Placental Glucose Transporter (GLUT1) Expression in Pre-Eclampsia

Placental Glucose Transporter (GLUT1) Expression in Pre- Eclampsia. INTRODUCTION: Glucose is the most important substrate for fetal growth. Indeed, there is no significant de novo glucose synthesis in the fetus and the fetal up-take of glucose rely on maternal supply and transplacental transport. Therefore, a defective placental transporter system may affect the intrauterine environment compromising fetal as well as mother well-being. On this line, we speculated that the placental glucose transport system could be impaired in pre-eclampsia (PE). METHODS: Placentae were obtained after elective caesarean sections following normal pregnancies and pre-eclamptic pregnancies. Syncytial basal membrane (BM) and apical microvillus membrane (MVM) fractions were prepared using differential ultra-centrifugation and magnesium precipitation. Protein expression was assessed by western blot. mRNA levels were quantified by quantitative real-time PCR. A radiolabeled substrate up-take assay was established to assess glucose transport activity. FACS analysis was performed to check the shape of MVM. Statistical analysis was performed using one way ANOVA test. RESULTS: GLUT1 protein levels were down-regulated (70%; P<0.01) in pre-eclamptic placentae when compared to control placentae. This data is in line with the reduced glucose up-take in MVM prepared from preeclamptic placentae. Of note, the mRNA levels of GLUT1 did not change between placentae affected by PE and normal placentae, suggesting that the levels of GLUT1 are post-transcriptionally regulated. FACS analysis on MVM vesicles from both normal placentae and pre-eclamptic placentae showed equal heterogeneity in the complexes formed. This excluded the possibility that the altered glucose up-take observed in pre-eclamptic MVM was caused by a different shape of these vesicles. CONCLUSIONS: Protein and functional studies of GLUT1 in MVM suggest that in pre-eclampsia the glucose transport between mother and fetus might be defective. To further investigate this important biological aspect we will increase the number of samples obtained from patients and use primary cells to study trans epithelial transport system in vitro.

Regulation of human trophoblast GLUT1 glucose transporter by insulin-like growth factor I (IGF-I)

Glucose transport to the fetus across the placenta takes place via glucose transporters in the opposing faces of the barrier layer, the microvillous and basal membranes of the syncytiotrophoblast. While basal membrane content of the GLUT1 glucose transporter appears to be the rate-limiting step in transplacental transport, the factors regulating transporter expression and activity are largely unknown. In view of the many studies showing an association between IGF-I and fetal growth, we investigated the effects of IGF-I on placental glucose transport and GLUT1 transporter expression. Treatment of BeWo choriocarcinoma cells with IGF-I increased cellular GLUT1 protein. There was increased basolateral (but not microvillous) uptake of glucose and increased transepithelial transport of glucose across the BeWo monolayer. Primary syncytial cells treated with IGF-I also demonstrated an increase in GLUT1 protein. Term placental explants treated with IGF-I showed an increase in syncytial basal membrane GLUT1 but microvillous membrane GLUT1 was not affected. The placental dual perfusion model was used to assess the effects of fetally perfused IGF-I on transplacental glucose transport and syncytial GLUT1 content. In control perfusions there was a decrease in transplacental glucose transport over the course of the perfusion, whereas in tissues perfused with IGF-I through the fetal circulation there was no change. Syncytial basal membranes from IGF-I perfused tissues showed an increase in GLUT1 content. These results demonstrate that IGF-I, whether acting via microvillous or basal membrane receptors, increases the basal membrane content of GLUT1 and up-regulates basal membrane transport of glucose, leading to increased transepithelial glucose transport. These observations provide a partial explanation for the mechanism by which IGF-I controls nutrient supply in the regulation of fetal growth.

Factors influencing the accuracy of fetal weight estimation with a focus on preterm birth at the limit of viability: a systematic literature review

BACKGROUND Fetal weight estimation (FWE) is an important factor for clinical management decisions, especially in imminent preterm birth at the limit of viability between 23(0/7) and 26(0/7) weeks of gestation. It is crucial to detect and eliminate factors that have a negative impact on the accuracy of FWE. DATA SOURCES In this systematic literature review, we investigated 14 factors that may influence the accuracy of FWE, in particular in preterm neonates born at the limit of viability. RESULTS We found that gestational age, maternal body mass index, amniotic fluid index and ruptured membranes, presentation of the fetus, location of the placenta and the presence of multiple fetuses do not seem to have an impact on FWE accuracy. The influence of the examiner's grade of experience and that of fetal gender were discussed controversially. Fetal weight, time interval between estimation and delivery and the use of different formulas seem to have an evident effect on FWE accuracy. No results were obtained on the impact of active labor. DISCUSSION This review reveals that only few studies investigated factors possibly influencing the accuracy of FWE in preterm neonates at the limit of viability. Further research in this specific age group on potential confounding factors is needed.

