Crucial factors for implementing treatment strategies in intractable atonic postpartum haemorrhage: early phase contrast medium extravasation on dynamic CT.

AIM: To identify the relationship between contrast medium extravasation (CME) on dynamic contrast-enhanced computed tomography (DCT) and clinical information in intractable atonic postpartum haemorrhage (PPH) and its relevance to treatment with uterine artery embolisation (UAE). MATERIALS AND METHODS: Of 90 patients who underwent DCT to diagnose PPH, 60 diagnosed with intractable atonic PPH were investigated retrospectively. Maternal background and clinical indicators were analysed to compare the positive and negative factors of early phase CME. Regression analysis was used to investigate the factors associated with CME. The sensitivity, specificity, and positive and negative predictive values of early phase CME for predicting UAE were calculated. Clinical outcomes were compared between the two groups according to the timing of the decision to undergo UAE. RESULTS: Of the 60 patients with intractable atonic PPH, 21 underwent UAE, 20 of whom had early phase CME on DCT. Pre-DCT clinical parameters and clinical indices were not significantly different in presence of early phase CME. Early phase CME was associated with UAE performance, with a sensitivity of 95%, specificity of 87%, positive predictive value of 80%, and negative predictive value of 97%. In cases where UAE was performed after conservative management, there was a significant increase in blood loss and transfusion volume. CONCLUSION: Early phase CME is not indicated by background factors or clinical findings. UAE is not required when CME cannot be detected in the uterine cavity. If early phase CME is present, UAE should be considered immediately.

Aggregated chromosomes/chromatin transfer: a novel approach for mitochondrial replacement with minimal mitochondrial carryover: the implications of mouse experiments for human aggregated chromosome transfer.

Nuclear transfer techniques, including spindle chromosome complex (SC) transfer and pronuclear transfer, have been employed to mitigate mitochondrial diseases. Nevertheless, the challenge of mitochondrial DNA (mtDNA) carryover remains unresolved. Previously, we introduced a method for aggregated chromosome (AC) transfer in human subjects, offering a potential solution. However, the subsequent rates of embryonic development have remained unexplored owing to legal limitations in Japan, and animal studies have been hindered by a lack of AC formation in other species. Building upon our success in generating ACs within mouse oocytes via utilization of the phosphodiesterase inhibitor 3-isobutyl 1-methylxanthine (IBMX), this study has established a mouse model for AC transfer. Subsequently, a comparative analysis of embryo development rates and mtDNA carryover between AC transfer and SC transfer was conducted. Additionally, the mitochondrial distribution around SC and AC structures was investigated, revealing that in oocytes at the metaphase II stage, the mitochondria exhibited a relatively concentrated arrangement around the spindle apparatus, while the distribution of mitochondria in AC-formed oocytes appeared to be independent of the AC position. The AC transfer approach produced a marked augmentation in rates of fertilization, embryo cleavage, and blastocyst formation, especially as compared to scenarios without AC transfer in IBMX-treated AC-formed oocytes. No significant disparities in fertilization and embryo development rates were observed between AC and SC transfers. However, relative real-time PCR analyses revealed that the mtDNA carryover for AC transfers was one-tenth and therefore significantly lower than that of SC transfers. This study successfully accomplished nuclear transfers with ACs in mouse oocytes, offering an insight into the potential of AC transfers as a solution to heteroplasmy-related challenges. These findings are promising in terms of future investigation with human oocytes, thus advancing AC transfer as an innovative approach in the field of human nuclear transfer methodology.

Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan.

