Circadian patterns of heart rate variability in fetal sheep after hypoxia-ischaemia: A biomarker of evolving brain injury.

Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and severe neurodevelopmental disability in survivors, including cerebral palsy, although there are no reliable biomarkers to detect at risk fetuses that may have suffered a transient period of severe HI. We investigated time and frequency domain measures of fetal heart rate variability (FHRV) for 3 weeks after HI in preterm fetal sheep at 0.7 gestation (equivalent to preterm humans) until 0.8 gestation (equivalent to term humans). We have previously shown that this is associated with delayed development of severe white and grey matter injury, including cystic white matter injury (WMI) resembling that observed in human preterm infants. HI was associated with suppression of time and frequency domain measures of FHRV and reduced their circadian rhythmicity during the first 3 days of recovery. By contrast, circadian rhythms of multiple measures of FHRV were exaggerated over the final 2 weeks of recovery, mediated by a greater reduction in FHRV during the morning nadir, but no change in the evening peak. These data suggest that the time of day at which FHRV measurements are taken affects their diagnostic utility. We further propose that circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury. KEY POINTS: Hypoxia-ischaemia (HI) before birth is a key risk factor for stillbirth and probably for disability in survivors, although there are no reliable biomarkers for antenatal brain injury. In preterm fetal sheep, acute HI that is known to lead to delayed development of severe white and grey matter injury over 3 weeks, was associated with early suppression of multiple time and frequency domain measures of fetal heart rate variability (FHRV) and loss of their circadian rhythms during the first 3 days after HI. Over the final 2 weeks of recovery after HI, exaggerated circadian rhythms of frequency domain FHRV measures were observed. The morning nadirs were lower with no change in the evening peak of FHRV. Circadian changes in FHRV may be a low-cost, easily applied biomarker of antenatal HI and evolving brain injury.

Impact of statins based on high-risk plaque features on coronary plaque progression in mild stenosis lesions: results from the PARADIGM study.

AIMS: To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA). METHODS AND RESULTS: We analyzed mild stenosis (25-49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02-3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09-2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07-2.22; P = 0.020). CONCLUSION: In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02803411.

Speech Outcomes of a National Cohort of Children with Orofacial Cleft at 5 and 10 Years of age.

OBJECTIVE: To assess speech outcomes at five and ten years of age in a nationwide study of children with orofacial cleft. DESIGN: Prospective study. PARTICIPANTS: Children born with orofacial cleft and having primary surgery in New Zealand. Speech samples were available for 151 five-year-old, and 163 ten-year-old children. MAIN OUTCOME MEASURES: Intelligibility, Acceptability, Velopharyngeal function, Hypernasality, Hyponasality, severity of airflow evaluated by perceptual speech assessment (using the standardised Rhinocleft assessment), and overall assessment of requirement for clinical intervention. RESULTS: A large proportion of five-year-old children had speech that was considered to be not completely intelligible, was not acceptable, and had inadequate velopharyngeal function. The noted deficiencies led to a clinical judgement that further speech and/or surgical intervention was required in 85% with cleft lip and palate, 65% with cleft palate and 26% with cleft lip. The proportion of children with poor speech outcomes in the ten-year-old children was lower, though of clinical importance, further intervention required for 25% with CLP, 15% with CP and 3% with CL. The number of sound production errors in both age groups followed the same pattern with fewest in those with CL and most in those with CLP. CONCLUSIONS: A significant proportion of children with orofacial cleft were found to have poor speech outcomes requiring further treatment. The outcomes are poor compared to centres reported in the UK and Scandinavia. New Zealand requires a review of the current services for individuals born with cleft to improve speech outcomes and interdisciplinary care.

Association between Aortic Valve Calcification Progression and Coronary Atherosclerotic Plaque Volume Progression in the PARADIGM Registry.

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized ß = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (ß = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (ß = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (ß = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (ß = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (ß = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.

Quality of Life Using General Population Validated Questionnaires in Children With Cleft Lip and/or Palate in New Zealand.