Prenatal management of monoamniotic twin pregnancies

OBJECTIVE To evaluate antenatal surveillance strategies and the optimal timing of delivery for monoamniotic twin pregnancies. METHODS Obstetric and perinatal outcomes were retrospectively retrieved for 193 monoamniotic twin pregnancies. Fetal and neonatal outcomes were compared between fetuses followed in an inpatient setting and those undergoing intensive outpatient follow-up from 26 to 28 weeks of gestation until planned cesarean delivery between 32 and 35 weeks of gestation. The risk of fetal death was compared with the risk of neonatal complications. RESULTS Fetal deaths occurred in 18.1% of fetuses (70/386). Two hundred ninety-five neonates from 153 pregnancies were born alive after 23 weeks of gestation. There were 17 neonatal deaths (5.8%), five of whom had major congenital anomalies. The prospective risk of a nonrespiratory neonatal complication was lower than the prospective risk of fetal death after 32 4/7 weeks of gestation (95% confidence interval 32 0/7-33 4/7). The incidence of death or a nonrespiratory neonatal complication was not significantly different between fetuses managed as outpatients (14/106 [13.2%]) or inpatients (15/142 [10.5%]; P=.55). Our statistical power to detect a difference in outcomes between these groups was low. CONCLUSIONS The in utero risk of a monoamniotic twin fetus exceeds the risk of a postnatal nonrespiratory complication at 32 4/7 weeks of gestation. If close fetal surveillance is instituted after 26-28 weeks of gestation and delivery takes place at approximately 33 weeks of gestation, the risk of fetal or neonatal death is low, no matter the surveillance setting. LEVEL OF EVIDENCE II.

Transmission of border disease virus from a persistently infected calf to seronegative heifers in early pregnancy

BACKGROUND: This study describes the transmission of border disease virus (BDV) from a persistently infected calf to seronegative heifers in early pregnancy, resulting in persistently infected fetuses. On day 50 of pregnancy (= day 0 of the infection phase), six heifers were co-housed in a free stall with a bull calf persistently infected with BDV (pi BVD) for 60 days. The heifers underwent daily clinical examination, and blood samples were collected regularly for detection of pestiviral RNA and anti-pestivirus antibodies. After day 60 (= day 110 of pregnancy), the heifers were slaughtered, and the fetuses and placentae underwent post-mortem and immunohistochemical examination and RT-PCR for viral RNA detection. RESULTS: Three heifers had mild viraemia from day 8 to day 14, and by day 40 all heifers had pestivirus antibodies identified as anti-BDV antibodies in the serum neutralisation test. The placenta of the three viraemic heifers had histological evidence of inflammation, and fetal organs from these heifers were positive for pestivirus antigen by immunohistochemical examination and for BD viral RNA by RT-PCR and sequencing. Thus, co-housing of heifers in early pregnancy with a pi-BDV calf led to seroconversion in all heifers and persistent fetal infection in three. CONCLUSIONS: Considering that pi-BDV cattle can infect other cattle and lead to persistent infection of the fetus in pregnant cows, BDV should not be ignored in the context of the mandatory BVDV eradication and monitoring program. This strongly suggests that BDV should be taken into account in BVD eradication and control programs.

Placental plasticity in monochorionic twins: Impact on birth weight and placental weight