BACKGROUND: The efficacy of proton pump inhibitors (PPIs) for treating functional dyspepsia (FD) is not well established. AIM: This study, named the SAMURAI study, aimed to assess the efficacy and dose-response relationship of rabeprazole in Japanese patients with FD in a multicentre, double-blinded, randomised, placebo-controlled trial. METHODS: Investigated FD was diagnosed using the Rome III criteria. Subjects who did not respond to 1 week of single-blind placebo treatment in a run-in period were randomly assigned to 8 weeks of double-blind treatment with rabeprazole 10 mg, 20 mg, 40 mg or placebo, once daily. Dyspeptic symptoms were assessed by a dyspepsia symptom questionnaire (7-point Likert scale) and symptom diary. RESULTS: Of 392 subjects entered into the run-in period, 338 were randomly assigned. Although there was no significant difference between placebo and rabeprazole groups in complete symptom relief for four major dyspeptic symptoms, the satisfactory symptom relief of rabeprazole 20 mg was significantly higher than placebo according to the dyspepsia symptom questionnaire (45.3% vs. 28.2%, P = 0.027) and the symptom diary assessment (48.7% vs. 30.0%, P = 0.016). The efficacy was not influenced by syndrome type or Helicobacter pylori status. No statistically significant differences in the incidence of adverse events were seen among treatment groups. CONCLUSIONS: Rabeprazole 20 mg once daily but not 10 or 40 mg significantly provides satisfactory symptom relief for functional dyspepsia (ClinicalTrials.gov, Number NCT01089543).

Treatment with a constitutive androstane receptor ligand ameliorates the signs of preeclampsia in high-fat diet-induced obese pregnant mice.

Constitutive androstane receptor (CAR) has been reported to decrease insulin resistance, while obesity and insulin resistance may also be involved in the pathogenesis of preeclampsia. We examined whether a CAR ligand, 1,4-bis(2-(3,5-dichloropyridyloxy)) benzene (TCPOBOP), can ameliorate the signs of preeclampsia in high-fat diet (HFD)-induced obese pregnant mice to examine a possibility of CAR as a therapeutic target. We employed six groups including non-pregnant, HFD-fed or control diet-fed pregnant mice with or without TCPOBOP treatment (n=6). In HFD pregnant mice, insulin resistance increased with increasing expression of gluconeogenic and lipogenic genes and abnormal adipocytokine levels. TCPOBOP treatment, which was once-weekly intraperitoneal injections (0.5 mg/kg) and started at day 0.5 of pregnancy, improved glucose tolerance with significant changes of gluconeogenic, lipogenic and adipocytokine genes. HFD pregnant mice had hypertension and proteinuria, while TCPOBOP treatment ameliorated these signs. Our data suggested CAR might be a potential therapeutic target for obese preeclampsia patients with insulin resistance.

Different profiles of circulating angiogenic factors and adipocytokines between early- and late-onset pre-eclampsia.

OBJECTIVE: Circulating angiogenic factors have been shown to be important in the pathophysiology of pre-eclampsia. Blood levels of adipocytokines differ in pre-eclampsia relative to controls and may also play an important role in disease pathogenesis. Differences in the circulating levels of these molecules were compared between matched normotensive controls and women with pre-eclampsia with onset before or at/after 32 weeks, and according to whether the women were of normal weight (18.5 < body mass index < 25) or overweight. DESIGN: A cross-sectional study of 110 pregnant Japanese women who visited the Department of Obstetrics and Gynecology, Okayama University Hospital, Okayama, Japan. SETTING: Tertiary referral centre serving 2000 births. METHODS: Serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), soluble endoglin (sEng), adiponectin and leptin were measured in women with pre-eclampsia and in normotensive controls matched for age, gestational week, parity and body mass index. Main outcome measures Serum levels of sFlt-1, PlGF, the sFlt-1/PlGF ratio, sEng, adiponectin and leptin. RESULTS: The sFlt-1/PlGF ratio in early-onset pre-eclampsia was significantly higher than that in late-onset pre-eclampsia (112.0 +/- 30.2 versus 45.4 +/- 43.8, P = 0.037). There was a significant elevation of leptin in both subtypes relative to controls (early: 58.6 +/- 18.3 ng/ml versus 26.0 +/- 6.7 ng/ml, P = 0.001; late: 39.5 +/- 9.2 ng/ml versus 22.0 +/- 4.3 ng/ml, P = 0.005), but adiponectin was increased only in late-onset pre-eclampsia (36.5 +/- 13.4 microg/ml versus 12.0 +/- 4.3 microg/ml, P = 0.003). Significant differences in angiogenic factors and adiponectin were found between normal and overweight women only in late-onset pre-eclampsia. CONCLUSIONS: These data suggest that there are different profiles of angiogenic factors and adipocytokines between women who develop early- and late-onset pre-eclampsia.

