Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model.

Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.

Surveys of postpartum depression in Miyagi, Japan, after the Great East Japan Earthquake.

This study explores the correlation between the impact of the Great East Japan Earthquake and the incidence of postpartum depression in Miyagi prefecture, Japan. The design used was a cross-sectional study with self-administered questionnaires, 6-9 months after the disaster. The results showed the prevalence of postnatal women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥9 to be 21.3 %. Multivariate analysis showed that exposure to tsunami (odds ratio, 1.80; 95 % confidence interval, 1.16-2.78) was significantly and independently associated with an EPDS score of ≥9. Postnatal women and their children should be treated as a vulnerable population, and a protective framework must be established to prepare for future devastating disasters.

Preterm birth, infection, and inflammation advances from the study of animal models.

Inflammation is a protective response mediated by both innate and adaptive arms of the immune system following exposure to a range of harmful stimuli. Although inflammation is an essential mechanism in response to challenges including tissue injury and microbiological insult, inappropriate or excessive induction of the inflammatory response is itself a well-characterized cause of morbidity and mortality in adult populations. There is currently a growing appreciation of the potential for inflammation to play an adverse role in fetal health. The expression of cytokines (notably interleukin 1beta [IL-1beta], IL-6, IL-8, and tumor necrosis factor alpha [TNF-alpha]) by either the fetal or maternal tissues has been demonstrated to upregulate the activity of a number of uterine and cervical factors (eg, prostaglandin hormones and their receptors, matrix metalloproteinases, vascular endothelial growth factor [VEGF]), leading to premature initiation of the parturition process. Herein, we review important developments in our understanding of the link between preterm birth and fetal inflammation subsequent to infection, gained from studies undertaken in animal models.

Steroid and Xenobiotic Receptor (SXR) as a possible prognostic marker in epithelial ovarian cancer.

We examined the expression of the steroid and xenobiotic receptor (SXR) and evaluated its clinical significance in human epithelial ovarian carcinoma. One hundred forty-one cases were examined using immunohistochemistry for SXR with archival specimens. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with an HSCORE > 60 were regarded as SXR-positive. Various clinicopathologic variables were examined. SXR showed significant differences in age, histology, grade, ER alpha and PR. SXR was detected in 35 of 141 (24.8%) ovarian cancer tissues. There was a statistically significant negative correlation between SXR-positive status and both disease-free survival and overall survival (P= 0.0415 and 0.0316, respectively), independent of stage (P= 0.0167 and 0.021, respectively). In multivariate analysis, SXR was a statistically independent risk factor for both disease-free survival and overall survival (P= 0.049 and 0.0354). Our results support an association of SXR between ER alpha and PR in epithelial ovarian cancers. Our data suggest that SXR is a prognostic factor in epithelial ovarian cancer and may represent a useful marker to identify patients at risk of recurrence or death.

Case-control study of coffee consumption and the risk of endometrial endometrioid adenocarcinoma.

This study examined the association between coffee consumption and the risk of endometrial endometrioid adenocarcinoma (EEA) in Japan by a case-control design. The cases consisted of 107 women less than 80 years of age from two medical centers who had been histopathologically diagnosed to have EEA. The controls, selected from the participants of a cancer-screening program, were 214 women, with two controls selected for each case (matched for age and for area of residence). A self-administered questionnaire containing questions to determine dietary and beverage consumption, as well as reproductive history, was distributed to the cases and controls. Conditional logistic regression analysis was used to estimate the odds ratio (OR) of EEA for three levels of coffee consumption with adjustment for potential confounding factors. The multivariate-adjusted OR of EEA for individuals in the highest tertile of coffee consumption (2 to 3 cups or more/day) was 0.4 [95% confidence interval (CI), 0.2-0.9], and that of cases in the intermediate tertile (5 to 6 times/week-1 cup/day) was 0.6 (95% CI, 0.3-1.2), relative to the individuals in the lowest tertile of coffee consumption (3 to 4 times or less/week) (P for trend=0.014). The above association was observed in postmenopausal women (P for trend=0.016), but not in premenopausal women (P for trend=0.90). This study thus revealed an inverse dose-response relationship between coffee consumption and the risk of EEA, and its strong association in postmenopausal women but not in premenopausal women.

A phase II multicenter trial of concurrent chemoradiotherapy with weekly nedaplatin in advanced uterine cervical carcinoma: Tohoku Gynecologic Cancer Unit Study.

