Prevention of transgenerational transmission of disease susceptibility through perinatal intervention.

The observational findings of Barker's original epidemiological studies were generalized as the Barker hypothesis and extended as the Developmental Origins of Health and Disease (DOHaD) theory. Barker et al. proposed that low birthweight (LBW) was associated with the occurrence of various noncommunicable diseases (NCDs) later in life. In other words, LBW itself is associated with the development of NCDs. This led to the DOHaD theory which proposed that an organism may have a specific period of developmental plasticity that is highly sensitive to the factors in its environment, and that combinations of acquired constitution and environmental factors may adversely affect health and risk the formation of NCDs. Due to undernutrition during the fetal period, the fetus acquires an energy-saving constitution called a thrifty phenotype due to adaptations of the metabolic and endocrine systems. It has been suggested that stimuli experienced early in development can persist throughout life and induce permanent physiological changes that predispose to NCDs. It has since become clear that the adverse environmental effects during the prenatal period are also intergenerationally and transgenerationally inherited, affecting the next generation. It has been shown that nutritional interventions such as methyl-donner and epigenome editing can restore some of the impaired functions and reduce the risk of developing some diseases in the next generation. This review thus outlines the mechanisms underlying various disease risk formations and their genetic programs for the next generation, which are being elucidated through studies based on our fetal undernutrition rat models.

Screening methods for gestational diabetes mellitus in Japan in 2018: a retrospective cohort study using a national surveillance questionnaire.

This study aimed to investigate the relationship between gestational diabetes mellitus (GDM) screening methods and GDM incidences. In 2018, a national questionnaire was administered at 231 institutions (56.6%) of all 408 perinatal medical centers in Japan. Of 100,485 women, 2,982 (3.0%) were diagnosed with GDM during their first pregnancy period (FPP) and 7,289 (7.3%) were diagnosed with GDM during their middle pregnancy period (MPP). The proportion of women diagnosed with GDM during FPP and MPP using 95 mg/dL as the cutoff value (CV) for random plasma glucose (PG) at FPP (4.3% and 9.2%) was significantly higher than that of women diagnosed with GDM using 100 mg/dL as the CV for random PG (2.7% and 6.9%, p < 0.0001, respectively). Compared with women screened for GDM using "random PG and random PG," women who were screened for GDM using "random PG and 50-g glucose challenge test (GCT)" had a significantly higher incidence of GDM (6.6% versus 8.9%, p < 0.0001). Using random PG and 50-g GCT, the incidence of GDM among women diagnosed at MPP using a CV of 95 mg/dL at FPP was significantly higher than that of women diagnosed using a CV of 100 mg/dL (16.5% versus 7.8%: p < 0.0001). While, using "random PG and random PG," the incidences of GDM among women were similar between institutions using a CV of 100 mg/dL and those using a CV of 95 mg/dL at FPP (6.7% versus 6.9%: p = 0.3581). This study showed random PG as a first-step screening method in MPP may overlook women with GDM.

Perinatal mortality in Japanese women diagnosed with gestational diabetes mellitus and diabetes mellitus.

AIMS: The objective of this study was to determine how many pregnant Japanese women with diabetes mellitus (DM)/gestational diabetes mellitus (GDM) experience perinatal mortality in the presence of fetal anomalies. METHODS: Our investigation included data from 205 secondary/tertiary obstetric facilities located widely in Japan. The Japan Ministry of Health, Labour and Welfare Vital Statistics of Japan was used for comparison. RESULTS: Of 237 941 women giving birth at 205 hospitals, 1796 (0.8%) and 13 037 (5.5%) had DM and GDM, respectively. The perinatal mortality rates (per 1000 births) were 10.6 (19/1796) for women with DM, 5.2 (68/13037) for women with GDM, and 3.7 (7612/2039504) for the general Japanese population. Detailed information was available for 63 (72%) of the 87 perinatal deaths occurring in women with diabetes including DM and GDM; fetal anomalies were associated with 40% (25/63) of perinatal deaths, exceeding 16% (1211/7612) in the general Japanese population (P < 0.0001). The leading four fetal anomalies associated with perinatal mortality in women with diabetes were fetal trisomy (6 cases: 1 of trisomy-13 and 5 of trisomy-18), non-immune hydrops fetalis (5 cases), cardiac deformities (3 cases) and holoprosencephaly (2 cases). CONCLUSIONS: Perinatal mortality was more likely to occur in women with glucose intolerance. In the Japanese infants that succumbed to perinatal mortality, fetal anomaly was more prevalent in those born to women with a glucose intolerance than in those born to the general population.