Heritable artificial sex chromosomes in the medaka, Oryzias latipes.

Chromosomal sex determination is widely used by vertebrates, however, only two genes have been identified as master sex-determining genes: SRY/Sry in mammals and DMY in the teleost medaka. Transfer of both genes into genetically female (XX) individuals can induce male development. However, transgenic strains have not been established in both cases because of infertility of the transgenic founders in mammals and low germline transmission rates in medaka. In this study, we used a BAC clone containing DMY in a 117 kb genomic region and two types of fluorescent marker to establish two DMY-transgenic medaka strains. In these strains, exogenous DMY is completely linked to a male phenotype and early gonadal development is not different from that of the wild-type strain. Sex-linkage analysis showed that the exogenous DMY was located on linkage group (LG) 23 in one strain and on LG 5 in the other strain, whereas the sex chromosome in medaka is on LG 1. Real-time PCR analysis indicated that these strains have multiple copies of DMY and higher DMY expression levels than the wild-type strain. These results showed that LGs 23 and 5 function as sex chromosomes in the two strains, respectively. This is not only the first example of the artificial generation of heritable sex chromosomes in vertebrates but also the first evidence showing plasticity of homomorphic sex chromosomes. This plasticity appears to be a characteristic of lower vertebrates and the underlying cause of frequent sex chromosome switching, recently reported in several fish and frog species.

Effect of radiation monitoring method and formula differences on estimated physician dose during percutaneous coronary intervention.

BACKGROUND: Currently, one or two dosimeters are used to monitor radiation exposure in most cardiac laboratories. In addition, several different formulas are used to convert exposure data into an effective dose (ED). PURPOSE: To clarify the effect of monitoring methods and formula selection on the estimated ED for physicians during percutaneous coronary interventions (PCIs). MATERIAL AND METHODS: The ED of physicians during cardiac catheterization was determined using an optically stimulated luminescence dosimeter (Luxel badge). Two Luxel badges were worn: one beneath a personal lead apron (0.35-mm lead equivalent) at the chest and one outside of the apron at the neck. RESULTS: The difference in the average ED of seven physicians was approximately fivefold (range 1.13-5.43 mSv/year) using the six different formulas in the clinical evaluation. The estimated physician ED differed markedly according to both the monitoring method and formula selected. CONCLUSION: ED estimation is dependent on both the monitoring method and the formula used. Therefore, it is important that comparisons among laboratories are based on the same monitoring method and same formula for calculating the ED.

Expression and potential role of peroxisome proliferator-activated receptor gamma in the placenta of diabetic pregnancy.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed predominantly in adipose tissue and is known to be involved in adipocyte differentiation and insulin sensitivity. Recent reports indicated that PPARgamma-deficient mice were embryonic lethal due to abnormal placental development, suggesting that PPARgamma plays an important role in normal development of placenta. On the other hand, expression of vascular endothelial growth factor (VEGF), the other important factor in placental development, has been demonstrated to be regulated by PPARgamma in vascular smooth muscle cells. Also, diabetic pregnancy is often associated with defective placental functions. In order to investigate physiological roles of PPARgamma and VEGF in placental development during diabetic pregnancy, we examined the expressions of PPARgamma and VEGF in placentas, which were obtained from normal and streptozotocin-induced diabetic pregnant mouse, and studied in vitro effects of hyperglycemic condition and PPARgamma ligands (rosiglitazone and 15-deoxy-delta(12,14)prostaglandin J(2)) on trophoblasts using human choriocarcinoma cell lines. In diabetic mouse placentas (n=5), expressions of PPARgamma and VEGF proteins significantly increased as compared with these in normal placenta (n=3 or 4). In vitro studies indicated that hyperglycemic condition (42 mM) significantly enhanced the PPARgamma expression and hCG production, and significantly suppressed cell proliferation, however these effects were attenuated by PPARgamma ligands that accompanied with increased VEGF production. These data suggest that the PPARgamma pathway might be involved in the impairment of placental development induced by high glucose conditions, and that VEGF might play some roles in this pathway.

