The role of STIM1 and SOCE in smooth muscle contractility.

Contraction is a central feature for skeletal, cardiac and smooth muscle; this unique feature is largely dependent on calcium (Ca2+) signaling and therefore maintenance of internal Ca2+ stores. Stromal interaction molecule 1 (STIM1) is a single-pass transmembrane protein that functions as a Ca2+ sensor for the activation store-operated calcium channels (SOCCs) on the plasma membrane in response to depleted internal sarco(endo)plasmic (S/ER) reticulum Ca2+ stores. STIM1 was initially characterized in non-excitable cells; however, evidence from both animal models and human mutations suggests a role for STIM1 in modulating Ca2+ homeostasis in excitable tissues as well. STIM1-dependent SOCE is particularly important in tissues undergoing sustained contraction, leading us to believe STIM1 may play a role in smooth muscle contraction. To date, the role of STIM1 in smooth muscle is unknown. In this review, we provide a brief overview of the role of STIM1-dependent SOCE in striated muscle and build off that knowledge to investigate whether STIM1 contributes to smooth muscle contractility. We conclude by discussing the translational implications of targeting STIM1 in the treatment of smooth muscle disorders.

Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect?

INTRODUCTION: Although antifibrinolytic agents are used to prevent and treat hemorrhage, there are concerns about a potential increased risk for peripartum venous thromboembolism. We sought to determine the impact of tranexamic acid and ɛ-aminocaproic acid on in vitro clotting properties in pregnancy. METHODS: Blood samples were obtained from healthy pregnant, obese, and preeclamptic pregnant women (n = 10 in each group) prior to delivery as well as from healthy non-pregnant controls (n = 10). Maximum clot firmness (MCF) and clotting time (CT) were measured using rotation thromboelastometry in the presence of tranexamic acid (3, 30, or 300 µg/mL) or ɛ-aminocaproic acid (30, 300, or 3000 µg/mL). ANOVA and regression analyses were performed. RESULTS: Mean whole blood MCF was significantly higher in healthy pregnant vs. non-pregnant women (66.5 vs. 57.5 mm, p < 0.001). Among healthy pregnant women, there was no significant difference between mean MCF (whole blood alone, and with increasing tranexamic acid doses = 66.5, 66.1, 66.4, 66.3 mm, respectively; p = 0.25) or mean CT (409, 412, 420, 424 sec; p = 0.30) after addition of tranexamic acid. Similar results were found using ɛ-aminocaproic acid. Preeclamptic women had a higher mean MCF after the addition of ɛ-aminocaproic acid and tranexamic acid (p = 0.05 and p = 0.04, respectively) compared to whole blood alone. CONCLUSIONS: Pregnancy is a hypercoagulable state, as reflected by an increased MCF compared to non-pregnant women. Addition of antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant, pregnant, and obese women. Whether antifibrinolytics are safe in preeclampsia may require further study.

Midregional pro-adrenomedullin plasma concentrations are blunted in severe preeclampsia.

Levels of the peptide hormone adrenomedullin (AM) are elevated during normal pregnancy, but whether this differs during complications of pregnancy remains unresolved. AM can be quantified by measuring its pre-prohormone byproduct, midregional pro-adrenomedullin (MR-proADM). MR-proADM has shown prognostic value as a biomarker of heart failure, sepsis, and community-acquired pneumonia. Given the relevance of AM to pregnancy, we tested the hypothesis that MR-proADM provides a biomarker for preeclampsia. We find that MR-proADM plasma concentrations are blunted in severe preeclampsia and that MR-proADM is similarly effective as established biomarkers endoglin and placental growth factor at discriminating patients with severe preeclampsia from controls.

Progesterone receptor membrane component 1 (PGRMC1) expression in fetal membranes among women with preterm premature rupture of the membranes (PPROM).

