The TGF-ß/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta.

Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-ß1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-ß1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-ß1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-ß1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-ß1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta.

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy.

BACKGROUND: Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists. CASE PRESENTATION: A 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired. CONCLUSIONS: To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Liver disease in pregnancy.

Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre-eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non-alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up-to-date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes.

Elevated Expression of Vascular Adhesion Molecule-1, Plasminogen Activator Inhibitor-1, Cyclooxygenase-2, and Thrombomodulin in Human Umbilical Vein Endothelial Cells from Hospitalized Gestational Diabetes Mellitus Patients.

Protein expression in human umbilical vein endothelial cells (HUVECs) is a useful indicator of maternal condition and the intrauterine environment during pregnancy. Therefore, we investigated protein expression in HUVECs obtained from patients with gestational diabetes mellitus (GDM). HUVECs were prepared from the umbilical cords of GDM patients and controls who underwent planned cesarean section between 2013 and 2014 at Teikyo University Hospital (Tokyo, Japan). There were no differences in blood glucose levels between the GDM patients and controls at admission. However, pre-pregnancy body mass index (BMI) was higher in GDM patients, although the changes in gestational BMI were smaller during hospitalization. To evaluate the state of the endothelium, we examined the protein expression levels of vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, thrombomodulin (TM), endothelial nitric oxide synthase, plasminogen activator inhibitor-1 (PAI-1), cyclooxygenase-2 (COX-2), and VE-cadherin, which are altered by various factors in endothelial tissue. VCAM-1, PAI-1, and COX-2 expression was higher in HUVECs from patients with GDM than the controls. Because the pre-pregnancy BMI was higher in GDM patients, we examined the relationship between BMI and protein expression. However, the expression levels of these proteins were not correlated with pre-pregnancy BMI and were higher in HUVECs from BMI-matched GDM patients than from BMI-matched controls. Intriguingly, TM expression was also higher in HUVECs from BMI-matched GDM patients. Thus, expression of VCAM-1, PAI-1, COX-2, and TM may reflect certain factors in the intrauterine environment that are altered in hospitalized GDM patients with controlled body weight.

[Association between Job Stress and Number of Physical Symptoms among Female Nurses of Medical-university-affiliated Hospitals].

OBJECTIVES: To clarify the association between job stress and the number of physical symptoms among newly certified female nurses. METHODS: In this cross-sectional self-administered survey, we investigated 313 female nurses working at three medical-university-affiliated hospitals in February 2016. We investigated working conditions including numbers of working and on-call hours, work-life balance, Job Content Questionnaire (JCQ) scores, and 16 physical symptoms perceived more often than once a week. RESULTS: Among the 313 participants (mean age, 31.9), 57% were aged 21-29 years and 70% were single. Of the 16 physical symptoms investigated, fatigability was the most frequent complaint (66.1%), followed by lower back pain (44.7%). Univariate analysis showed that significant factors related to physical symptoms are job demands (p<0.001) and social support (p<0.001) in JCQ, binary index of supports (p<0.001), and total working hours per day (p =0.025). Multivariable-adjusted logistic regression analyses demonstrated that the likelihood of reporting a greater number (n≥3) of physical symptoms increased by 7% [95% confidence interval (CI), 2-13%] with a one-unit increase in job demand degree, and decreased by 16% (95% CI, 10-22%) in social support degree. When binary JCQ indexes were assessed, the high-support group [odds ratio (OR) 0.36; 95% CI, 0.23-0.59] was protectively associated with a greater number of physical symptoms while long working hours was significantly associated with a higher risk (OR 18%, 95% CI, 1-38%). CONCLUSIONS: Reporting a greater number of physical symptoms may be a good indicator of job stress perceived by a nurse in a university hospital setting.

Effects of gaps in priorities between ideal and real lives on psychological burnout among academic faculty members at a medical university in Japan: a cross-sectional study.

BACKGROUND: Accumulating evidence from medical workforce research indicates that poor work/life balance and increased work/home conflict induce psychological distress. In this study we aim to examine the existence of a priority gap between ideal and real lives, and its association with psychological burnout among academic professionals. METHODS: This cross-sectional survey, conducted in 2014, included faculty members (228 men, 102 women) at a single medical university in Tokyo, Japan. The outcome of interest was psychological burnout, measured with a validated inventory. Discordance between ideal- and real-life priorities, based on participants' responses (work, family, individual life, combinations thereof), was defined as a priority gap. RESULTS: The majority (64%) of participants chose "work" as the greatest priority in real life, but only 28% chose "work" as the greatest priority in their conception of an ideal life. Priority gaps were identified in 59.5% of respondents. A stepwise multivariable general linear model demonstrated that burnout scores were associated positively with respondents' current position (P < 0.0018) and the presence of a priority gap (P < 0.0001), and negatively with the presence of social support (P < 0.0001). Among participants reporting priority gaps, burnout scores were significantly lower in those with children than in those with no children (P interaction = 0.011); no such trend was observed in participants with no priority gap. CONCLUSIONS: A gap in priorities between an ideal and real life was associated with an increased risk of burnout, and the presence of children, which is a type of "family" social support, had a mitigating effect on burnout among those reporting priority gaps.

Spinal cord infarction in diabetic pregnancy: a case report.

Spinal cord infarction (SCI) is uncommon as compared to cerebral stroke. Moreover, SCI during pregnancy is rare. Here, we report a case of SCI in diabetic pregnancy, properly diagnosed, promptly treated, and a good prognosis achieved. A 38-year-old, pregnant woman, para 1, with type 1 diabetes mellitus on insulin since 14 years of age, was admitted to our hospital for paresthesia and numbness in the lower left side of the body, with movement disturbances. On the basis of the temporal profile of the onset and the multiple resonance imaging scans, SCI was diagnosed. Steroid pulse therapy and low-dose aspirin administration was initiated. Her symptoms were improved and discharged. A repeat cesarean section was performed at 37 weeks of gestation and her postoperative course was uneventful. Her daily activities were not hindered severely, though she experienced defecation discomfort.

Erythematous and bullous rash strongly indicating toxic epidermal necrolysis associated with the use of intravenous ritodrine hydrochloride.

Toxic epidermal necrolysis (TEN) is a very rare drug reaction associated with a high mortality rate. This condition warrants prompt recognition, diagnosis and treatment. Only one case report of TEN that was possibly induced by ritodrine hydrochloride, a tocolytic agent, was found in English literature. Here, we report the case of a 26-year-old pregnant woman who was suspected with TEN following the intravenous administration of ritodrine hydrochloride in the 35(th) week of gestation. An emergency cesarean section was performed because the labor pains caused systemic intolerable haphalgesia. After the surgery, intensive dermatological treatment commenced, which helped her recover from the serious condition. The result of the drug-induced lymphocyte stimulation test for ritodrine hydrochloride was positive. When a skin eruption appears during the administration of ritodrine, we must consider the benefits as well as the risks of continuous use of tocolytic agents because there is a risk of Stevens-Johnson syndrome or TEN.