The purpose of this study was to evaluate the effectiveness and safety of concurrent chemoradiotherapy using weekly nedaplatin for the treatment of locally advanced squamous cell carcinoma of the uterine cervix. Nedaplatin at 30 mg/m(2) was administered weekly 6 times with a concurrent external beam and intracavity radiotherapy. External beam radiation was delivered with a fraction dose of 2 Gy per day for 5 days a week during a 5-week period and intracavitary brachytherapy, of which the fraction size is 6 Gy to point A, was given once a week for a total of 4 times using a remote after-loading system. Forty-five patients were enrolled in this trial between April 2003 and December 2006. Of the 45 patients, 40 (88.9%) completed the scheduled treatment and were evaluated for efficacy and safety. Of these, 4 were stage Ib2, 12 were stage IIb, 18 were stage IIIb and 6 were stage IVa. The age distribution ranged from 27 to 79 years with a median age of 58. The 40 patients achieved an objective response, 36 (90%) a complete response and 4 (10%) a partial response. At a median follow-up of 29 months (range, 8-52), the 3-year progression-free and overall survival were 58.7% (95% confidence interval, 42-75%) and 78.0% (95% confidence interval, 56-90.0%), respectively. Acute toxicities were transient and rendered non-lethal. Of the 45 patients enrolled for the trial, only 3 (6.7%) had grade 4 leukopenia and neutropenia, respectively. Grade 3 diarrhea and nausea/ vomiting were observed in 2 (4.4%) and 1 (2.2%), respectively. These results indicate that weekly nedaplatin of 30 mg/m(2) with concurrent radiotherapy is an effective and well-tolerated regimen for advanced squamous cell carcinoma of the uterine cervix.

Selective accumulation of PpIX and photodynamic effect after aminolevulinic acid treatment of human adenomyosis xenografts in nude mice.

OBJECTIVE: To evaluate the effect of photodynamic therapy with aminolevulinic acid (ALA) on human adenomyosis xenografts in a mouse model. DESIGN: Human adenomyosis tissues were implanted SC into nude mice. We measured 5-aminolevulinic acid pharmacokinetics in these mice by analyzing tissue sections 1 to 6 hours after intraperitoneal administration. Twenty-four hours after photodynamic therapy, we evaluated tissue morphologic features. SETTING: Department of obstetrics and gynecology at a university hospital in Japan. PATIENT(S): Immunodeficient mice. Tissue grafts were taken from women with adenomyosis attending a university hospital. INTERVENTION(S): Photodynamic treatment. MAIN OUTCOME MEASURE(S): Peak fluorescence after intraperitoneal ALA administration and tissue histological changes 24 hours after photodynamic therapy. RESULT(S): Peak fluorescence was observed 3 hours after intraperitoneal administration. Histological studies revealed decreased numbers of epithelial and stromal cells in adenomyosis models after therapy. CONCLUSION(S): Photodynamic therapy with ALA caused extensive cell death in human adenomyosis tissues implanted into nude mice. Photodynamic treatment using ALA is a potential treatment for patients with adenomyosis uteri.

Intramanchette transport during primate spermiogenesis: expression of dynein, myosin Va, motor recruiter myosin Va, VIIa-Rab27a/b interacting protein, and Rab27b in the manchette during human and monkey spermiogenesis.

AIM: To show whether molecular motor dynein on a microtubule track, molecular motor myosin Va, motor recruiter myosin Va, VIIa-Rab27a/b interacting protein (MyRIP), and vesicle receptor Rab27b on an F-actin track were present during human and monkey spermiogenesis involving intramanchette transport (IMT). METHODS: Spermiogenic cells were obtained from three men with obstructive azoospermia and normal adult cynomolgus monkey (Macaca fascicularis). Immunocytochemical detection and reverse transcription-polymerase chain reaction (RT-PCR) analysis of the proteins were carried out. Samples were analyzed by light microscope. RESULTS: Using RT-PCR, we found that dynein, myosin Va, MyRIP and Rab27b were expressed in monkey testis. These proteins were localized to the manchette, as shown by immunofluorescence, particularly during human and monkey spermiogenesis. CONCLUSION: We speculate that during primate spermiogenesis, those proteins that compose microtubule-based and actin-based vesicle transport systems are actually present in the manchette and might possibly be involved in intramanchette transport.

Predicting outcome of one-step total hysteroscopic resection of sessile submucous myoma.