Minimal change oesophagitis: a disease with characteristic differences to erosive oesophagitis.

BACKGROUND: The majority of gastro-oesophageal reflux disease (GERD) seems to be non-erosive reflux disease. Nonerosive reflux disease includes minimal change oesophagitis (whitish or reddish, oedematous change and erosion that is not regarded as mucosal break) and no endoscopic abnormalities. AIM: To investigate the accurate proportion of those with minimal change oesophagitis and to clarify its characteristics. In addition, we evaluated the effect of famotidine (40 mg/day) in those with minimal change. METHODS: Prospective endoscopic assessment was performed for consecutive 606 out-patients. Of the 582 patients suitable for analysis, 347 were non-treated. The latter were divided into those with erosive GERD or minimal change, and their endoscopic findings and characteristics were compared. RESULTS: Among 347 non-treated patients, 88 (25%) had erosive GERD and 249 (72%) had minimal change. Compared with patients who have erosive GERD and those with minimal change, the latter were less likely to have hiatal hernia or bile reflux, but more likely to have gastric atrophy. Symptomatic patients (n = 55) with minimal change oesophagitis were more likely to have hiatal hernia than those who were asymptomatic (n= 194). Most patients preferred taking famotidine on-demand, during a 4-week follow-up period. CONCLUSIONS: Most non-erosive reflux disease can be classified as minimal change oesophagitis, and that have different characteristics from erosive GERD. On-demand famotidine may be a suitable alternative treatment for patients with minimal change disease.

The different effects of endocrine-disrupting chemicals on estrogen receptor-mediated transcription through interaction with coactivator TRAP220 in uterine tissue.

An endocrine-disrupting chemical (EDC) can alter endocrine functions through a variety of mechanisms, including nuclear receptor-mediated changes in protein synthesis, interference with membrane receptor binding, steroidogenesis or synthesis of other hormones. Although major chemicals have been shown to disrupt estrogenic actions mainly through their binding to estrogen receptor (ER) or androgen receptor, it is not clear how EDCs affect endocrine functions in vivo. We present evidence that the EDCs bisphenol A and phthalate activate ER-mediated transcription through interaction with TRAP220. Moreover, bisphenol A had positive effects on the interaction between ER-beta and TRAP220 and on the expression of ER-beta and TRAP220 compared with phthalate and estradiol in uterine tIssue. These data suggested that some EDCs might alter endocrine function through the change of the receptor and coactivator levels in uterine tIssue and through the different effect on the interaction between ERs and coactivator TRAP220.

Coexistence of Graves' disease and struma ovarii: case report and literature review.

We report a rare case of Graves' disease associated with struma ovarii. A 26-year-old Japanese woman had preexisting Graves' disease and was positive for TSH receptor antibody. She had been on antithyroid medication at presentation. She noted a mass in the lower left abdomen, which was diagnosed as a left struma ovarii by radiological work-up including computed tomography, magnetic resonance imaging and scintigraphy. The surgically excised teratomatous tumor, containing cystic spaces with thyroid tissue, was histologically proved to be struma ovarii. Since thyroid function tests and TSH receptor antibody did not change after surgery, her hyperthyroidism was considered to be due to Graves' disease. Our case was diagnosed as struma ovarii before surgery using various imaging studies.

The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse.