Isolated gestational proteinuria preceding the diagnosis of preeclampsia - an observational study.

INTRODUCTION: Some pregnant women develop significant proteinuria in the absence of hypertension. However, clinical significance of isolated gestational proteinuria (IGP) is not well understood. This study aimed to determine the prevalence of IGP in singleton pregnancies and the proportion of women with IGP who subsequently developed preeclampsia (IGP-PE) among all PE cases. MATERIAL AND METHODS: This was an observational study of 6819 women with singleton pregnancies at 12 centers, including 938 women with at least once determination of protein-to-creatinine ratio (P/Cr). Significant proteinuria in pregnancy (SPIP) was defined as P/Cr (mg/mg) level >0.27. IGP was defined as SPIP in the absence of hypertension. Gestational hypertension (GH) preceding preeclampsia (GH-PE) was defined as preeclampsia (PE) in which GH preceded SPIP. Simultaneous PE (S-PE) was defined as PE in which both SPIP and hypertension occurred simultaneously. RESULTS: IGP and PE were diagnosed in 130 (1.9%) and 158 (2.3%) of 6819 women, respectively. Of 130 women with IGP, 32 (25%) progressed to PE and accounted for 20% of all women with PE. Hence, women with IGP had a relative risk of 13.1 (95% CI; 9.2-18.5) for developing PE compared with those without IGP [25% (32/130) vs. 1.9% (126/6689)]. At diagnosis of SPIP, P/Cr levels already exceeded 1.0 more often in women with S-PE than in those with IGP-PE [67% (33/49) vs. 44% (14/32), respectively, p = 0.031]. CONCLUSIONS: IGP is a risk factor for PE, and IGP-PE accounts for a considerable proportion (20%) of all PE.

Urinary protein-to-creatinine ratio in pregnant women after dipstick testing: prospective observational study.

BACKGROUND: The dipstick test is widely used as a primary screening test for detection of significant proteinuria in pregnancy (SPIP). However, it often shows a false positive test result. This study was performed to determine which pregnant women should be recommended to undergo determination of urinary protein-to-creatinine ratio (mg/mg, P/Cr test) after dipstick test for confirmation of SPIP. METHODS: This was a multicenter, prospective, and observational study of 2212 urine specimens from 1033 pregnant women who underwent simultaneous dipstick and P/Cr tests in the same spot urine samples at least once. SPIP was defined as P/Cr > 0.27. Preeclampsia was diagnosed in women with both hypertension and SPIP. RESULTS: Preeclampsia, hypertension alone, and SPIP alone developed in 202 (20 %), 73 (7.1 %), and 120 (12 %) women, respectively. Creatinine concentration [Cr] varied greatly, ranging from 8.1 to 831 mg/dL in the 2212 urine samples. Rate of positive dipstick test results increased with increasing [Cr], while SPIP prevalence rate was lower in urine samples with higher [Cr], yielding higher false positive rates in samples with higher [Cr]. Postpartum urine samples had significantly lower [Cr] compared to those obtained antepartum (60 [8.7-297] vs. 100 [10-401] mg/dL, respectively). At the first P/Cr test among women with similar dipstick test results, the risk of having SPIP was consistently and significantly higher for hypertensive women than for normotensive women at any dipstick test result: 18 % (14/77) vs. 3.2 % (8/251), 47 % (26/55) vs. 8.7 % (37/425), 91 % (82/90) vs. 59 % (44/75) for negative/equivocal, 1+, and ≥ 2+ test results, respectively. The risk of SPIP was 16 % (9/55) for normotensive women when two successive antenatal urine samples showed a dipstick test result of 1 + . CONCLUSIONS: For prediction of SPIP, the dipstick test was more likely to show a false positive result in concentrated urine samples with higher [Cr]. Hypertensive women with ≥ 1+ as well as normotensive women with ≥ 2+ on dipstick test should be advised to undergo the P/Cr test.