STUDY OBJECTIVE: To analyze variables for successful 1-step hysteroscopic myomectomies of sessile submucous myomas. DESIGN: Retrospective case-control study. (Canadian Task Force classification II-2). SETTING: Single operator's practice in a university hospital and its related hospitals. PATIENTS: Twenty-eight patients with sessile submucous myomas and menorrhagia, infertility, or both. INTERVENTIONS: Our strategy for hysteroscopic myomectomy is as follows. First, we scraped and/or vaporized intrauterine dome of myoma until top of myoma was even with level of wall of cavity. Next, the remnant intramural node was squeezed by uterine contractions induced by prostaglandin F2alpha injection. Finally, the newly raised myoma dome was sectioned or vaporized electrosurgically only within the space of the intrauterine cavity and/or was separated mechanically from healthy myometrium without electrosurgery. MEASUREMENTS AND MAIN RESULTS: Submucous myomas in 16 (57.1%) patients were completely removed after 1 surgery. By logistic regression analysis, thickness of outer myometrial layer of myoma node (OR 3.06, p = .02), myoma size (OR 0.86, p = .04), and intramural extension degree (OR 0.91, p = .03) were significantly associated with outcome of complete resection. CONCLUSION: Thickness of outer myometrial layer of myoma node, myoma size, and intramural extension degree predicted outcome of 1-step hysteroscopic myomectomy. The chance of performing successful surgery increased with increased thickness of outer myometrial layer of myoma, and decreased with larger myomas and greater degrees of intramural extension.

Effect of the interaction between lipoxygenase pathway and progesterone on the regulation of hydroxysteroid 11-Beta dehydrogenase 2 in cultured human term placental trophoblasts.

Placental hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) plays an important role in pregnancy maintenance and fetal maturation. In the event of intrauterine infection, lipoxygenase (LOX) metabolites are produced in the placenta and contribute to preterm labor and adverse fetal outcomes. On the other hand, LOX metabolites are involved in production of progesterone, which is required for pregnancy maintenance. In this study, we evaluated the interaction between the LOX pathway, progesterone, and HSD11B2. Specifically, we hypothesized that LOX metabolites would alter HSD11B2 and this effect would be mediated by progesterone. We cultured human term placental trophoblasts in the presence and absence of the LOX inhibitors Nordihydroguaiaretic acid (NDGA), AA861, and Baicalein; the LOX metabolites Leukotriene B(4) and 12(S)-Hydroxyeicosatetraenoate (12-HETE); and progesterone and progesterone receptor antagonist RU486. By radiometric conversion assay, real-time quantitative PCR, Western blot analysis, and ELISA, we examined HSD11B2 enzyme activity, HSD11B2 mRNA and HSD11B2 protein expression, and progesterone output. LOX metabolites down-regulated HSD11B2 activity and HSD11B2 expression. LOX inhibitors up-regulated HSD11B2 activity and HSD11B2 and HSD11B2 expression, and these effects were attenuated by addition of LOX metabolites. Net progesterone output was increased by LOX metabolites and decreased by LOX inhibitors. Progesterone down-regulated HSD11B2 activity and HSD11B2 and HSD11B2 expression, and these effects were blocked by RU486. Furthermore, the suppressive effect of 12-HETE on HSD11B2 activity was also reversed by RU486. We conclude that HSD11B2 in human placental trophoblasts is decreased by progesterone and increased by inhibition of endogenous LOX metabolites, and that a component of the effect of LOX metabolites on HSD11B2 is mediated by their stimulation of endogenous progesterone output.

Sloughing off of a cervical myoma after cesarean section: a case report.

BACKGROUND: Occasionally a submucous myoma is sloughed off during the puerperium, but it is seldom that the initial location of the myoma is identified before its expulsion. CASE: A 32-year-old, nulliparous woman with a cervical myoma underwent an elective cesarean section at 37 weeks. At surgery a cervical myoma was identified as not endophytic to the intrauterine cavity but exophytic to the uterine exterior and was left without any intervention. Part of the cervical myoma was sloughed off into the vagina after 16 days, and an abdominal myomectomy was performed for a refractory infection. CONCLUSION: Comparison with analogous cases following intervention indicates that myoma degeneration due to blood supply depletion, uterine contractions and endometrial sparseness must be important factors in this phenomenon. When these conditions are met, a shallow, intramural myoma could be sloughed off in the puerperium.

Clinical pitfalls of pain recurrence in endometriosis arising in the posterior vaginal fornix.