OBJECTIVE: To determine the level of quality of life (QoL) in children with cleft lip and/or palate (CL/P) and whether this differs by cleft phenotype. DESIGN: A cohort of children with CL/P born in New Zealand. SETTING: A nationwide study of children born with CL/P and having primary surgery in New Zealand. PARTICIPANTS: Children with CL/P and their families (n = 397) who attended a cleft clinic between October 1, 2014, and September 30, 2017, and agreed to complete questionnaires on QoL. MAIN OUTCOMES: Primary outcomes were QoL from the PedsQL 4.0 core generic questionnaires and the PedsQL 2.0 Family impact scale. RESULTS: Children with CL/P in New Zealand generally have a high QoL as assessed by the PedsQL. The impact of cleft phenotype had limited effects on the child, however there were significant impacts on parents and families. We found that the family impact scale differed by cleft phenotype with those with CL having the highest QoL and those with cleft palate the lowest, and this was consistent across QoL subscales. Quality of life improved as a whole by age, particularly in physical and cognitive functioning, as well as in the ability to undertake family activities. CONCLUSIONS: Children with CL/P have generally good levels of QoL in New Zealand, however cleft phenotype impacts on the level, with the lowest levels in those with cleft palate. Psychological support of children with cleft and their families should be an integral part of cleft care.

LncRNA VINAS regulates atherosclerosis by modulating NF-κB and MAPK signaling.

Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor-deficient (LDLR-/-) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1ß, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow-derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.

Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence.

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr -/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr -/- mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

Association of High-Density Calcified 1K Plaque With Risk of Acute Coronary Syndrome.

Importance: Plaque morphologic measures on coronary computed tomography angiography (CCTA) have been associated with future acute coronary syndrome (ACS). However, the evolution of calcified coronary plaques by noninvasive imaging is not known. Objective: To ascertain whether the increasing density in calcified coronary plaque is associated with risk for ACS. Design, Setting, and Participants: This multicenter case-control cohort study included individuals enrolled in ICONIC (Incident Coronary Syndromes Identified by Computed Tomography), a nested case-control study of patients drawn from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, which included 13 study sites in 8 countries. Patients who experienced core laboratory-verified ACS after baseline CCTA (n = 189) and control individuals who did not experience ACS after baseline CCTA (n = 189) were included. Patients and controls were matched 1:1 by propensity scores for age; male sex; presence of hypertension, hyperlipidemia, and diabetes; family history of premature coronary artery disease (CAD); current smoking status; and CAD severity. Data were analyzed from November 2018 to March 2019. Exposures: Whole-heart atherosclerotic plaque volume was quantitated from all coronary vessels and their branches. For patients who underwent invasive angiography at the time of ACS, culprit lesions were coregistered to baseline CCTA lesions by a blinded independent reader. Low-density plaque was defined as having less than 130 Hounsfield units (HU); calcified plaque, as having more than 350 HU and subcategorized on a voxel-level basis into 3 strata: 351 to 700 HU, 701 to 1000 HU, and more than 1000 HU (termed 1K plaque). Main Outcomes and Measures: Association between calcium density and future ACS risk. Results: A total of 189 patients and 189 matched controls (mean [SD] age of 59.9 [9.8] years; 247 [65.3%] were male) were included in the analysis and were monitored during a mean (SD) follow-up period of 3.9 (2.5) years. The overall mean (SD) calcified plaque volume (>350 HU) was similar between patients and controls (76.4 [101.6] mm3 vs 99.0 [156.1] mm3; P = .32), but patients who experienced ACS exhibited less 1K plaque (>1000 HU) compared with controls (3.9 [8.3] mm3 vs 9.4 [23.2] mm3; P = .02). Individuals within the highest quartile of 1K plaque exhibited less low-density plaque, as a percentage of total plaque, when compared with patients within the lower 3 quartiles (12.6% [10.4%] vs 24.9% [20.6%]; P < .001). For 93 culprit precursor lesions detected by CCTA, the volume of 1K plaque was lower compared with the maximally stenotic lesion in controls (2.6 [7.2] mm3 vs 7.6 [20.3] mm3; P = .01). The per-patient and per-lesion results were similar between the 2 groups when restricted to myocardial infarction cases. Conclusions and Relevance: Results of this study suggest that, on a per-patient and per-lesion basis, 1K plaque was associated with a lower risk for future ACS and that measurement of 1K plaque may improve risk stratification beyond plaque burden.

Anterior abdominal wall defects managed at a tertiary maternal-fetal medicine service in New Zealand: What counselling advice can we offer parents?