Pregnancy outcomes in women with type 1 and type 2 diabetes mellitus in a retrospective multi-institutional study in Japan.

The present study was performed to evaluate pregnancy outcomes in women with type 1 and type 2 diabetes mellitus (DM) in Japan. This multi-institutional retrospective study was conducted in 40 general hospitals in Japan during 2003-2009. We evaluated 369 and 579 pregnant women with type 1 and type 2 DM, respectively, and compared pregnancy outcomes between the two groups. Glycosylated hemoglobin levels in the first trimester did not differ significantly between the studied groups. Gestational weight gain was lower in type 2 DM than in type 1 DM. Although there were no significant differences in perinatal outcomes between the groups, the primary cesarean section rate was higher in type 2 DM than in type 1 DM. Multiple logistic regression analysis revealed that primigravida status, pre-gestational body mass index (BMI), gestational weight gain, chronic hypertension, and microvascular disease including diabetic retinopathy or nephropathy were associated with onset of pregnancy-induced hypertension. Further, pre-gestational BMI was associated with the need for primary cesarean section. This study demonstrated that no differences were observed in the rates of perinatal mortality and congenital malformation between pregnant women with type 1 DM and type 2 DM; however, women with type 2 DM displayed a higher risk of primary cesarean section.

Pregnancy outcomes of gestational diabetes mellitus according to pre-gestational BMI in a retrospective multi-institutional study in Japan.

The aim of this study was to determine the effects of pre-gestational body mass index on pregnancy outcomes of women with gestational diabetes in Japan. A multi-institutional retrospective study was performed. We examined pregnant women who met the former criteria for gestational diabetes in Japan, receiving dietary intervention with self-monitoring of blood glucose with or without insulin therapy. Women with gestational diabetes were divided into three groups according to pre-gestational body mass index: body mass index <25 (control group), 25 ≤ body mass index <30 (overweight group), body mass index ≥30 (obese group). Data from a total of 1,758 eligible women were collected from 40 institutions. Participants included 960 controls, 426 overweight women, and 372 obese women with gestational diabetes. Gestational weight gain was highest in the control and lowest in the obese group. The prevalences of chronic hypertension and pregnancy induced hypertension were higher in the overweight and obese groups than in the control group. Multiple logistic regression analysis revealed pre-gestational body mass index, gestational weight gain, chronic hypertension, and nulliparity to be associated with the onset of pregnancy induced hypertension, while the 75-g OGTT results were unrelated to pregnancy induced hypertension. The prevalence of large-for-gestational age was lower in infants born to obese women than in those born to overweight or control women. The present results suggest that medical interventions for obese women with gestational diabetes may contribute to reducing the prevalence of large-for-gestational age but would not achieve marked reductions in maternal complications.

Lower systolic blood pressure levels in early pregnancy are associated with a decreased risk of early-onset superimposed preeclampsia in women with chronic hypertension: a multicenter retrospective study.

