenocarcinoma (35%) were commonly observed among women with ovarian cancer. By multivariate analysis, tumor size ≥9 cm in diameter and postmenopausal women were independent predictive factors of patients with development of ovarian cancer. Conclusions Some endometriosis lesions may predispose to clear cell and endometrioid ovarian cancers. Advancing age and the size of endometriomas were independent predictors of development of ovarian cancer among women with ovarian endometrioma.

Ovarian cancer is common in women from developed countries. We designed a prospective randomized controlled trial of ovarian cancer screening to establish an improved strategy for the early detection of cancers. Asymptomatic postmenopausal women were randomly assigned between 1985 and 1999 to either an intervention group (n= 41,688) or a control group (n= 40,799) in a ratio of 1:1, with follow-up of mean 9.2 years, in Shizuoka district, Japan. The original intention was to offer women in the intervention group annual screens by gynecological examination (sequential pelvic ultrasound [US] and serum CA125 test). Women with abnormal US findings and/or raised CA125 values were referred for surgical investigation by a gynecological oncologist. In December 2002, the code was broken and the Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry were searched to determine both malignant and nonmalignant diagnoses. Twenty-seven cancers were detected in the 41,688-screened women. Eight more cancers were diagnosed outside the screening program. Detection rates of ovarian cancer were 0.31 per 1000 at the prevalent screen and 0.38–0.74 per 1000 at subsequent screens; they increased with successive screening rounds. Among the 40,779 control women, 32 women developed ovarian cancer. The proportion of stage I ovarian cancer was higher in the screened group (63%) than in the control group (38%), which did not reach statistical significance (P= 0.2285). This is to our knowledge the first prospective randomized report of the ovarian cancer screening. The rise in the detection of early-stage ovarian cancer in asymptomatic postmenopausal women is not significant, but future decisions on screening policy should be informed by further follow-up from this trial.

We describe a case of synchronous peritoneal dissemination and multiple lung metastases after surgery for stage IA primary uterine papillary serous carcinoma (UPSC) of the endometrium, revealed by an uncontrollable retention of ascites.She was initially treated with a hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy after initial presentation. Tumor recurrence, diagnosed 12 months later, has been treated with six cycles of Paclitaxel 175 mg/m(2) and Carboplatin [area under the curve 5 (Calvert Formula)] every 3 weeks and showed an advantage of this regimen. Early recurrences of the stage IA UPSC can occur and continued close surveillance is recommended. We report herein the case about this entity.

Cancer antigen-125 (CA-25) is the only marker acknowledged to have an established role in diagnosing epithelial ovarian cancer, monitoring its treatment, and detecting relapses. The optimal upper limit of the normal range for CA-125 in screening for ovarian cancer is, however, not clear. Some believe that a level exceeding 35 U/ml has predictive value in diagnosing ovarian cancer. The investigators attempted to determine the prevalence of ovarian cancer in 48,027 women aged 45-85 years who enrolled in the Shizuoka Cohort Study on Ovarian Cancer Screening trial. Of these women, 40,801 never had a CA-125 level greater than 35 U/ml and underwent transvaginal ultrasonography. CA-125 levels were measured by an enzyme-linked immunosorbent assay. Of the 40,801 women in the study, 4859 had abnormal pelvic ultrasound findings: 4741 in category 1 with simple morphology and 118 in category 2 with complex morphology. Surgery was carried out on 912 category 1 and 69 category 2 women. Ovarian cancer was diagnosed in 8 women (0.815%). Five of the 8 cancers (63%) were stage 1 lesions. The prevalence of ovarian cancer associated with abnormal ultrasound findings rose from 0.207% in women having a CA-125 level of up to 15 U/ml to 6.12% among those with CA-125 levels of 30-35 U/ml. Logistic regression analysis demonstrated that the CA-125 level significantly affected the risk of ovarian cancer. The odds ratio for ovarian cancer was 3.88 per unit increase in the CA-125 level (95% confidence interval, 3.49-4.37; P < 0.001). These findings suggest that surgically-detected ovarian cancer is not rare in women whose CA-125 levels are 35 U/ml or less-levels formerly considered to be within the normal range.