Endometriotic nodules in the lower genital tract often cause dysmenorrhea and dyspareunia. We report here a case of posterior vaginal fornix endometriosis that was overlooked for several years. We performed a trans-vaginal resection after the associated pain was not relieved by repetitive gonadotropin-releasing hormone agonist (GnRHa) therapy or abdominal surgery. After the resection, the patient's symptoms disappeared. The patient subsequently conceived and proceeded to a full-term delivery. The pathological diagnosis was 'endometriosis of the vagina.' Immunohistochemical staining revealed that the progesterone receptor-positive cells outnumbered the estrogen receptor-positive cells. We emphasize that the existence of vaginal lesions should be considered in cases in which pain has not improved despite long-term GnRHa administration, or in cases involving dyspareunia. To provide appropriate treatment, attentive evaluation and careful examination of the disease are necessary for a patient with prolonged unsatisfactory progress.

Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer.

Gene silencing associated with aberrant DNA methylation of promoter CpG islands is one mechanism through which several genes may be inactivated in human cancers. Cyclin D2, a member of the D-type cyclins, implicated in cell cycle regulation, differentiation and malignant transformation, is inactivated due to aberrant DNA methylation in several human cancers. In the present study, we examined the promoter methylation status and expression of Cyclin D2 in human epithelial ovarian cancer, and then determined the relationship between methylation status and various clinicopathological variables. Twelve ovarian cancer cell lines and 71 surgical specimens were examined by methylation-specific polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction to evaluate the methylation status and expression of the Cyclin D2 gene. The relationship between methylation status and various clinicopathological variables was evaluated using statistical analysis. Aberrant methylation of Cyclin D2 was present in five of 12 ovarian cancer cell lines and 16 of 71 primary ovarian cancer tissues. In five cell lines with methylation, expression of the Cyclin D2 gene tended to be lower than in cell lines without methylation. In ovarian cancer tissues, methylation bands were detected in 16 of 71 cases. The methylation status of Cyclin D2 was associated with advanced stage and a residual tumor size (>2 cm) (P = 0.027 and P = 0.031, respectively). Based on univariate analysis, patients with aberrant methylation of the Cyclin D2 promoter had a significantly worse chance of disease-free survival than those without methylation (P = 0.021). Our results suggest that aberrant promoter methylation of the Cyclin D2 gene is significantly associated with patient prognosis in epithelial ovarian cancer.

Effects of photodynamic therapy using 5-aminolevulinic acid on cultured human adenomyosis-derived cells.

OBJECTIVE: To evaluate the potential of photodynamic therapy with aminolevulinic acid (ALA) on human adenomyosis-derived cells compared with endometrial stromal cells. DESIGN: In vitro study. SETTING: Department of Obstetrics and Gynecology, Tohoku University Hospital. PATIENT(S): Women with adenomyosis attending the University hospital. INTERVENTION(S): Photodynamic treatment. MAIN OUTCOME MEASURE(S): Cell survival rates. RESULT(S): Treatment with both ALA and irradiation caused significantly decreased survival of cells derived from human adenomyosis compared with ALA or irradiation alone. The combination of irradiation and ALA led to 79.3%, 68.0%, and 59.5% cell survival at 1.6, 4, and 8 J/cm2, respectively, whereas ALA and irradiation alone caused 92.8% and 97% survival, respectively. CONCLUSION(S): Photodynamic therapy using ALA caused extensive death of cells derived from human adenomyosis. Photodynamic treatment using ALA may be a new treatment for patients with adenomyosis uteri in the future.

Management of the pain associated with endometriosis: an update of the painful problems.

Endometriosis is a condition characterized by ectopic endometrial tissues located outside of the uterus, most commonly found on the pelvic peritoneum or ovary. Endometriosis, which occurs in 7-10% of women in the general population and 71-87% of women with chronic pelvic pain, is associated with dysmenorrhea, chronic pelvic pain, and infertility. There is considerable debate about the effectiveness of various interventions for endometriosis. This review discusses the benefits and drawbacks of pharmacologic and surgical treatments for the pain associated with endometriosis. Laparoscopic surgery has been demonstrated to relieve the pain associated with endometriosis. Hormonal therapies, such as gonadotropin-releasing hormone (GnRH) analogues or the weak androgen danazol, have also been effective at relieving the pain associated with endometriosis. Oral contraceptives appear to be as effective as GnRH analogues for pain relief. Although both surgical and pharmacologic treatments have been effective for relief of the pain associated with endometriosis, the recurrence rate remains significant. The management of pain associated with endometriosis has thus not been satisfied. Larger unified clinical trials are needed to evaluate the effectiveness of new treatments in managing the pain associated with endometriosis.

Association of maternal smoking during pregnancy and infant neurobehavioral status.