Recently, pregnane X receptor (PXR) has been described to mediate the genomic effects of several steroid hormones, such as progesterone (P), glucocorticoid (Dex), pregnenolone (Preg), and xenobiotics through the cytochrome P-450 3A gene family (CYP3A), which are monooxygenases, responsible for the oxidative metabolism of some endogenous substrates and xenobiotics. In the present study, we used a transient transfection reporter gene expression assay of COS-7 cells to demonstrate that P, Dex and Preg significantly stimulate PXR-mediated transcription at relatively high concentration comparable with that of progesterone near term pregnancy. In yeast two-hybrid protein interaction assay, PXR interacted with nuclear receptor coactivator proteins, SRC1, RIP140, and SUG1 in a ligand-dependent manner. The expression of PXR mRNA was observed in the liver, intestine, uterus, ovary and placenta. The expressions of PXR mRNA in the liver and ovary increased towards term about fifty-fold compared with that of non-pregnancy and decreased postpartum. Its expression in the placenta was not drastically changed towards term. CYP3A, a target gene of PXR, was also expressed in the liver, ovary, and placenta. The expressions of CYP3A mRNA as well as PXR in the liver and ovary increased about 20-fold during prenatal period. These data suggest that PXR may play certain roles in perinatal period, possibly in the protection of the feto-maternal system from the toxic effect of endogenous steroids and foreign substrates.

Heavy-for-date infants: their backgrounds and relationship with gestational diabetes.

OBJECTIVE: Gestational diabetes (GDM) is closely related to birth weight. Heavy-for-date (HFD) infants, especially those with macrosomia, cause many perinatal complications. This study was performed to examine the backgrounds of HFD infants and to determine such infants' relationship with GDM. METHOD: Eighty cases of HFD infants who were delivered from 1996 through 1998 were analyzed. The random blood-glucose level was used for screening for GDM. RESULTS: Maternal body weight and the body-mass index before pregnancy and at delivery and the blood glucose level at the second trimester were positively correlated with birth weight. However, only 8.8% of HFD cases were detected by this screening method in the first trimester, and 11.3% of HFD cases were detected in the second trimester and only 1 case of borderline-type was detected by subsequent 75-g OGTT. CONCLUSIONS: Maternal obesity is an independent and more important risk factor for HFD infants than glucose intolerance.

[On the differences in attitude and awareness of clinical doctors, health administrators and other health workers to tuberculosis treatment in Japan and the US].

Peculiarity of TB treatment in Japan is a higher rate and duration of hospitalization than in other developed countries. Improvement of the TB control policy in Japan necessitates reexamination of the issue of treatment policy, which requires consideration of recognition and understanding of the concept of TB infection, human rights and the protection of patients as well as the society. Therefore, this study aims at clarifying and analyzing the differences in TB treatment policies in Japan and the US. For the US, a questionnaire was sent to TB Directors of states and large cities in order to analyze TB control policies. Moreover, the author attended the NTCA meeting held in Chicago to interview 16 TB Directors. In Japan, the author sent the same questionnaire translated into Japanese to medical doctors in 54 National TB sanatoria. The hospitalization rates of new smear-positive TB patients were 100% (median) in Japan and 59% in the US. The periods of hospitalization of these patients were 150 days (median) in Japan and 10 days in the US. The total expenses of TB diagnosis and treatment per capita were approximately US $25,000 and 20,000, respectively in Japan and the US. If the DOT strategy were applied to the new smear-positive TB cases in Japan, those total expenses would be reduced to half. On the measures against the TB patients who pose a threat to the public, the US has the series of TB control strategies which contain the reporting system, home isolation, incarceration and penalties for violation, while Japan has only the strategy of hospitalization. The TB policies of Japan in future would need to focus more selectively and carry out thoroughly as seen in the US. The recommended TB policies for Japan obtained from this study are to set TB policies adapted to regional characteristics and to review the strategy against patients posing a threat to the public.

Streptozotocin-induced diabetic pregnant rats exhibit signs and symptoms mimicking preeclampsia.

The number of patients with hypertension, obesity, diabetes, and hyperlipidemia is increasing. This tendency is observed in pregnant women, in whom many obstetrical and perinatal complications occur. The prevention of these abnormalities is important in reducing perinatal mortality and the risk of coronary disease. We established a pregnant rat model with diabetes and signs and symptoms mimicking preeclampsia. On day 6 of pregnancy, streptozotocin (STZ) or citrate buffer was injected into the tail vein. After STZ administration, plasma glucose was increased within 48 hours and sustained at a high level until day 20 of pregnancy, and plasma insulin was decreased. Fetuses from STZ-treated mothers were growth-restricted, and plasma glucose was 6-fold higher in fetuses of STZ-treated versus control rats. The systolic blood pressure, urinary protein, and hematocrit were increased significantly in STZ-treated rats. Total cholesterol and triglycerides were also elevated in STZ-treated rats, but plasma leptin levels were decreased. The STZ-induced diabetic pregnant rat model exhibited preeclampsia, hemoconcentration, hyperlipidemia, hypoleptinemia, and intrauterine growth restriction. This model closely mimics the features of human pregnancy complicated by diabetes and is useful for the basic study of the pathophysiology of pregnancy with diabetes.