A soybean Kunitz trypsin inhibitor (KTI) interacts with cells as a negative modulator of the invasive cells. Using complementary pharmacological and genetic approaches, we provide novel findings regarding mechanisms by which KTI inhibits signaling pathways in ovarian cancer cells leading to invasion. Transforming growth factor-beta1 (TGF-beta1) directly activates Src kinase, which in turn activates ERK-phosphatidylinositol 3-kinase/Akt, the downstream targets of Src, for urokinase-type plasminogen activator (uPA) up-regulation in human ovarian cancer HRA cells. Preincubation of the HRA cells with KTI reduced the ability of TGF-beta1 to trigger the uPA expression at the gene level and at the protein level. To further elucidate the mechanism of the KTI-dependent suppressive effect of TGF-beta1-induced uPA expression and invasion, we investigated which signaling pathway transduced by KTI is responsible for this inhibitory effect. Here, we show that 1) KTI suppressed TGF-beta1-induced phosphorylation of Src, ERK1/2, and Akt by 40-60%; 2) KTI was insensitive to suppress the phosphorylation of ERK1/2 and Akt in the constitutively active (CA)-c-Src (Y529F) cells; 3) uPA expression was up-regulated in TGF-beta1-stimulated HRA cells and in unstimulated Y529F cells; 4) the addition of KTI reduced the TGF-beta1-induced increase of uPA gene and protein expression in the wild-type c-Src-transfected cells (in contrast, KTI could not inhibit uPA expression in the Y529F cells); and 5) CA-c-Src transfection resulted in a 2-fold increase in invasiveness, whereas KTI did not reduce invasion of the Y529F cells. Using additional complementary genetic approaches (CA-MEK1, CA-Akt, or kinase-dead-Akt), we conclude that KTI may suppress uPA expression and promotion of invasion possibly through one or more upstream targets of Src.

The purpose of this study is to predict pregnancy-induced hypertension (PIH) by standard methods at the first antenatal visit prior to the 12th gestational week (GW). This is a retrospective study of 1189 primipara and 957 multipara who delivered singleton babies having no major malformations after the 32nd GW. Multiple regression analysis for the development of PIH was performed using the mean arterial blood pressure (MBP), body mass index (BMI), hematocrit count at the first visit prior to the 12th GW, a family history of hypertension number of pregnancies, number of deliveries, past history of hypertension and evidence of threatened abortion as explanatory variables in primipara and multipara, respectively. We obtained a significant regression equation in both primipara and multipara. Multiple correlation coefficient for primipara was 0.40223 (p < 0.01) and for multipara was 0.50764 (p < 0.01). When MBP was over 80 mm Hg, BMI was over 23.6, a family history of hypertension was present, or a past history of hypertension was present, these variables were significantly correlated with the development of PIH both in primipara and multipara. By combining these variables, we obtained 32.7% positive predictive value, 93.5% negative predictive value, 31.7% sensitivity, and 93.7% specificity in primipara and 24.6%, 96.7%, 52.6%, and 89.8% in multipara, respectively. As the incidence of PIH was 8.7% in primipara and 5.9% in multipara, we could predict 3.7 and 4.1 times higher than the true incidence. PIH can therefore be predicted by the simple combination of MBP, BMI, a family history of hypertension, and a past history of hypertension prior to the 12th GW. It can also be predicted by the multiple-regression equation with the use of nine explanatory variables.

Problem: Preterm birth (PTB) is an oxidative stress-related disease that lacks effective therapies partly because of the poor understanding of disease pathogenesis. The aim of this manuscript was to review molecular pathways that could be responsible for the pathogenesis of PTB. Genomic and proteomic studies have started to delineate the wide array of mediators involved in this disorder. Understanding the mechanisms of the development of PTB and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for this disorder. Method of Study. This article reviews the English language literature for pathogenesis and pathophysiological studies on PTB. Several recent genomic and proteomic studies are discussed in the context of PTB biology. Results: Decidual hemorrhage has been identified histologically in the placentas of patients with PTB, which may result in high levels of free heme and iron. Several important PTB-specific genes and proteins overlap with those known to be regulated by iron. Others were genes involved in oxidative stress and detoxification. Free iron oxidatively modifies lipid and protein, leading to DNA and cell damage. This signaling pathway of PTB will be discussed as it provides new insights into regulation of inflammation, oxidative stress, and detoxification. Conclusion: This review summarizes recent advances in heme/iron-mediated signaling, the target genes thereof, and the potential challenges to the understanding of pathogenesis and pathophysiology of PTB. A novel model is proposed. Collectively, decidual hemorrhage and inflammation are considered to be major contributors to the pathogenesis of PTB. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to paraphrase the role of oxidative stress in pathogenesis of preterm birth, explain the idea of preterm birth as a “syndrome,” and summarize the potential role of early uterine bleeding in pathophysiology of preterm birth.