BACKGROUND: Anterior abdominal wall defects, including gastroschisis and omphalocoele, are common fetal anomalies. The management remains complicated, and their diagnosis may lead to significant parental distress. Effective parental counselling may impact on parental perceptions of the defect and help guide pregnancy management. AIMS: Using contemporary data, we aimed to describe clinical outcomes of patients with gastroschisis or omphalocoele in order to provide information for clinicians to assist in parental counselling. MATERIALS AND METHODS: We followed a case-series of patients with anterior abdominal wall defects referred to our regional Maternal Fetal Medicine services from 2011 to 2016. Outcomes of interest antenatally included details of diagnosis, associated anomalies and outcomes of pregnancy and postnatally included the nature of surgical repair, hospital stay and secondary complications until initial discharge. RESULTS: Eighty babies with gastroschisis were referred antenatally, and 72 were liveborn. Forty-nine babies with omphalocoele were referred antenatally, and 24 were liveborn. One further neonate with omphalocoele was postnatally diagnosed. Seventy-one neonates with gastroschisis progressed to operation, 30 developed complications post-surgery, and 68 survived until initial discharge. Twenty-two neonates with omphalocoele progressed to surgery, only two developed complications, and 21 survived until initial discharge. Eight of the surviving neonates with omphalocoele had associated structural abnormalities. The median hospital stay was 27 and eight days for gastroschisis and omphalocoele, respectively. CONCLUSION: Neonates with gastroschisis can have complex postnatal periods. Omphalocoele is associated with high antenatal mortality, especially in the presence of associated abnormalities; however, surviving neonates may have uneventful postnatal periods.

Phagocytosis of Extracellular Vesicles Extruded From the Placenta by Ovarian Cancer Cells Inhibits Growth of the Cancer Cells.

OBJECTIVE: Ovarian cancer is a common gynecological cancer, and parity is negatively associated with the incidence of this disease. This negative association is hypothesized to be due in part to shifting the balance of estrogen and progesterone toward more progesterone and reduced ovulation during pregnancy. However, studies suggested that parity is also associated with estrogen-independent gynecological cancers suggesting balance of hormones may not be the only protective factor. Extracellular vesicles (EVs) play an important role in cell-to-cell communication in physiological and pathological conditions. During pregnancy, large amounts of EVs are extruded from the placenta, and they seem to be involved in the remarkable adaptation of a woman's body to normal pregnancy. We hypothesized that EVs extruded from the placenta play a role in this protective effect. METHODS: Placental EVs were collected from first-trimester placentae, and cancer cell EVs were isolated from ovarian cancer cells. The EVs were exposed to ovarian cancer cells for 48 hours. The proliferation of cancer cells and the cell cycle were measured. In addition, phagocytosis of deported placental EVs by cancer cells was also measured. RESULTS: The proliferation of cancer cells was significantly reduced by treatment with placental EVs (P = 0.001, analysis of variance), but not EVs from monocytes (P = 0.195), compared with untreated cancer cells. Furthermore, placental EVs also prevented the proliferation of cancer cells induced by cancer cell-derived EVs (P = 0.001). This inhibition of proliferation of ovarian cancer cells was partially due to phagocytosis of placental EVs by cancer cells. Phagocytosis of placental EVs delayed progression through the cell cycle. Calreticulin, a phagocytic "eat me" signal carried by placental EVs significantly inhibited ovarian cancer growth (P = 0.001). CONCLUSIONS: Our data demonstrated that EVs extruded from the placenta prevented ovarian cancer cell growth by a mechanism that involved delaying progression of the cell cycle after phagocytosis of the EVs.

Inequity in timing of prenatal screening in New Zealand: Who are our most vulnerable?