To clarify the impact of blood pressure (BP) management ranges on pregnancy outcomes, we conducted a multicenter retrospective analysis of 215 women with singleton pregnancies diagnosed with essential hypertension either before or within 14 weeks of gestation. Patients were classified according to systolic BP (sBP; <130, 130-139, 140-159, and ≥160 mmHg) or diastolic BP (dBP; <80, 80-89, 90-109, and ≥110 mmHg) at 8-11, 12-15, and 16-19 weeks of gestation. The risk of early-onset superimposed preeclampsia and small-for-gestational-age neonates was assessed in each BP group. Moreover, a subgroup analysis was performed in 144 eligible patients whose BP was measured at both 12-13 and 14-15 weeks of gestation. At 16-19 weeks of gestation, higher sBP significantly increased the incidence of early-onset superimposed preeclampsia (13.3%, 24.6%, 32.2% and 75.0%, respectively) and small-for-gestational-age neonates (6.0%, 13.1%, 16.9% and 50.0%, respectively). Multivariate logistic regression analyses showed that women with sBP < 130 mmHg at 16-19 weeks of gestation had a significantly lower risk of early-onset superimposed preeclampsia than women with sBP of 140-159 mmHg. Subgroup analyses also showed that even at 14-15 weeks of gestation, sBP < 130 mmHg was associated with a significantly lower risk of early-onset superimposed preeclampsia than an sBP of 140-159 mmHg. In conclusion, sBP < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed preeclampsia in women with chronic hypertension.

A case of usual (basaloid)-type vulvar intraepithelial neoplasia that failed to respond to imiquimod cream: clinical implications.

The authors report a case of usual-type (basaloid-type) vulvar intraepithelial neoplasia (VIN) 3 that failed to respond to imiquimod cream. A 51-year-old Japanese woman visited her local gynecologist complaining of vulvar itching. Atypical cells were noted in cytology smears, but nine vulvar biopsy specimens showed benign proliferation of epithelial tissue. The patient was placed under careful observation for 8 months, when the vulvar smears once again showed atypical cells and biopsy specimens revealed VIN3. The patient was then referred to our hospital where she was given a diagnosis of VIN 3, basaloid type of usual type. The biopsy specimens were positive for p16 and the lesions were confirmed to be human papilloma virus (HPV)-related. We recommended simple vulvectomy but the patient requested conservative treatment with imiquimod cream. With her written informed consent, we prescribed imiquimod cream to be self-administered 3 times a week. Colposcopy and pap smear test were performed every 2 weeks. Four weeks after the start of treatment, a fingertip-sized papule was detected at the patient's vaginal introitus. By 6 weeks, the lesion had enlarged, and biopsy specimens revealed invasive squamous cell carcinoma. At 7 weeks, we performed simple vulvectomy. The surgical specimen showed stage pT1b keratinizing-type squamous cell carcinoma. HPV-16 DNA was detected in the specimen.

Role of premature leptin surge in obesity resulting from intrauterine undernutrition.

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

Efficacy of a sodium hyaluronate-carboxycellulose membrane (seprafilm) for reducing the risk of early postoperative small bowel obstruction in patients with gynecologic malignancies.

OBJECTIVE: To evaluate the effect of a sodium hyaluronate and carboxymethylcellulose membrane (Seprafilm) on early postoperative small bowel obstruction (EPSBO) in patients with gynecologic malignancies. METHODS: One hundred forty-five patients who had Seprafilm placed during gynecological surgery between April 2002 and March 2007 (Seprafilm group) were compared with a historical control group of patients managed without Seprafilm between January 1997 and March 2002. All patients undergoing primary surgery with pelvic or combined pelvic and para-aortic lymphadenectomy for gynecological malignancies were retrospectively assessed for EPSBO and surgical infections. RESULTS: The incidence of EPSBO was significantly lower (P < 0.05) in the Seprafilm group (3.1%, 6/191) than in the control group (13.9%, 25/180). According to logistic regression analysis, the use of Seprafilm (odds ratio, 0.18; 95% confidence interval, 0.07-0.47; P < 0.0005) and the performance of pelvic lymphadenectomy alone (odds ratio, 0.27; 95% confidence interval, 0.09-0.78; P < 0.02) were independent predictors of a lower rate of EPSBO. The incidence of surgical infection showed no significant difference between the Seprafilm group (3.6%) and the control group (6.7%). CONCLUSIONS: Placement of Seprafilm helped to prevent EPSBO and had no significant adverse effect on surgical infections in patients who underwent lymphadenectomy for gynecological malignancy.

