Is Fetal Growth Restriction Associated with a More Severe Maternal Phenotype in the Setting of Early Onset Pre-Eclampsia? A Retrospective Study

BACKGROUND: Both pre-eclampsia and fetal growth restriction are thought to result from abnormal placental implantation in early pregnancy. Consistent with this shared pathophysiology, it is not uncommon to see growth restriction further confound the course of pre-eclampsia and vice versa. It has been previously suggested that superimposed growth restriction is associated with a more severe pre-eclamptic phenotype, however this has not been a consistent finding. Therefore, we set out to determine whether the presence of fetal growth restriction among women with severe early-onset pre-eclampsia was associated with more severe maternal disease compared to those without a growth-restricted fetus. METHODS AND FINDINGS: We undertook a retrospective cohort study of women presenting to a tertiary hospital with severe early-onset pre-eclampsia (<34 weeks' gestation) between 2005-2009. We collected clinical data, including severity of pre-eclampsia, maternal and neonatal outcomes. Of 176 cases of severe pre-eclampsia, 39% (n = 68) were further complicated by fetal growth restriction. However, no significant difference was seen in relation to the severity of pre-eclampsia between those with or without a growth-restricted baby. The presence of concomitant growth restriction was however associated with a significantly increased risk of stillbirth (p = 0.003) and total perinatal mortality (p = 0.02). CONCLUSIONS: The presence of fetal growth restriction among women with severe early-onset pre-eclampsia is not associated with increased severity of maternal disease. However the incidence of stillbirth and perinatal death is significantly increased in this sub-population

Etk/Bmx Regulates Proteinase-Activated-Receptor1 (PAR1) in Breast Cancer Invasion: Signaling Partners, Hierarchy and Physiological Significance

BACKGROUND: While protease-activated-receptor 1 (PAR(1)) plays a central role in tumor progression, little is known about the cell signaling involved. METHODOLOGY/PRINCIPAL FINDINGS: We show here the impact of PAR(1) cellular activities using both an orthotopic mouse mammary xenograft and a colorectal-liver metastasis model in vivo, with biochemical analyses in vitro. Large and highly vascularized tumors were generated by cells over-expressing wt hPar1, Y397Z hPar1, with persistent signaling, or Y381A hPar1 mutant constructs. In contrast, cells over-expressing the truncated form of hPar1, which lacks the cytoplasmic tail, developed small or no tumors, similar to cells expressing empty vector or control untreated cells. Antibody array membranes revealed essential hPar1 partners including Etk/Bmx and Shc. PAR(1) activation induces Etk/Bmx and Shc binding to the receptor C-tail to form a complex. Y/A mutations in the PAR(1) C-tail did not prevent Shc-PAR(1) association, but enhanced the number of liver metastases compared with the already increased metastases obtained with wt hPar1. We found that Etk/Bmx first binds via the PH domain to a region of seven residues, located between C378-S384 in PAR(1) C-tail, enabling subsequent Shc association. Importantly, expression of the hPar1-7A mutant form (substituted A, residues 378-384), which is incapable of binding Etk/Bmx, resulted in inhibition of invasion through Matrigel-coated membranes. Similarly, knocking down Etk/Bmx inhibited PAR(1)-induced MDA-MB-435 cell migration. In addition, intact spheroid morphogenesis of MCF10A cells is markedly disrupted by the ectopic expression of wt hPar1. In contrast, the forced expression of the hPar1-7A mutant results in normal ball-shaped spheroids. Thus, by preventing binding of Etk/Bmx to PAR(1) -C-tail, hPar1 oncogenic properties are abrogated. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration that a cytoplasmic portion of the PAR(1) C-tail functions as a scaffold site. We identify here essential signaling partners, determine the hierarchy of binding and provide a platform for therapeutic vehicles via definition of the critical PAR(1)-associating region in the breast cancer signaling niche

Mild gestational diabetes in pregnancy and the adipoinsular axis in babies born to mothers in the ACHOIS randomised controlled trial