Endocrine disrupting chemicals, phthalic acid and nonylphenol, activate Pregnane X receptor-mediated transcription.

Recently, Pregnane X receptor (PXR), a new member of the nuclear receptor superfamily, was shown to mediate the effects of several steroid hormones, such as progesterone, glucocorticoid, pregnenolone, and xenobiotics on cytochrome P450 3A genes (CYP3A) through the specific DNA sequence for CYP3A, suggesting that PXR may play a role in steroid hormone metabolism. In this paper, we demonstrated that phthalic acid and nonylphenol, endocrine-disrupting chemicals (EDCs), stimulated PXR-mediated transcription at concentrations comparable to those at which they activate estrogen receptor-mediated transcription using a transient reporter gene expression assay in COS-7 cells. However, bisphenol A, another EDC, had no effect on PXR-mediated transcription, although this chemical significantly enhanced ER-mediated transcription. In the yeast two-hybrid protein interaction assay, PXR interacted with two nuclear receptor coactivator proteins, steroid hormone receptor coactivator-1 and receptor interacting protein 140, in the presence of phthalic acid or nonylphenol. Thus, EDC-occupied PXR may regulate its specific gene expression through the receptor-coactivator interaction. In contrast, these EDCs had no effect on the interaction between PXR and suppressor for gal 1, a component of proteasome. Finally, the expression of CYP3A1 mRNA in the liver of rats exposed to phthalic acid or nonylphenol markedly increased compared with that in rats treated with estradiol, bisphenol A, or ethanol as assessed by competitive RT-PCR. These data suggest that EDCs may affect endocrine functions by altering steroid hormone metabolism through PXR.

Effects of invaginating anastomosis in Kasai hepatic portoenterostomy on resolution of jaundice, and long-term outcome for patients with biliary atresia.

BACKGROUND/PURPOSE: This report describes a technique of hepatic portoenterostomy (HPE) to keep sustained bile drainage in biliary atresia patients. In conventional HPE, the medial posterior row of the anastomosis is placed behind the main portal vein. But around both lateral corners where the portal branches enter the liver parenchyma, the anastomosis is placed across and outside of the portal veins. Resultantly, the proximal part of the portal veins become included in anastomosis attaching directly to the dissected area where bile ducts are copious. In a devised procedure designated as invaginating anastomosis (IA), an anastomotic line was placed to invaginate the medial branch of the right portal vein and also placed behind the veins even at their roots. This technique puts all portal branches outside of the anastomosis, preventing cicatricial adhesion at the dissected area with the posterior wall of the veins. METHODS: The effect of IA was evaluated in terms of resolution of jaundice and long-term outcome compared with conventional anastomosis (CA). Group IA consisted of 20 patients and group CA of 18 patients. RESULTS: Patients in whom jaundice resolved included 19 (95%) in group IA and 11 (61%) in group CA (P < .05). Reoperation was needed in only one infant in group IA, and in six in CA (P < .05). In patients with reoperation in group CA, the portahepatis was found to be contracted with dense cicatricial tissues. The survival rates for patients with a native liver, calculated excluding those in whom the cause of death was not liver deterioration, was 87% for IA compared with 41% for CA (P < .05). Averaged biliary atresia prognostic index at the last follow-up evaluation was 20.2+/-24.5 for group IA and 62.6+/-29.8 for group CA (P < .001). CONCLUSION: The invaginating anastomosis in portoenterostomy promised a sustained bile drainage and improved long-term outcome by preventing cicatricial contraction of the portahepatis.