Activated neutrophils contribute to the development of preterm delivery. Because of its ability to suppress inflammation, bikunin, a Kunitz-type protease inhibitor, is currently in clinical trials. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on pro-inflammatory cytokine production and nuclear factor-kappaB (NF-kappaB) activation in mouse neutrophils stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show that bikunin: (i) blocks LPS-induced secretion of pro-inflammatory cytokines, including TNF-alpha and IL-1beta, in a dose-dependent manner; (ii) has an inhibitory effect on cytokine production at a concentration of 0.2 microM, reaching 65% inhibition at the highest doses of bikunin tested (5 microM); (iii) has the suppressive capacity of ERK1/2 and p38 signaling pathways; and (iv) inhibited sequentially the LPS-induced phosphorylation of IkappaB-alpha, degradation of IkappaB-alpha, and nuclear translocation of NF-kappaB. When the MAPK data are analyzed, a significant decrease in phosphorylation is not seen at 0.2 microM bikunin but is at 1.0 microM dosing. Bikunin can inhibit LPS-induced neutrophil activation and cytokine release, although it is unlikely that it works primarily through the inhibition of MAPK phosphorylation. These data suggest that such effects are important in vivo and play a major contributory role in abrogation of neutrophil-mediated inflammatory responses, such as preterm delivery.

Preeclampsia is a hypertensive disorder that is unique to pregnancy. Magnesium (Mg2+) supplementation is a potential new therapy to ameliorate development of hypertension. The aim of this work was to compare the effects of Mg2+ supplementation on systolic blood pressure (SBP) in young and aged rats. Spontaneously hypertensive rats (SHR) were divided into young (6-week-old male, n = 10) and old (16-week-old male, n = 10) groups. Each group of rats comprised two subgroups made of a control subgroup fed with normal rat chow (0.2% Mg2+, n = 5) and a high Mg2+ subgroup nourished with a Mg2+ rich diet (0.8% Mg2+, n = 5). Age-matched Wistar-Kyoto rats (WKY) were also allocated into two groups. SBP was assessed weekly for 12 weeks indirectly by the tail-cuff method. SBP increased progressively in SHR-young rats after 7 weeks. This increase was greater in the control subgroup compared to high Mg2+ subgroup at 7 weeks (p0.05). No difference in the SBP was registered between old SHR subgroups. Mg2+ supplementation does not exert antihypertensive effects in the WKY rats. In conclusion, Mg2+ supplementation may provide beneficial effect in the developmental phase of hypertension but not in established hypertension.

Objective: We performed a detailed molecular analysis of bikunin-mediated anti-inflammation (suppressive effect of cytokine release, MAP kinase activation, and nuclear translocation of NF-kB) using a truncated form of bikunin. Materials and methods: We obtained bikunin derivatives that contained O -glycoside-linked N-terminal glycopeptide (Bik-m1), N -glycoside-linked C-terminal tandem Kunitz domains (Bik-m2), bikunin lacking O -glycoside (Bik-c), asialo bikunin (Bik-a), bikunin lacking N -glycoside (Bik-n), and purified C-terminal Kunitz domain II (kII) of bikunin (HI-8). Enzyme-linked immunosorbent assay and Western blot were carried out to measure secreted TNF-α and MAP kinase activation. Results: We examined the TNF-α secretion in control and lipopolysaccharide (LPS)-treated neutrophils and did not see any changes of its protein levels in the cells pretreated with Bik-m1, Bik-m2, Bik-c, or HI-8. In all of the derivatives tested, only the derivatives that lacked N -glycoside side chain showed a significant suppression of TNF-α secretion by LPS. Only a small (21 amino acids) deletion of the N-terminal portion of bikunin (which corresponds to Bik-m2) abolished its suppressing activity of TNF-α secretion, thus suggesting that the N-terminal 21 amino acids play a critical role in anti-inflammation. Bik-m1 alone failed to show anti-inflammatory response. Bikunin failed to inhibit ionomycin-induced phosphorylation of MAP kinases. Conclusion: These data allow us to conclude that the cytokine expression was inhibited only by the O -glycoside-linked core protein without the N -glycoside side chain. Our results also suggest a possible role of bikunin for receptor-dependent MAP kinase activation.

The purpose of this study was to determine whether Akt and mammalian target of rapamycin (mTOR), downstream targets of phosphatidylinositol 3-kinase, are activated in endometriosis and ovarian cancer specimens. We measured total and phosphorylated levels of Akt and mTOR from 17 frozen ovarian cancers and 15 benign endometriosis specimens (nine from premenopausal women and six from postmenopausal women) by quantitation of signals from western blots using antibodies against these proteins. Elevated phospho-Akt was detected in ovarian cancer versus endometriosis specimens from premenopausal women and endometriosis specimens from postmenopausal women (2.3 +/- 0.45 versus 0.10 +/- 0.06 and 0.17 +/- 0.11; P < 0.05) when the western blot signal of activated kinase was normalized to total kinase levels. Elevated phospho-mTOR was detected in ovarian cancer and postmenopausal endometriosis versus premenopausal endometriosis (0.52 +/- 0.19 and 0.46 +/- 0.29 versus 0.13 +/- 0.08; P < 0.05). Expression of total kinases (normalized to beta-actin) was higher in carcinoma versus endometriosis specimens. Elevation of the active mTOR was specifically detected in postmenopausal endometriosis.

Thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. It has been shown previously that increased levels of urokinase-type plasminogen activator receptor (uPAR) correlate well with higher invasive phenotype. We examined whether thalidomide is able to suppress the expression of uPAR mRNA and protein in human ovarian cancer cell line HRA and human chondrosarcoma cell line HCS-2/8. Here, we show that: (a) thalidomide suppresses the expression of constitutive and transforming growth factor-beta1 (TGF-beta1)-induced uPAR mRNA and protein; (b) a nuclear factor kappaB (NF-kappaB) activation system (phosphorylation of IkappaB-alpha and degradation of IkappaB-alpha) is necessary for the TGF-beta1-induced increase in uPAR expression, because L-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-kappaB inhibitor, reduced the uPAR production as well as mRNA expression; (c) thalidomide failed to further strengthen L-1-tosylamido-2-phenylethyl chloromethyl ketone's action; (d) the once-daily i.p. administration of thalidomide (400 microg/g body weight/d) decreased progressive growth of HRA tumors and ascites formation in an in vivo animal model; and (e) the once-daily i.p. administration of thalidomide in combination with paclitaxel (i.p., 100 microg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. We conclude that thalidomide down-regulates constitutive and TGF-beta1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-kappaB activation. Furthermore, combination therapy with thalidomide plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian cancer dissemination.

Objective: The purpose of this study is to clarify whether the taking of a calcium dietary supplement is able to prevent the development of pregnancy-induced hypertension (PIH) in Japanese people. Study Design: Forty-five nulliparous women (Ca-group) with various high-risk factors for PIH started to take a calcium supplement (1 g/day in the form of calcium salts) from the 12th gestational week (GW). Obstetrical outcome of Ca-group was compared to that of the nullipara (n = 453) who did not take a calcium supplement during pregnancy (Non-Ca Group) and that of the nullipara (n = 413) who did not develop PIH among Non-Ca group (normotensive group). Results: The incidence of PIH in the Ca-group was 2.2%, compared to 8.8% of Non-Ca group. The decrease in blood pressure after taking calcium during the first half of the pregnancy was much greater in Ca-group than in the normotensive group. The urinary excretion of sodium and calcium and serum free calcium at the 28th GW were much lower in a woman with PIH, despite of the taking of a calcium supplement, than in the normotensive calcium group. Also, the parathyroid hormone level at the 28th GW was higher in the calcium-taking woman with PIH than in the normotensive calcium group. Conclusion: Our preliminary study suggests that among the possible effects of taking a calcium supplement are a decrease in blood pressure and the prevention of PIH in Japanese people, and that calcium metabolism might be related to the development of PIH. However, more study is needed before it will be possible to reach a final conclusion.

BACKGROUND Cytokines are produced as a consequence of photo-damaged DNA and oxidative stress in ultraviolet (UV)-exposed keratinocytes. A soybean Kunitz trypsin inhibitor (KTI) down-regulates the expression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) in tumor cells and inflammatory cells. AIM The effect of KTI on TNF-alpha production in UV-exposed primary human keratinocytes was analyzed. RESULTS We show (i) UV induced up-regulation of TNF-alpha mRNA and protein expression in keratinocytes; (ii) cells treated with KTI before UV irradiation showed a significantly lower accumulation of TNF-alpha protein in a dose-dependent manner and a reduced UV-induced up-regulation of TNF-alpha mRNA expression; (iii) KTI inhibited the induction of TNF-alpha target molecules interleukin-1beta (IL-1beta) and IL-6 proteins; (iv) UV irradiation transiently activated c-Jun N-terminal kinase (JNK) and Akt signaling but only weakly activated extracellular signal-regulated kinase (ERK) and p38; (v) KTI specifically inhibited UV-induced activation of ERK, JNK, and p38, but not Akt; (vi) treatment of cells with SP600125, a pharmacological inhibitor of JNK, predominantly suppressed UV-induced up-regulation of TNF-alpha expression; and (vii) KTI did not enhance suppression of UV-induced JNK phosphorylation by SP600125. CONCLUSIONS KTI specifically inhibited UV-induced up-regulation of cytokine expression predominantly through suppression of JNK signaling pathway.

A comparative study of intrauterine fetal resuscitation by administration of β-stimulant and maternal oxygen inhalation was performed. Type II dips in labor recovered in 18% (8/44) of the cases after maternal O2 inhalation; the effectiveness of this therapy was apparent in only the 1st stage of labor. The administration of β-stimulant (5 mg Isoxsuprine + 20 ml of 5% glucose solution) brought about recovery from fetal distress in 95% (54/57) of cases, but its effective duration was less than 30 minutes.