BACKGROUND: In New Zealand (NZ), Maori and Pacific women are less likely to complete prenatal screening for Down syndrome and other aneuploidies than other ethnic groups. Young women <20 have low rates of completed screening compared with women >20 years. Women living in deprived areas have lower completed screen rates than women living in more affluent areas. Combined first trimester screening has a superior sensitivity (85%) compared with second trimester screening (75%) for trisomy 21. The relative contribution of demographic factors to timing of screening uptake (first vs second trimester) has not previously been examined. AIM: To evaluate the association of ethnicity, deprivation, District Health Board (DHB) of domicile and maternal age with timing of prenatal screening (first vs second trimester) in pregnant women screened in NZ from 2010 to 2013. METHODS AND MATERIALS: Univariate logistic regression analyses were used to explore the association between timing of completed screening and each of ethnicity, deprivation index, DHB of domicile and maternal age. Multivariate logistic regression models were developed to calculate odds ratios (OR) and 95% confidence intervals (CI). Statistical analyses were performed using SAS v9.3 RESULTS: Of completed prenatal screens, 88% were completed in the first trimester. Ethnicity, age, deprivation and DHB were all significant predictors of completed first versus second trimester screening. Maori women were almost 60% less likely (adjusted OR 0.37, CI 0.35-0.39) and Pacific women almost 80% less likely (adjusted OR 0.23, CI 0.21-0.24) than NZ European women to have completed first versus second trimester screening. Women <30 years were less likely to have completed first trimester screening, as were more deprived women. Variation was also seen by DHB with women living in Whanganui DHB less likely to have completed first versus second trimester screening than women living in Auckland (adjusted OR 0.76, CI 0.71-0.81). Women living in Bay of Plenty DHB were more likely to be screened in the first versus second trimester compared with women living in Auckland (adjusted OR 1.55, CI 1.38-1.74). Within Auckland itself, women living in Counties Manukau DHB were less likely to be screened in the first versus second trimester than women living in Auckland DHB even after adjusting for ethnicity, deprivation and maternal age. CONCLUSION: Maori and Pacific women have the lowest uptake of completed first versus second trimester screening after adjusting for age, deprivation and DHB. Research is required to understand if this relates to characteristics of the carer making the offer of screening, language and/or cultural barriers to care or specific collective cultural or religious views held by women from these ethnicities. The lower completed first trimester versus second trimester prenatal screening in deprived areas, as well as variation by DHB, may relate to the availability of ultrasound and/or laboratory services in specific regions. Cost may be a contributing factor to inequity in timing of completed prenatal screening uptake, as first trimester screening incurs a part-charge to the individual, while second trimester screening is fully funded. Systemic factors within the NZ maternity model of care may also be contributory with a potential disconnect occurring for the woman between primary medical care and later registration with a Lead Maternity Carer in the first trimester.

Clopidogrel response variability is associated with endothelial dysfunction in coronary artery disease patients receiving dual antiplatelet therapy.

OBJECTIVES: Dual antiplatelet therapy with aspirin and a platelet P2Y12 ADP receptor antagonist is the cornerstone of treatment following percutaneous coronary intervention (PCI). Several clinical and genetic factors can cause suboptimal clopidogrel response. We examined the impact of endothelial dysfunction on clopidogrel response variability in subjects with stable coronary artery disease (CAD) after PCI. METHODS: We consecutively enrolled 198 patients with stable CAD one month after successful PCI. All patients were receiving dual antiplatelet therapy (clopidogrel 75 mg and aspirin 100 mg/day). Platelet reactivity was measured by VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230. Endothelial function was evaluated by flow mediated dilation (FMD). RESULTS: Patients with high on treatment platelet reactivity (32% of the study population), compared to subjects with low on treatment platelet reactivity, presented decreased FMD values (4.35 ± 2.22% vs. 5.74 ± 3.29%, p = 0.01). Moreover, an inverse association between endothelial function measurement and platelet reactivity (r = -0.24, p = 0.001) was found. Importantly, multivariate analysis after adjustment for age, gender and confounders revealed by the univariate analysis (left ventricle ejection fraction, body mass index, diabetes, dyslipidemia, coronary lesion number) showed that for every decrease in FMD by 1% there is an anticipated increased in the odds of patients to have HPR by 1.66 (95% CI 1.03-2.57, p = 0.037). CONCLUSIONS: Endothelial dysfunction is associated with clopidogrel response variability in patients after PCI receiving dual antiplatelet therapy. These findings shed some light on the mechanisms affecting individual platelet response to antiplatelet therapy and may explain the non-straight forward association between clopidogrel dose, platelet inhibition and cardiovascular outcome.

Calcium supplementation prevents endothelial cell activation: possible relevance to preeclampsia.

OBJECTIVES: Preeclampsia is a leading cause of maternal and fetal mortality and morbidity. A hallmark of preeclampsia is endothelial cell dysfunction/activation in response to 'toxins' from the placenta. Necrotic trophoblastic debris (NTD) is one possible placental toxin and other activators of endothelial cells include inflammatory cytokines. Calcium supplementation appears to protect 'at-risk' women from developing preeclampsia but how is unclear. METHODS: Placental explants were cultured with interleukin-6 (IL-6) in varied concentrations of calcium. The resultant trophoblastic debris was exposed to endothelial cells. Endothelial cells were exposed to activators including NTD, IL-6, and preeclamptic sera in the presence of varied concentrations of calcium and activation monitored by quantifying cell surface markers by ELISA. RESULTS: Raising the levels of calcium did not prevent the IL-6-induced shedding of NTD from placental explants but did prevent the activation of endothelial cells in response to IL-6, preeclamptic sera, or NTD. Reducing the level of calcium directly induced the activation of endothelial cells. Inhibiting nitric oxide synthetase ablated the ability of high calcium levels to protect endothelial cell activation. The activity of endothelial cell nitric oxide synthetase was blocked with L-N-nitroarginine methyl ester. CONCLUSION: Our results demonstrate calcium levels do not affect the shedding of trophoblastic debris but are important to endothelial cell activation and supplemental calcium may reverse the activation of the endothelium in preeclamptic women. These results may in part explain the benefits of calcium supplementation in the reduction of risk for developing preeclampsia and provide in-vitro mechanistic support for the use of calcium supplementation in at-risk women.

