Upregulation of autotaxin by oxidative stress via Nrf2 activation: A novel insight into the compensation mechanism in preeclamptic placenta.

The response of autotaxin (ATX)-lysophosphatidic acid (LPA) signaling system to placental oxidative stress (OS) and its significance to preeclampsia were investigated. For this purpose, oxidative stress index (OSI) and ATX levels were measured in the serum of pregnant women with preeclampsia. The expression levels of ATX and LPA receptors were assessed in trophoblast cells under high OS and glucose deprivation/re-oxygenation (OGD/R) conditions, with particular emphasis on the antioxidative nuclear factor erythroid 2-related factor 2 (NRF2) pathway. The influence of ATX-LPA signaling on cell migration was also evaluated using the wound healing assay. ATX concentrations and OSI in the serum were found to be elevated in preeclamptic women. The serum ATX levels were also positively correlated with OSI. Trophoblast cells responded to OS by increasing ATX mRNA expression concomitantly with intranuclear translocation of Nrf2, whereas inhibition of Nrf2 activation reverted this effect. The ATX-LPA signaling pathway facilitated trophoblast cell motility after Nrf2 activation. In conclusion, OS accumulation in preeclamptic placenta may activate the ATX-LPA system in trophoblasts via the Nrf2 pathway to sustain trophoblast functionality.

Surgical resection of retinoblastoma-associated bladder leiomyosarcoma during pregnancy: a case report.

BACKGROUND: Management of a bladder tumor during pregnancy is an uncommon clinical situation. Leiomyosarcoma of the urinary bladder is a rare histological type of bladder tumor and a rare secondary cancer in survivors of retinoblastoma (RB). However, there has been no report of RB-associated bladder leiomyosarcoma during pregnancy. CASE PRESENTATION: A 37-year-old pregnant woman with a medical history of RB in infancy presented with gross hematuria at the 17th week of gestation. Cystoscopy revealed a 40-mm papillary tumor on the left lateral wall of the urinary bladder. At the 25th week of gestation, she underwent transurethral resection of the bladder tumor, and the pathological diagnosis was bladder leiomyosarcoma with loss of RB1 expression. At the 31st week of gestation, she gave birth by caesarean section. One month after the delivery (to allow for involution of the uterus), she underwent partial cystectomy, and the specimen contained no residual leiomyosarcoma tissue. CONCLUSIONS: We have reported a case of RB-associated bladder leiomyosarcoma that was successfully treated during and after pregnancy.

The head direction to the angle of progression ratio: a quantitative parameter for intrapartum evaluation of cephalic malposition.

BACKGROUND: No previous study has evaluated the transitions of intrapartum transperineal ultrasound parameters during labor progression in cephalic malposition. OBJECTIVE: We aimed to quantitate the characteristic trends of fetal head position and descent in cephalic malposition by analyzing the transitions of intrapartum transperineal ultrasound parameters and explore an indicator associated with the degree of cephalic malposition. STUDY DESIGN: We retrospectively analyzed pregnant women who delivered at term from January 2018 to December 2020 at the University of Tokyo Hospital. The fetal occipital position was classified as occiput anterior and nonocciput anterior according to the fetal occipital angle of 0° to 75° and 75° to 180°, respectively. Fetal occipital angle was defined by the midline angle and position of the ocular orbit. The differences in the trends of head direction, head-symphysis distance, and progression distance relative to the angle of progression between occiput anterior and nonocciput anterior cases were evaluated. In addition, the parameters that showed differences were analyzed to evaluate their relationship to the degree of cephalic malposition. RESULTS: A total of 502 images (occiput anterior, 319; nonocciput anterior, 183) met the inclusion criteria. The distribution of head direction values relative to the angle of progression was smaller in the nonocciput anterior group than in the occiput anterior group, whereas the head-symphysis distance and progression distance values relative to the angle of progression showed no difference in their distribution between the occiput anterior and nonocciput anterior groups. The ratio of head direction to the angle of progression was significantly smaller in the nonocciput anterior group than in the occiput anterior group (median [interquartile range], 0.03 [-0.02 to 0.10] vs 0.21 [0.12-0.28]; P<.0001). Furthermore, this ratio was negatively correlated with fetal occipital angle (Spearman correlation coefficient, -0.66). CONCLUSION: Our results indicated that the head direction to angle of progression ratio reflects the deviation in the fetal head direction toward the maternal dorsal side, and decreases in proportion to the degree of cephalic malposition. This concept of deviation in the head direction as an indicator for evaluating cephalic malposition with intrapartum transperineal ultrasound may contribute to improving labor management in the case of cephalic malposition.

The impact of fetal growth restriction in diagnosing preeclampsia on the severity of maternal features.