Group A streptococcal toxic shock syndrome with extremely aggressive course in the third trimester.

Group-A-streptococcus-(GAS)-induced toxic shock syndrome (TSS) is uncommon, but carries a high risk of maternal mortality during pregnancy. The onset of gravidic GAS-TSS has been reported mostly during the puerperium. A 16-year-old woman, who was at 37 weeks of gestation, and without obstetrical care during the last 30 weeks, was referred to our hospital. She complained of fever for one day with headache and abdominal pain after the fever developed. On admission, her consciousness was drowsy, intrauterine fetal death was recognized, and she rapidly developed shock status with coma and hypotension, hemolysis, disseminated intravascular coagulation (DIC), and multi-organ failure. Although we had not obtained the results of a bacterial culture, we suspected sepsis with DIC with homolysis and multi-organ failure resulting from an infection. The patient was treated with antibiotics and intubation because of respiratory insufficiency. Twelve hours after admission to the intensive care unit in our hospital, she died. Cultures from blood, subcutaneous tissue, vaginal discharge, and pharynx all revealed GAS bacteria, and therefore she was diagnosed as having GAS-TSS. GAS-TSS in pregnancy is rare. However, once the infection occurs in a pregnant woman, it rapidly develops into sepsis with multi-organ failure. Therefore, early recognition and intensive treatment for GAS during pregnancy is recommended in women with high fever, muscular pain, hemolysis and DIC during pregnancy.

Comparison of pregnancy outcomes between women with early-onset and late-onset gestational diabetes in a retrospective multi-institutional study in Japan.

AIMS/INTRODUCTION: To compare pregnancy outcomes between women with gestational diabetes mellitus (GDM) diagnosed early and late in pregnancy in Japan. MATERIALS AND METHODS: We examined women diagnosed with GDM in this multi-institutional retrospective study. Women were divided into two groups by gestational age at diagnosis: <24 weeks of gestation (early group, 14.4 ± 4.2 weeks) and ≥24 weeks of gestation (late group, 29.6 ± 3.4 weeks). Dietary counseling with self-monitoring of blood glucose with or without insulin therapy was initiated for both groups. Pregnancy outcomes were compared between the groups. RESULTS: Data from 600 early and 881 late group participants from 40 institutions were included. Although pre-pregnancy body mass index was higher in the early group than in the late group, gestational weight gain was lower in the early group. Hypertensive disorders of pregnancy and cesarean section were more prevalent in the early than in the late group (9.3% vs 4.8%, P < 0.001; 34.2% vs 32.0%, P < 0.001, respectively). The prevalence of large-for-gestational-age infants was higher in the late than in the early group (24.6% vs 19.7%, respectively, P = 0.025). There was no significant difference in other neonatal adverse outcomes between the groups. Multiple logistic regression analysis showed that early group, nulliparity and pre-pregnancy body mass index were associated with hypertensive disorders of pregnancy. CONCLUSIONS: These results suggest that maternal complications, including hypertensive disorders of pregnancy and cesarean delivery, were higher in the early group than in the late group. Earlier intervention for GDM might be associated with a reduction in large-for-gestational-age infants.

Factor XII gene expression in endometrial stromal cells during decidualisation.