BACKGROUND: Mild gestational diabetes is a common complication of pregnancy, affecting up to 9% of pregnant women. Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries, such as shoulder dystocia, bone fractures and nerve palsies. This study aimed to compare the plasma glucose concentrations and serum insulin, leptin and adiponectin in cord blood of babies of women (a) without gestational diabetes mellitus (GDM), (b) with mild GDM under routine care, or (c) mild GDM with treatment. METHODS: 95 women with mild GDM on oral glucose tolerance testing (OGTT) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and randomised to either Treatment (n = 46) or Routine Care (n = 49) and Control women with a normal OGTT (n = 133) were included in the study. Women with mild GDM (treatment or routine care group) and OGTT normal women received routine pregnancy care. In addition, women with treated mild GDM received dietary advice, blood glucose monitoring and insulin if necessary. The primary outcome measures were cord blood concentrations of glucose, insulin, adiponectin and leptin. RESULTS: Cord plasma glucose was higher in women receiving routine care compared with control, but was normalized by treatment for mild GDM (p = 0.01). Cord serum insulin and insulin to glucose ratio were similar between the three groups. Leptin concentration in cord serum was lower in GDM treated women compared with routine care (p = 0.02) and not different to control (p = 0.11). Adiponectin was lower in both mild GDM groups compared with control (Treatment p = 0.02 and Routine Care p = 0.07), while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment (p = 0.08) and control (p = 0.05). CONCLUSION: Treatment of women with mild GDM using diet, blood glucose monitoring and insulin if necessary, influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy

Inhibition of cell motility by troglitazone in human ovarian carcinoma cell line

<p>Abstract</p> <p>Background</p> <p>Troglitazone (TGZ) is a potential anticancer agent. Little is known about the effect of this agent on cancer cell migration.</p> <p>Methods</p> <p>Human ovarian carcinoma cell line, ES-2 cells were treated with various concentrations of TGZ. Cell migration was evaluated by wound-healing and Boyden chamber transwell experiments. PPARγ expression was blocked by PPARγ small interfering RNA. The effects of TGZ on phosphorylation of FAK, PTEN, Akt were assessed by immunoblotting using phospho-specific antibodies. The cellular distribution of paxillin, vinculin, stress fiber and PTEN was assessed by immunocytochemistry.</p> <p>Results</p> <p>TGZ dose- and time-dependently impaired cell migration through a PPARγ independent manner. TGZ treatment impaired cell spreading, stress fiber formation, tyrosine phosphorylation of focal adhesion kinase (FAK), and focal adhesion assembly in cells grown on fibronectin substratum. TGZ also dose- and time-dependently suppressed FAK autophosphorylation and phosphorylation of the C-terminal of PTEN (a phosphatase). At concentration higher than 10 μM, TGZ caused accumulation of PTEN in plasma membrane, a sign of PTEN activation.</p> <p>Conclusion</p> <p>These results indicate that TGZ can suppress cultured ES-2 cells migration. Our data suggest that the anti-migration potential of TGZ involves in regulations of FAK and PTEN activity.</p

Association of bovine leptin polymorphisms with energy output and energy storage traits in progeny tested Holstein-Friesian dairy cattle sires

peer-reviewedBackground: Leptin modulates appetite, energy expenditure and the reproductive axis by signalling via its receptor the status of body energy stores to the brain. The present study aimed to quantify the associations between 10 novel and known single nucleotide polymorphisms in genes coding for leptin and leptin receptor with performance traits in 848 Holstein-Friesian sires, estimated from performance of up to 43,117 daughter-parity records per sire. Results: All single nucleotide polymorphisms were segregating in this sample population and none deviated (P > 0.05) from Hardy-Weinberg equilibrium. Complete linkage disequilibrium existed between the novel polymorphism LEP-1609, and the previously identified polymorphisms LEP-1457 and LEP-580. LEP-2470 associated (P < 0.05) with milk protein concentration and calf perinatal mortality. It had a tendency to associate with milk yield (P < 0.1). The G allele of LEP-1238 was associated (P < 0.05) with reduced milk fat concentration, reduced milk protein concentration, longer gestation length and tended to associate (P < 0.1) with an increase in calving difficulty, calf perinatal mortality and somatic cells in the milk. LEP-963 exhibited an association (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and gestation length. It also tended to associate with milk yield (P < 0.1). The R25C SNP associated (P < 0.05) with milk fat concentration, milk protein concentration, calving difficulty and length of gestation. The T allele of the Y7F SNP significantly associated with reduced angularity (P < 0.01) and reduced milk protein yield (P < 0.05). There was also a tendency (P < 0.1) for Y7F to associate with increased body condition score, reduced milk yield and shorter gestation (P < 0.1). A80V associated with reduced survival in the herd (P < 0.05). Conclusions Several leptin polymorphisms (LEP-2470, LEP-1238, LEP-963, Y7F and R25C) associated with the energetically expensive process of lactogenesis. Only SNP Y7F associated with energy storage. Associations were also observed between leptin polymorphisms and calving difficulty, gestation length and calf perinatal mortality. The lack of an association between the leptin variants investigated with calving interval in this large data set would question the potential importance of these leptin variants, or indeed leptin, in selection for improved fertility in the Holstein-Friesian dairy cow.Department of Agriculture, Food and Fisheries, Ireland - Research Stimulus Fund (RSF-06-0353; RSF-06-0409); Irish Dairy Research Trust; Teagasc Walsh Fellowshi

