Upregulation of Angiogenic Factors via Protein Kinase C and Hypoxia-induced Factor-1α Pathways under High-glucose Conditions in the Placenta

Abnormal glucose metabolism during pregnancy is an established risk factor for preeclampsia (PE). Disruption of the balance between placental angiogenic factors is linked to PE pathophysiology. We examined whether hypoxia-induced factor-1α (HIF-1α) and protein kinase Cβ (PKCβ) are involved in the regulation of placental angiogenic factors under high-glucose conditions in vitro. The human choriocarcinoma cell lines BeWo and JEG-3, and the human trophoblast cell line HTR-8/SVneo were cultured with 10 and 25 mmol/L glucose [control glucose group (CG) and high-glucose group (HG), respectively]. We examined the changes in HIF-1α, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) expression in the CG and HG by real-time PCR and ELISA. PKC activation was also measured by ELISA. The expressions of HIF-1α, sFlt-1, PlGF, and VEGF were significantly higher in the HG than in the CG. PKC activity was significantly increased in the HG. High glucose affected the expression of angiogenic factors in choriocarcinoma cells via the PKCβ and HIF-1α pathways, suggesting their involvement in PE pathogenesis

Comparison of Kidney Function between Gestational Hypertension and Preeclampsia

Although gestational hypertension (GH) is thought to be different from preeclampsia (PE), in Japan GH and PE are usually treated as the same disease (i.e., pregnancy-induced hypertension). Here we sought to determine whether there are any differences in fetal growth and maternal kidney function between pregnancies with PE and those with GH. We retrospectively analyzed 61 GH patients and 60 PE patients with singleton pregnancies who delivered at Okayama University Hospital (2008-2015). We compared maternal and perinatal outcomes and maternal kidney function parameters between the GH and PE pregnancies. The mean values of maternal age (p=0.01), gestational age at delivery (p<0.0001), placental weight (p=0.002), birth weight and height (p<0.0001, p=0.0001), and head circumference standard deviation score (p=0.007) of newborns of the GH group were significantly higher than those of the PE group. The duration until termination of PE or GH was not significantly correlated with kidney function. The birth weight percentile was significantly correlated with kidney function in PE but not GH. However, GH patients with poor kidney function and small-for-gestational age infants showed perinatal outcomes similar to those of the PE group. Monitoring kidney function is thus important for determining the severity of PE and GH

Successful Delivery after Abdominal Radical Trachelectomy, Using Transabdominal Cerclage in Early Pregnancy

Radical trachelectomy (RT) is a fertility-sparing surgery for cervical cancer. Postoperative pregnancies have a high risk of abortion and prematurity. To prevent this, a procedure involving transabdominal cerclage (TAC) was devised for shortened cervical canals post-RT. Here we describe the successful management of a pregnancy after abdominal RT (ART). The 34-year-old patient was gravida 1, para 0. When she was 27, she underwent ART for stage Ib1 cervical cancer, and she became pregnant 7 years later. Because her cervical canal was 16.7 mm during early pregnancy, we performed TAC at 12 weeks of pregnancy. Post-surgery, we administered an infusion of ritodrine hydrochloride for tocolysis. A selective caesarean section was performed at 36 weeks, with the delivery of a healthy infant

Relationship between Intracellular Signaling of the (Pro)renin Receptor and the Pathogenesis of Preeclampsia

An association between preeclampsia and (pro)renin was recently reported. Intracellular signaling of the (pro) renin receptor [(P)RR] increases the expressions of TGF-β and PAI-1. In this study we sought to clarify the involvement of (pro)renin in the pathogenesis of preeclampsia via the intracellular signaling of (P)RR on preeclampsia placentas. Activated (pro)renin plasma concentrations were compared between pregnant women with (n=15) and without (n=28) preeclampsia. The placentas were immunohistochemically evaluated with anti-HIF-1α and anti-(P)RR antibodies. HTR-8/SVneo cells were cultured under hypoxic conditions and treated with human recombinant (pro)renin. The mRNA expressions of HIF-1α, (P)RR, PAI-1, TGF-β, and ET-1 were also examined by real-time RCR. The activated (pro)renin plasma concentration was significantly higher in the third vs. the second trimester in the preeclampsia patients. HIF-1α and (P)RR expressions were significantly increased in the preeclampsia placentas. The mRNA expressions of PAI-1, TGF-β, and ET-1 were significantly increased in the experiments using recombinant (pro)renin vs. hypoxic conditions. (P)RR expression in preeclampsia placentas is increased by persistent hypoxia through the second and third trimesters, and PAI-1, TGF-β, and ET-1 production is increased via (P)RR. Our results suggest that ET-1 production via the intracellular signaling of (P)RR is important in the pathogenesis of preeclampsia