PGRMC1 function is implicated in maintaining fetal membrane (FM) integrity. PGRMC1 was detectable primarily in the cytoplasm of FM cells and was actively regulated in FMs and relevant for PGRMC1-mediated progesterone action. By cell type, PGRMC1 expression was higher in amnion and chorion compared with decidua. By clinical phenotype, PGRMC1 expression was higher among preterm-no-labor and term-no-labor subjects compared to PPROM. PGRMC1 expression appears to be diminished in PPROM subjects.

Factors associated with the change in prevalence of cardiomyopathy at delivery in the period 2000-2009: a population-based prevalence study.

OBJECTIVE: Cardiomyopathy (CM) at delivery is increasing in prevalance. The objective of this study was to determine which medical conditions are attributable to this increasing prevalance. DESIGN: Population prevalence study from 2000 to 2009. SETTING: The Nationwide Inpatient Sample (NIS). SAMPLE: Pregnant women admitted for delivery were identified in the NIS for the years 2000-2009. METHODS: Temporal trends in pre-existing medical conditions and in medical and obstetric complications at delivery admissions were determined by linear regression. The change in the prevalence of CM among all pregnant women was compared with the change in the prevalance of CM among pregnant women without pre-existing conditions or complications. MAIN OUTCOME MEASURE: Prevalence of CM. RESULTS: The prevalence of CM increased from 0.25 per 1000 deliveries in 2000 to 0.43 per 1000 deliveries in 2009 (P < 0.0001). Women with chronic hypertension had increased odds of developing CM compared with women without chronic hypertension (odds ratio, OR, 13.2; 95% confidence interval, 95% CI, 12.5-13.7). The linear increase in chronic hypertension over the 10-year period was the single identified pre-existing medical condition that explained the increasing prevalence of CM at delivery (P = 0.005 for the differences in slopes for linear trends). CONCLUSIONS: Pregnant women with chronic hypertenion are at an increased risk for CM at delivery, and the increasing prevalence of chronic hypertension is an important factor associated with the increasing prevalence of CM at the time of delivery. Among women without chronic hypertension, the prevalence of CM at delivery did not change during the time period.

Cervical dilation as a predictor of pregnancy outcome following emergency cerclage.

OBJECTIVE: To determine whether cervical dilation at the time of physical examination indicated cerclage placement can predicts latency and gestational age at delivery. METHODS: A retrospective cohort study of all women who underwent physical examination indicated cerclage placement from 1996 to 2011 at Duke University Hospital (DUH) was performed. Physical examination indicated cerclage was defined as cerclage placement after 16 weeks in women with a cervical length of less than 2.5 cm and/or cervical dilation greater than or equal to 1 cm at time of procedure. Subjects were divided into two groups depending on cervical dilation at time of procedure (2 cm, <2 cm) for comparison. A multivariate linear regression model for the outcome gestational age of delivery was constructed, controlling for confounding variables. RESULTS: A total of 110 women with complete data were available for analysis. Median gestational age at cerclage placement was similar between the two groups (20.3 vs. 20.3 weeks, p = 0.8). Women with cervical dilatation ≥ 2 cm dilation delivered at an earlier median gestational age than women with cervical dilation <2 cm (27.0 vs. 35.6 weeks, p < 0.001). Cervical dilation at the time of cerclage placement independently predicted gestational age at delivery while controlling for use of intracervical Foley balloon catheter for membrane reduction, cerclage suture type, history of prior preterm birth, race, insurance status, and tobacco use. CONCLUSIONS: Women who receive a rescue cerclage are more likely to deliver at an earlier gestational age when cervical dilation is ≥ 2 cm at the time of procedure.

Bleeding per vaginam is associated with funisitis in women with preterm prelabour rupture of the fetal membranes.

OBJECTIVE: To evaluate the risk of funisitis among women with preterm prelabour rupture of the membranes (PPROM) and subsequent bleeding per vaginam. DESIGN: Prospective cohort study. SETTING: A University Hospital in the USA. POPULATION: A total of 157 women with PPROM, divided into those with bleeding per vaginam during the hospital admission (n = 46) and those without bleeding per vaginam (n = 111). METHODS: Pathologist blinded to bleeding status assessed placental pathology for funisitis. MAIN OUTCOME MEASURES: Funisitis. RESULTS: Women with bleeding per vaginam were more likely to have funisitis (67.4% versus 36%, P < 0.001) compared with those without bleeding. Logistic regression demonstrated that bleeding per vaginam predicted funisitis after controlling for gestational age at admission, latency period and gestational age at delivery. CONCLUSIONS: Among women with PPROM, those with bleeding per vaginam are more likely to have funisitis than those without bleeding per vaginam.