The association of maternal smoking during pregnancy with neurobehavioral status was examined in 344 Japanese infants. Based on a questionnaire, their mothers were classified into three groups, Nonsmokers, Exsmokers, and Smokers. The Neonatal Behavioral Assessment Scale was administered three days after birth. Among the three groups, on the seven clusters and their 28 behavioral subscales there were no significant differences. The infants of Smokers had lower scores than those of Exsmokers and Nonsmokers on two behavioral items, general tone and peak of excitement. General tone remained significant after adjustment for covariates.

Progesterone receptor isoforms as a prognostic marker in human endometrial carcinoma.

The possible role of specific progesterone receptor (PR) isoforms (PRA and PRB) as predictive factors in endometrial carcinoma is unclear. The present study was undertaken to evaluate the clinical significance of intratumoral PR isoform status in patients with endometrioid endometrial carcinoma. We studied 103 cases of endometrioid endometrial carcinoma using immunohistochemistry. We correlated the findings with various clinicopathological parameters of the patients. PRA and PRB immunoreactivity was detected in 51/103 (48.5%) and 79/103 (76.7%) of carcinoma cases, respectively. A significant positive correlation was detected between the status of PRB immunoreactivity and the amount of PRB mRNA by real-time reverse transcription-polymerase chain reaction (P = 0.012). PR isoform expression was significantly lower in the cases with higher histological grade (P = 0.0001 and P = 0.002, for PRA and PRB, respectively). Cases that were negative for either one or both PR isoforms were significantly associated with shorter disease-free and overall survival of the patients. The absence of either one or both of these two PR isoforms was detected in all nine patients who died (100.0%), whereas the absence of these immunoreactivities was detected only in 43 of 94 (45.7%) patients who had lived during the same period. In addition, multivariate analysis demonstrated that an absence of PRA immunoreactivity was an independent risk factor in disease-free survival of the patients (P = 0.0258). The results of our study demonstrated that loss or absence of PR isoform expression determined by immunohistochemistry could become an important prognostic indicator in patients with endometrioid endometrial carcinoma.

Successful strategy for the hysteroscopic myomectomy of a submucous myoma arising from the uterine fundus.

OBJECTIVE: To introduce a technique for hysteroscopic resection of submucous myoma arising from the uterine fundus. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 43-year-old nulliparous Japanese woman. INTERVENTION(S): An original combination technique of hysteroresectoscopy using circumferential myoma scraping, central vaporization, and intraoperative injection of prostaglandin F2alpha. MAIN OUTCOME MEASURE(S): Evaluation of clinical symptoms and imaging diagnosis. RESULT(S): Resection of a 40-mm fundal myoma was performed hysteroscopically, and the menorrhagia of the patient was remedied by the operation. CONCLUSION(S): Although large sessile fundal myomas are difficult to resect by hysteroscopic myomectomy, our original strategy may allow safe and certain surgery in such cases.

A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis xenografts via antiangiogenic activity in severe combined immunodeficiency mice.

OBJECTIVE: To investigate the effects of a selective cyclooxygenase (COX)-2 inhibitor on endometriosis xenografts in immunodeficient mice. DESIGN: Prospective placebo-controlled study. SETTING: An academic facility at a Japanese university graduate school of medicine. PATIENT(S): Eight human ovarian endometriomas from seven patients. ANIMAL(S): Twenty-three female severe combined immunodeficiency (SCID) mice. INTERVENTION(S): Human ovarian endometriomas were implanted into the peritonea of SCID mice. Vehicle alone or NS398 (a selective COX-2 inhibitor, 10 mg/kg of weight per day) were administered orally daily for 56 days after implantation. Mice were killed on the 56th day. MAIN OUTCOME MEASURE(S): Change in explants size and immunohistochemical analyses to evaluating the proliferation index, apoptosis index, microvessel density, and labeling index assessing vascular endothelial growth factor and COX-2 expression by the endometriotic lesion. RESULT(S): NS398 significantly decreased implant size in comparison to vehicle alone (NS398 [medians, with range in brackets]: 22.0% [19.0%-36.7%] vs. vehicle: 41.2% [31.0%-55.3%], P<.01). Microvessel density (85.3 per mm2 [53.9-157.0 per mm2] vs. 121.8 per mm2 [97.2-259.6 per mm2], P=.02) and the vascular endothelial growth factor (0.4 [0-1.1] vs. 0.6 [0.5-2.1], P=.03) and COX-2 (0.4 [0.4-0.5] vs. 0.6 [0.4-0.8], P=.03) labeling indices in stromal cells were significantly lower in the NS398 group than in the vehicle group. There were no differences in the proliferation or apoptosis indices between the two groups. CONCLUSION(S): Selective COX-2 inhibitors decreased the size of implants and effectively treated endometriosis.