Prognostic Impact of Genetic Polymorphism in Mineralocorticoid Receptor and Comorbidity With Hypertension in Androgen-Deprivation Therapy

Mineralocorticoid receptor (MR) signaling which is closely associated with hypertension plays important roles in resistance to antiandrogen therapy in prostate cancer. However, its impact on the prognosis in androgen-deprivation therapy (ADT) has not been elucidated. Then, we investigated the impact of genetic variation in MR and comorbidity with hypertension on the prognosis in ADT. This study included 182 Japanese patients with prostate cancer treated with ADT, whose comorbidity status with hypertension were available. The associations of MR polymorphism (rs5522) and comorbidity with hypertension with clinicopathological parameters as well as progression-free survival and overall survival were examined. Clinicopathological characteristics were comparable between genetic variation in MR. However, homozygous variant in MR was associated with shorter time to castration resistance (P = 0.014) and any-cause death (P = 0.024). In patients' background, presence of comorbidity with hypertension showed the trend with lower PSA level at diagnosis and lower biopsy Gleason score, as well as significant association with less incidence of N1. Comorbidity with hypertension was associated with longer time to castration resistance (P = 0.043) and any-cause death (P = 0.046), which was diminished on multivariate analysis including age, PSA level at diagnosis, biopsy Gleason score, clinical stage, and the modality of hormonal therapy. Genetic variation in MR (rs5522) and comorbidity with hypertension were significantly and potentially associated with prognosis when treated with ADT, respectively. This suggests that the individual intensity of MR signaling may be associated with resistance to ADT and a promising biomarker in ADT

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-Inducible Transcription Factor-Based In Vivo Bioluminescence Imaging

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential

A Case of Nager Syndrome Diagnosed Before Birth

Nager syndrome is a rare disease involving severe micrognathia and upper limb shortening. In this report, we describe a case in which micrognathia of the fetus was suspected based on the observation of upper limb shortening during detailed B mode and 3D/4D ultrasonographic observation, and combined fetal MRI and 3D-CT led to a prenatal diagnosis of Nager syndrome. Upon birth, because severe micrognathia caused airway obstruction and made it difficult to spread the larynx for intubation, effective ventilation could not be carried out and a tracheostomy was necessary. Since a differential diagnosis of Nager syndrome can be made based on the fact that micrognathia typically co-occurs with upper limb shortening, it is possible to diagnose the disease before birth and prepare for life-saving measures accordingly

Kondo effect in coupled quantum dots: a Non-crossing approximation study

The out-of-equilibrium transport properties of a double quantum dot system in the Kondo regime are studied theoretically by means of a two-impurity Anderson Hamiltonian with inter-impurity hopping. The Hamiltonian, formulated in slave-boson language, is solved by means of a generalization of the non-crossing approximation (NCA) to the present problem. We provide benchmark calculations of the predictions of the NCA for the linear and nonlinear transport properties of coupled quantum dots in the Kondo regime. We give a series of predictions that can be observed experimentally in linear and nonlinear transport measurements through coupled quantum dots. Importantly, it is demonstrated that measurements of the differential conductance ${\cal G}=dI/dV$, for the appropriate values of voltages and inter-dot tunneling couplings, can give a direct observation of the coherent superposition between the many-body Kondo states of each dot. This coherence can be also detected in the linear transport through the system: the curve linear conductance vs temperature is non-monotonic, with a maximum at a temperature $T^*$ characterizing quantum coherence between both Kondo states.Comment: 20 pages, 17 figure