AIM: We aimed to assess the impact of fetal growth restriction (FGR) as a diagnostic criterion for preeclampsia (PE) on the severity of maternal preeclamptic features by comparing it with other diagnostic criteria for PE, maternal organ dysfunction. METHODS: We performed a retrospective cohort study of singleton pregnancies. Based on the status at diagnosis, PE cases preceded by FGR without maternal organ dysfunction (Group F; n = 28) and those preceded by maternal organ dysfunction without FGR (Group M; n = 87) were analyzed. RESULTS: Group F had an earlier PE diagnosis (32.5 ± 4.9 vs. 36.7 ± 3.5 weeks, p < 0.01) and delivery (33.7 ± 4.5 vs. 37.5 ± 3.1 weeks, p < 0.01) than Group M. No significant differences in maternal morbidities were observed between the groups, including severe hypertension (75.0 vs. 60.0%), need for intravenous antihypertensives (42.9 vs. 48.3%) or magnesium sulfate (60.7 vs. 54.5%), or a composite of major maternal complications (17.9 vs. 21.8%). When limited to early-onset PE diagnosed before 34 weeks of gestation (17 and 17 cases in Group F and M, respectively), the frequencies of maternal morbidities (severe hypertension: 70.6 vs. 52.9%, intravenous antihypertensives: 35.3 vs. 35.3%, magnesium sulfate: 58.8 vs. 47.1%, major complications: 29.4 vs. 23.5%) and the duration from diagnosis until delivery (11.2 ± 14.7 vs. 16.5 ± 21.7 days) were comparable between two groups. CONCLUSIONS: Our results suggest that the presence of FGR on PE diagnosis is associated with the development of severe maternal symptoms as much as that of maternal organ dysfunction at diagnosis, and it may be reasonable to include FGR in PE diagnostic criteria.

Ultrasonographic vascularity assessment for predicting future severe hemorrhage in retained products of conception after second-trimester abortion.

Objectives: To investigate the spontaneous outcomes of vascularized retained products of conception (RPOC) detected by ultrasonography after second-trimester abortion, and to identify the predictive factors for the development of severe postpartum hemorrhage (SPPH).Study design: This is a retrospective cohort study on all cases after second-trimester abortion managed at our institute between January 2014 and December 2016. We assessed the associations between the occurrence of SPPH requiring invasive treatment and clinical factors including ultrasonographic findings (size and the vascularity status of RPOC classified as follows: type 1: vascularity confined to endometrium, type 2: vascularity reaching <1/2 myometrium, and type 3: vascularity reaching ≥1/2 myometrium) in vascularized RPOC cases.Results: Among 103 cases after second-trimester abortion, 19 patients (18.4%) were diagnosed as RPOC, and five patients eventually failed expectant management due to SPPH. Of them, 66.7% (4/6) of patients with type 3 developed SPPH as compared with 7.7% (1/13) of patients with type 1/type 2 (p < .05). The maximum vascularized mass diameter was significantly greater among the five patients who experienced SPPH than among the 14 patients who demonstrated spontaneous remission (43.0 ± 12.0 mm versus 20.7 ± 8.3 mm, p < .01). Patients with type 3 RPOC and a maximum vascularized mass diameter ≥30 mm, compared with other patients, demonstrated sensitivity, specificity, and risk ratio related to SPPH of 80, 92.9%, and 11.2, respectively.Conclusions: Our findings suggest that the ultrasonographic assessment of RPOC focused on the depth of vascularity in combination with the measurement of its size appears to be essential in determining women with RPOC who are at high risk for SPPH.

Secretory leukocyte protease inhibitor and progranulin as possible regulators of cervical remodeling in pregnancy.

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (<35 mm) and with a history of threatened PD. In women with short cervix, cervical SLPI concentrations were positively correlated with inflammatory cytokines, interleukin-6 (R2 = 0.75) and interleukin-8 (R2 = 0.71). In pregnant mice, cervical mRNA expressions of PGRN and SLPI were increased in response to progesterone supplementation and were suppressed by a progesterone antagonist, mifepristone. Lipopolysaccharide-induced inflammation caused remarkable upregulation in cervical SLPI mRNA level but not in PGRN. Progesterone and local inflammation are the factors controlling expression levels of PGRN and SLPI at the cervix. The observed relationship of PGRN and SLPI levels in the cervical mucus with PD-related clinical parameters supports that those anti-inflammatory molecules possibly play a significant role in appropriate regulation of cervical remodeling.

Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell-mediated pregnancy loss in mice.