Amniotic fluid embolism: A rare complication of second-trimester amniocentesis

Amniotic fluid embolism occurring following diagnostic amniocentesis is extremely rare. Only 2 cases have been reported in the English literature over the past 55 years, the most recent one approximately 3 decades ago. We present a case of amniocentesis at 24 weeks' gestation that was performed as part of an evaluation of abnormal fetal ultrasound findings. Immediately following amniotic fluid aspiration, maternal hemodynamic collapse occurred, initially diagnosed and treated as anaphylactic shock. Shortly after initial therapy, coagulopathy was noted and amniotic fluid syndrome suspected. Rapid response restored maternal hemodynamic stability; however, the fetus had suffered fatal damage

Amniotic fluid embolism: A rare complication of second-trimester amniocentesis

Amniotic fluid embolism occurring following diagnostic amniocentesis is extremely rare. Only 2 cases have been reported in the English literature over the past 55 years, the most recent one approximately 3 decades ago. We present a case of amniocentesis at 24 weeks' gestation that was performed as part of an evaluation of abnormal fetal ultrasound findings. Immediately following amniotic fluid aspiration, maternal hemodynamic collapse occurred, initially diagnosed and treated as anaphylactic shock. Shortly after initial therapy, coagulopathy was noted and amniotic fluid syndrome suspected. Rapid response restored maternal hemodynamic stability; however, the fetus had suffered fatal damage

Impact of surgeon annual volume on short-term maternal outcome in cesarean delivery

Background The annual procedure volume is an accepted marker for quality of care and has been documented in various medical fields. Surgeon volume has been shown to correlate with morbidity and mortality in surgical and high risk medical procedures. Though cesarean delivery is one of the most common surgical procedures in the USA, the link between surgeon's annual cesarean delivery volume and maternal outcome has never been tested. Objective To evaluate the impact of surgeons' annual volume on short term maternal outcome in cesarean deliveries. Study Design Retrospective cohort study in a single tertiary center between 2006 and 2013. Cesarean deliveries were categorized into two groups based on the annual volume of cesarean delivery of the attending obstetrician. LOW group included low annual volume obstetricians, whose annual volume of cesarean delivery was lower than median. HIGH group comprised high annual volume obstetricians whose annual volume was median and above. Further analyses were done for quartiles and for four clinical relevant groups according to the annual number of cesarean delivery performed/supervised by the attending (20 or less, 21-60 , 61-120 and more than 120) The primary outcome was a composite adverse maternal outcome including one or more of the following: urinary or gastrointestinal tract injuries, hemoglobin drop > three gm/dL, blood transfusion, re-laparotomy, puerperal fever, prolonged maternal hospitalization and readmission. Secondary outcomes were operative times (skin incision to delivery and overall). Results A total of 11,954 cesarean deliveries were included, the median annual number of cesarean delivery performed/supervised by one obstetrician was 48. Unadjusted analysis suggested that HIGH group patients, had fewer urinary and gastrointestinal injuries 18/9278 (0.2%) vs. 16/2676 (0.6%), P three gm/dL 1053/9278 (11.5%) vs. 366/2676 (13.8%), P three gm/dL and lower incidence of prolonged maternal hospitalization. Operative times were significantly shorter for HIGH group. Composite adverse maternal outcome ranged from 21.8% in the lowest quartile , to 17.9% in Q2, to 17.4% in Q3, and 15.6% in Q4. With Q4 defined as the reference, Q3 had an OR of 1.14 95%CI[1.01-1.29] , p=0.029, Q2 had an OR 1.18 95%CI[1.02-1.36] , p=0.021 and Q1 had an – OR 1.51 95%CI[1.14-1.99], p=0.004 for composite adverse maternal outcome. Composite adverse maternal outcome ranged from 21.5% in clinical group 1, to 17.5% in clinical group 2 to 17.9% in clinical group 3, and 15.2% in clinical group 4, p value=0.001). Cesarean delivery performed/supervised by clinical groups 2, 3 and 4 in compare to clinical group 1 were associated with a statistically significant risk reduction, (23%, 25% and 34% respectively). Conclusion Maternal composite morbidity is decreased as the volume of cesarean deliveries performed or supervised by obstetricians increases.</p