Cervicovaginal fistula presenting during miscarriage.

Cervicovaginal fistula is a recognized complication of induced mid-trimester termination of pregnancy, but more recently it has also been recognized as representing a complication of prior cervical cerclage. We report the ultrasound findings of prolapse of the amniotic sac through a cervicovaginal fistula in a woman with prior cervical cerclage. A woman with cervical incompetence and prior failed McDonald cerclage presented for prophylactic Shirodkar cerclage. Before the procedure, transvaginal ultrasonography revealed a live intrauterine pregnancy at 14 weeks' gestation. Upon further ultrasound examination, the amniotic sac appeared to protrude through the posterior wall of the cervix into the vaginal vault. Pelvic examination verified prolapse of the amniotic sac through a cervicovaginal fistula. The patient underwent an uncomplicated dilatation and evacuation. Women with a history of cervical cerclage are at risk for the development of cervicovaginal fistula, the detection of which is important to prevent potential morbidity.

Noninvasive fetal RhCE genotyping from maternal blood.

BACKGROUND: The successful prevention of RhD disease has brought attention to other red blood cells' antigens causing alloimmunisation including RhC/c and RhE/e. Prenatal diagnosis of fetal Rh genotype from maternal blood is in clinical use in Europe but not in the USA. OBJECTIVE: To estimate the collective reported diagnostic accuracy of fetal RhCE genotyping from peripheral maternal blood and compare the results of genotyping when fetal cells and free fetal DNA (FfDNA) are used. SEARCH STRATEGY: English-written literature describing fetal RhCE determination from maternal blood using fetal cells or FfDNA was performed using medical subject headings and text words. The sources included Pubmed (1966-2007), Ovid (1966-2007), CINAHL, The Cochrane Library, ACP Journal Club and OCLC. Key words were prenatal diagnosis, fetal RhCE, fetal DNA in maternal blood and alloimmunisation. SELECTION CRITERIA: A study was considered eligible if it described fetal RhCE type determination using maternal peripheral blood reported in the English literature. Abstracts were excluded. DATA COLLECTION AND ANALYSIS: From each study, we determined the number of samples tested, fetal RhCE genotype, the source of the fetal DNA, gestational age, presence of alloimmunisation and confirmation of fetal RhCE type. Exclusions and inclusions were noted. We calculated composite estimates of accuracy using a weighted random effects model. We assessed the papers against an international quality, STARD checklist which is standards for reporting studies of diagnostic accuracy. MAIN RESULTS: We identified 20 protocols in six English-written publications reporting fetal RhC/c (seven protocols) and/or E/e (13 protocols) genotyping using DNA obtained from maternal blood for a total of 369 samples. For RhC/c, 176 samples were tested and for RhE/e, 193 samples were tested. Accuracy was determined for each study and for all studies. The combined accuracy of fetal genotype was 96.3% for RhC/c and 98.2% for RhE/e. Only a few samples of the sorted cells were found to be a source for accurate diagnosis, but plasma was consistently the best source of fetal RhCE genotyping in 147/147 (100%) for RhC/c and 168/168 (100%) for RhE/e. CONCLUSIONS: The combined accuracy of noninvasive fetal RhC/c or RhE/e determination using maternal peripheral blood is 96.3% and 98.2%, respectively. FfDNA in maternal plasma is a better source for genotyping reported to be 100% correct for both RHCE genotypes. Further studies and reports of accuracy from laboratories performing the tests are required before prenatal determination of fetal RhC/c or RhE/e genotypes from maternal blood can safely replace the current methods used in the management of the RhC/c or RhE alloimmunised pregnancies.