OBJECTIVE: Tokishakuyakusan (TSS) is a traditional herbal medicine that has been used empirically to prevent recurrent pregnancy loss. Its mode of action remains unclear. With their potent capacity to produce cytokines, invariant natural killer (iNKT) cells are involved in the control of fetomaternal immunity in early gestation. This study aimed to clarify the effect of TSS on iNKT cell activities in a well-studied murine miscarriage model. METHODS: Pregnant mice were fed 1% TSS-containing or control diet from the day of vaginal plug formation. Alpha-galactosylceramide (AGC) was administered intraperitoneally to the pregnant mice at day 9.5 postcoitus (pc) to stimulate iNKT cells. Peripheral cytokine levels were evaluated using cytokine arrays. The percentage of iNKT cells among splenocytes was examined by flow cytometric analysis. The incidence of pregnancy loss was assessed at day 12.5 pc. RESULTS: The ratio of fetal resorptions to total conceptuses was significantly higher in the group exposed to TSS (34%) than in controls (78%). A rapid and robust surge in inflammatory cytokines, including IFN-γ and TNF-α, was detected in the peripheral blood of control animals 2 hours after AGC administration. This peripheral cytokine induction was significantly attenuated in the TSS-fed group compared with the control. The percentage of iNKT cells among total splenocytes was lower in the TSS-fed group than in controls. CONCLUSION: The findings in this study suggest that the inhibitory effects of TSS on pregnancy loss may involve immune modulation of iNKT cells during early pregnancy.

Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice.

OBJECTIVE: This study aimed to investigate the association of Th1/Th2 polarity induced by CD1d-restricted invariant natural killer T (iNKT) cells with pregnancy outcome. METHODS: Two types of iNKT cell stimulants with different cytokine induction properties, alpha-galactosylceramide (AGC; Th1-biased inducer), and a sphingosine-truncated derivative of AGC (OCH; Th2-biased inducer) were administered to pregnant mice on day 9.5 post-coitus (pc), and the incidence of pregnancy loss was evaluated. Serum Th1/Th2 cytokine levels after the iNKT cell stimulations were assessed. Cytokine production from cultured splenocytes following iNKT cell activation was analyzed. RESULTS: No fetal loss was observed after OCH administration, in clear contrast with the high frequency of pregnancy loss after AGC exposure. High serum levels of IL-4 and IL-10 were detected upon OCH administration, whereas a temporary surge of IFN-γ was observed after AGC administration. In splenocyte cultures, increases in IL-4 and IL-10 were noted after OCH administration, whereas IL-12 production was enhanced by AGC. Additionally, AGC-induced pregnancy loss was inhibited by IL-4 administration. CONCLUSION: The resistance of mouse pregnancy to iNKT cell stimulation by OCH and the prevention of AGC-induced fetal loss by IL-4 were demonstrated. In pregnancy, the regulation of Th1/Th2 polarity by iNKT cells is a key to healthy fetal growth.

Risk factors and a prediction model for lower limb lymphedema following lymphadenectomy in gynecologic cancer: a hospital-based retrospective cohort study.

BACKGROUND: Lower limb lymphedema (LLL) is a chronic and incapacitating condition afflicting patients who undergo lymphadenectomy for gynecologic cancer. This study aimed to identify risk factors for LLL and to develop a prediction model for its occurrence. METHODS: Pelvic lymphadenectomy (PLA) with or without para-aortic lymphadenectomy (PALA) was performed on 366 patients with gynecologic malignancies at Yaizu City Hospital between April 2002 and July 2014; we retrospectively analyzed 264 eligible patients. The intervals between surgery and diagnosis of LLL were calculated; the prevalence and risk factors were evaluated using the Kaplan-Meier and Cox proportional hazards methods. We developed a prediction model with which patients were scored and classified as low-risk or high-risk. RESULTS: The cumulative incidence of LLL was 23.1% at 1 year, 32.8% at 3 years, and 47.7% at 10 years post-surgery. LLL developed after a median 13.5 months. Using regression analysis, body mass index (BMI) ≥25 kg/m2 (hazard ratio [HR], 1.616; 95% confidence interval [CI], 1.030-2.535), PLA + PALA (HR, 2.323; 95% CI, 1.126-4.794), postoperative radiation therapy (HR, 2.469; 95% CI, 1.148-5.310), and lymphocyst formation (HR, 1.718; 95% CI, 1.120-2.635) were found to be independently associated with LLL; age, type of cancer, number of lymph nodes, retroperitoneal suture, chemotherapy, lymph node metastasis, herbal medicine, self-management education, or infection were not associated with LLL. The predictive score was based on the 4 associated variables; patients were classified as high-risk (scores 3-6) and low-risk (scores 0-2). LLL incidence was significantly greater in the high-risk group than in the low-risk group (HR, 2.19; 95% CI, 1.440-3.324). The cumulative incidence at 5 years was 52.1% [95% CI, 42.9-62.1%] for the high-risk group and 28.9% [95% CI, 21.1-38.7%] for the low-risk group. The area under the receiver operator characteristics curve for the prediction model was 0.631 at 1 year, 0.632 at 3 years, 0.640 at 5 years, and 0.637 at 10 years. CONCLUSION: BMI ≥25 kg/m2, PLA + PALA, lymphocyst formation, and postoperative radiation therapy are significant predictive factors for LLL. Our prediction model may be useful for identifying patients at risk of LLL following lymphadenectomy. Providing an intensive therapeutic strategy for high-risk patients may help reduce the incidence of LLL and conserve the quality of life.