INTRODUCTION The knowledge about adaptive mechanisms of monochorionic placentas to fulfill the demands of two instead of one fetus is largely speculative. The aim of our study was to investigate the impact of chorionicity on birth weight and placental weight in twin pregnancies. METHODS Forty Monochorionic (MC) and 43 dichorionic (DC) twin pregnancies were included in this retrospective study. Individual and total (sum of both twins) birth weights, placental weights ratios between placental and birth weights and observed-to-expected (O/E)-ratios were calculated and analyzed. Additionally, we investigated whether in twin pregnancies placental and birth weights follow the law of allometric metabolic scaling. RESULTS MC pregnancies showed higher placental O/E-ratios than DC ones (2.25 ± 0.85 versus 1.66 ± 0.61; p < 0.05), whereas the total neonatal birth weight O/E-ratios were not different. In DC twins total placental weights correlated significantly with gestational age (r = 0.74, p < 0.001), but not in MC twins. Analysis of deliveries ≤32 weeks revealed that the placenta to birth weight ratio in MC twins was higher than in matched DC twins (0.49 ± 0.3 versus 0.24 ± 0.03; p = 0.03). Allometric metabolic scaling revealed that dichorionic twin placentas scale with birth weight, while the monochorionic ones do not. DISCUSSION The weight of MC placentas compared to that of DC is not gestational age dependent in the third trimester. Therefore an early accelerated placental growth pattern has to be postulated which leads to an excess placental mass particularly below 32 weeks of gestation. The monochorionic twins do not follow allometric metabolic scaling principle making them more vulnerable to placental compromise.

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy.

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome.

Importance of cholesterol and cholesterol transporters in the placental trophoblast during pregnancy

Membrane transporters are essential during pregnancy, being a core component of the exchange of nutrients, gases, and metabolic products between the mother and the developing fetus. Important compounds to be transported include vitamins and minerals, amino acids, glucose, as well as cholesterol. Cholesterol transport across the plasma membrane is mediated mainly by members of the ATP-binding cassette (ABC) transporter family. Cholesterol is present in every cell of the body, where it helps maintain the integrity of cell membranes and also plays an important role in cell signaling events. Cholesterol also acts as a precursor for the biosynthesis of steroids that include sex hormones, glucocorticoids, mineralcorticoids, as well as bile acids and oxysterols. Cholesterol transport is therefore crucial for a host of different physiological processes. The following chapter addresses the involvement and importance of ABC transporters in these different processes. The critical role that ABC transporters Play for a successful pregnancy outcome is highlighted by pathological processes that result malfunction of cholesterol transport during pregnancy. Avenues of future research are also described, which may help to further delineate the function and mechanism of action of ABC transporters.

Vaccines against neosporosis: what can we learn from the past studies?

Neospora caninum is an intracellular apicomplexan parasite, which is a leading cause of abortion in cattle; thus neosporosis represents an important veterinary health problem and is of high economic significance. The parasite can infect cattle via trans-placental transmission from an infected cow to its fetus (vertical transmission), or through the oral route via ingestion of food or water contaminated with oocysts that were previously shed with the feces of a canid definitive host (horizontal transmission). Although vaccination was considered a rational strategy to prevent bovine neosporosis, the only commercialized vaccine (Neoguard®) produced ambiguous results with relatively low efficacy, and was recently removed from the market. Therefore, there is a need to develop an efficient vaccine capable of preventing both, the horizontal transmission through infected food or water to a naïve animal as well as the vertical transmission from infected but clinically asymptomatic dams to the fetus. Different vaccine strategies have been investigated, including the use of live attenuated vaccines, killed parasite lysates, total antigens or antigen fractions from killed parasites, and subunit vaccines. The vast majority of experimental studies were performed in mice, and to a certain extent in gerbils, but there is also a large number of investigations that were conducted in cattle and sheep. However, it is difficult to directly compare these studies due to the high variability of the parameters employed. In this review, we will summarize the recent advances made in vaccine development against N. caninum in cattle and in mice and highlight the most important factors, which are likely to influence the degree of protection mediated by vaccination.

Approaches for the vaccination and treatment of Neospora caninum infections in mice and ruminant models.

Neospora caninum is a leading cause of abortion in cattle, and is thus an important veterinary health problem of high economic significance. Vaccination has been considered a viable strategy to prevent bovine neosporosis. Different approaches have been investigated, and to date the most promising results have been achieved with live-attenuated vaccines. Subunit vaccines have also been studied, and most of them represented components that are functionally involved in (i) the physical interaction between the parasite and its host cell during invasion or (ii) tachyzoite-to-bradyzoite stage conversion. Drugs have been considered as an option to limit the effects of vertical transmission of N. caninum. Promising results with a small panel of compounds in small laboratory animal models indicate the potential value of a chemotherapeutical approach for the prevention of neosporosis in ruminants. For both, vaccines and drugs, the key for success in preventing vertical transmission lies in the application of bioactive compounds that limit parasite proliferation and dissemination, without endangering the developing fetus not only during an exogenous acute infection but also during recrudescence of a chronic infection. In this review, the current status of vaccine and drug development is presented and novel strategies against neosporosis are discussed.