Decidualisation of endometrial stromal cells (ESC) is a prerequisite for the implantation of human embryos. Identification of genes that are upregulated or downregulated during decidualisation could lead to a better understanding of the molecular mechanisms involved in this process. In the present study, we examined differences in gene expression between decidualised and non-decidualised cells using microarray analysis and found that Factor XII (FXII) gene expression was upregulated during decidualisation. Furthermore, we also examined the expression of FXII by human ESC before and during pregnancy, as well as its expression by cells that had undergone decidualisation in vitro. Weak expression of FXII mRNA was detected in the non-pregnant endometrium that increased gradually from the proliferative to the secretory endometrium. During pregnancy, FXII mRNA expression was markedly increased in decidualised endometrium. When sex steroids (200 pg mL(-1) of 17beta-oestradiol and 100 ng mL(-1) of progesterone) were used to induce in vitro decidualisation of ESC, the expression of FXII mRNA increased by approximately 25.3-fold compared with that in non-decidualised ESC. Using western blotting, we confirmed the presence of FXII protein (80 kDa) in ESC after in vitro decidualisation. Increased expression of FXII in ESC during decidualisation suggests that the kallikrein-kininogen-kinin system may be activated during the implantation of human embryos.

Isocaloric high-protein diet ameliorates systolic blood pressure increase and cardiac remodeling caused by maternal caloric restriction in adult mouse offspring.

Epidemiologic studies have shown that in utero malnutrition is a risk factor for adult cardiovascular disease (CVD). Recently, we reported a mouse animal model of 30% maternal caloric reduction, in which offspring showed a significant increase in systolic blood pressure (SBP) as well as in cardiac remodeling-associated morphological parameters such as cardiac enlargement and coronary perivascular fibrosis in adulthood. Using a similar animal model, we here demonstrated that an increased level of protein consumption during an undernourished pregnancy (high-protein diet; HPD) corrected for the development of CVD risk factors found in fetal undernourishment with less protein consumption (standard-protein diet; SPD). In contrast, maternal ad libitum feeding with HPD resulted in significantly elevated SBP and cardiac enlargement in offspring at 16 wks. Appropriate maternal protein ingestion might partly protect against the development of CVD risk factors in offspring.

A case of fulminant type 1 diabetes mellitus associated with pregnancy.

Fulminant type 1 diabetes associated with pregnancy is very rare. However if it occurs, the rapid onset is associated with an extremely high risk of fetal death. Therefore, it is important for physicians to make an appropriate diagnosis as early as possible and to begin immediate treatment of both the mother and the fetus. We report a case of fulminant type 1 diabetes associated with pregnancy in which a good outcome was achieved for both the mother and the fetus.

Difference in the prevalence of gestational diabetes mellitus according to gestational age at 75-g oral glucose tolerance test in Japan: The Japan Assessment of Gestational Diabetes Mellitus Screening trial.

AIMS/INTRODUCTION: To evaluate the differences in the results of 75-g oral glucose tolerance tests (OGTTs) according to gestational age in Japan. MATERIALS AND METHODS: In this prospective cohort study, 2,578 pregnant women were divided into three categories based on their gestational age during the 75-g OGTT: <14 weeks' gestation, 14-23 weeks' gestation and 24-32 weeks' gestation. The association between gestational age and the results of the 75-g OGTT were evaluated using multivariable analysis. RESULTS: Early gestational age was associated with high fasting plasma glucose levels at the time of the 75-g OGTT, and low corresponding 1-h and 2-h plasma glucose levels. Compared with women with a gestational age of 24-32 weeks, women who had undergone the 75-g OGTT at <14 weeks' gestation had significantly higher odds of gestational diabetes mellitus diagnosis based on the currently used criteria in Japan (adjusted odds ratio 1.42, 95% confidence interval 1.07-1.90). CONCLUSIONS: The results of the 75-g OGTT varied by gestational age. The use of the same 75-g OGTT cut-off values for the diagnosis of gestational diabetes mellitus, regardless of gestational age, might lead to increases in the prevalence of gestational diabetes mellitus diagnosis in Japan.

Overexpression of thioredoxin-1 reduces oxidative stress in the placenta of transgenic mice and promotes fetal growth via glucose metabolism.

Oxidative stress occurs where there is an imbalance between the production and scavenging of free radicals. Pregnancy per se is a state of oxidative stress due to the increased metabolic activity of placental mitochondria and reduced scavenging ability of antioxidant systems. Overproduction of reactive oxygen species may be associated with impaired fetal growth. However, the physiological influence of antioxidant systems on fetal growth is not well understood. In this study we assessed the effects of antioxidant systems on fetal growth using human thioredoxin (hTRX)-1 overexpressing transgenic (Tg) mice. Tg or C57BL/6 [wild-type (WT)] male mice were mated with WT female mice, and dams were killed to obtain the fetuses and placentas on gestational d 15. Tg fetuses were significantly heavier than WT fetuses, whereas placental weight did not differ significantly between the two groups. Immunohistochemically, hTRX-1 was localized to the nuclei of labyrinthine trophoblasts in Tg mice. In addition, placental expression of 8-hydroxy-2'-deoxyguanosine, which reflects DNA damage caused by oxidative stress, was reduced in Tg mice compared with WT mice. Placental expression of glucose transporter-1 mRNA and protein was significantly higher in Tg mice than WT mice, whereas no significant differences were observed for glucose transporter-3, IGF, and IGF-binding protein mRNA expression. These results suggest that placental and/or systemic antioxidant systems can influence fetal growth. In particular, increased hTRX-1 activity and the resulting modified placental redox state may play an important role in fetal growth by increasing the availability of glucose.

Rho-associated kinase inhibitor Y-27632 promotes survival of cynomolgus monkey embryonic stem cells.

Non-human primates are suitable models for preclinical research aimed at cell-replacement therapies. Recently, it has been reported that Rho-associated kinase inhibitor Y-27632 markedly reduced dissociation-induced apoptosis of human embryonic stem (hES) cells, and is expected as a novel supplement for hES cell maintenance or differentiation inductions; however, the effects of the chemical are still to be determined in model animals. Here, we demonstrated the effect of Y-27632 on cynomolgus monkey ES (cyES) cells. Also, in cyES cells, Y-27632 treatment dramatically improved the efficiency of colony formation from single cells without affecting the pluripotent state and karyotype. Y-27632 supplementation was also effective for feeder-free culture and differentiation induction. Neural stem cells directly induced from cyES cells could give rise to neurons, astrocytes and dopamine producing cells. The present result not only suggests that the chemical was effective for improving the culture system of primate ES cells, but also the similarity between cyES and hES cells regarding the reactions to the chemical, which might be further evidence that cyES cells are superior models for hES cells.

Weekly low-dose paclitaxel and carboplatin therapy in gynecological cancer patients with venous thrombosis.

BACKGROUND: To evaluate the safety and toxicity of weekly low-dose paclitaxel plus carboplatin therapy in gynecological cancer patients with venous thrombosis (VT). MATERIALS AND METHODS: Ovarian or endometrial cancer patients with VT who were scheduled to receive neoadjuvant or adjuvant chemotherapy were eligible. Each 21-day cycle of treatment consisted of carboplatin (AUC 2.0) and paclitaxel (80 mg/m2) on days 1, 8 and 15. At the end of chemotherapy, each patient's VT was checked by ultrasonography. RESULTS: Twenty-five gynecological cancer patients who received warfarin therapy with a target international normalized ratio (INR) of 1.5-2.5 were enrolled in this study. Neutropenia and peripheral neuropathy (grades 3 or 4) occurred in 26% and 4% of the patients, respectively. Chemotherapy did not cause any changes of the INR in any patient. After chemotherapy, the VT showed resolution in 19 patients (76%) and no patient developed fresh thrombosis. CONCLUSION: Weekly low-dose paclitaxel plus carboplatin therapy is a reasonable treatment option for gynecological cancer patients with VT.