Calcium channel blockers prevent endothelial cell activation in response to necrotic trophoblast debris: possible relevance to pre-eclampsia.

AIMS: Pre-eclampsia is characterized by endothelial activation, which is triggered by placental factor(s). One such factor may be trophoblastic debris that is shed into the maternal blood to become trapped against the maternal pulmonary endothelium. Phagocytosis of necrotic trophoblastic debris (NTD) induces endothelial cell activation with increased secretion of interleukin-6 (IL-6) and transforming growth factor ß1 (TGFß1), which may induce systemic endothelial cell activation. In addition to its effects on vascular smooth muscle, evidence suggests that nifedipine may also affect the endothelium, contributing to the therapeutic benefits of the drug. We investigated whether nifedipine could reverse the endothelial cell activation induced by NTD. METHODS AND RESULTS: Trophoblastic debris was collected from placental explants and exposed to endothelial cells with or without nifedipine, verapamil, or a nitric oxide (NO) donor for 24 h. Endothelial cell activation was measured by cell-surface intracellular adhesion molecule-1 and E-selectin, as well as monocyte adhesion. The activation of endothelial cells exposed to NTD or sera from pre-eclamptic women was significantly reduced by nifedipine or verapamil. In addition, the increases in the levels of IL-6 or TGFß1 in conditioned media from endothelial cells following phagocytosis of NTD were significantly reduced by nifedipine. These actions of nifedipine were reversed by the NO synthetase inhibitor l-NAME and mimicked by a NO donor. CONCLUSION: Our results suggest that calcium channel blockers may have a direct effect upon endothelial cells, reducing the endothelial cell activation that is a key pathogenic feature of pre-eclampsia. This action may be mediated, in part, by NO.

Mifepristone for uterine fibroids.

BACKGROUND: Uterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials. OBJECTIVES: To determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women. SEARCH METHODS: We searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions. SELECTION CRITERIA: Only truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included. DATA COLLECTION AND ANALYSIS: Four authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model. MAIN RESULTS: Three studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I(2) = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I(2) = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes. AUTHORS' CONCLUSIONS: Mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.

Validation of the Edinburgh Postnatal Depression Scale (EPDS) as a screening tool for postnatal depression in Samoan and Tongan women living in New Zealand.

AIM: To validate the EPDS as a screening tool for postnatal depression in Samoan and Tongan women living in New Zealand. METHODS: 85 Samoan and 85 Tongan women who delivered babies at Middlemore Hospital from February 2009 to June 2010 completed the EPDS questionnaire and from 4 weeks after delivery followed by an interview using a Composite International Diagnostic Interview (CIDI) within 4 weeks of the EPDS completion. RESULTS: The EPDS in English, Tongan and Samoan languages is a valid and consistent tool for screening for PND in Samoan and Tongan women. A cut-off score of ≥10 for Tongan and ≥11 for Samoan women gave the best sensitivity (80%) and specificity (80%) combination whereas a higher cut-off of ≥16 for Tongan and ≥17 Samoan women gave the best positive predictive value (82%) and negative predictive value (86%) for serious depression. The lower cut-off scores correctly diagnosed 82% and the higher cut-offs more than 87% of women with serious depression. CONCLUSION: The EPDS was an acceptable and valid tool for PND screening in English, Samoan and Tongan languages amongst Samoan and Tongan women. The cut-offs for PND screening were dissimilar in the two groups with a ≥10 for Tongan and ≥11 for Samoan women. A higher cut-off of ≥16 for Tongan and ≥17 for Samoan women improves the predictive value of the instrument.

Minor histocompatibility antigens are expressed in syncytiotrophoblast and trophoblast debris: implications for maternal alloreactivity to the fetus.

The fetal semi-allograft can induce expansion and tolerance of antigen-specific maternal T and B cells through paternally inherited major histocompatibility complex and minor histocompatibility antigens (mHAgs). The effects of these antigens have important consequences on the maternal immune system both during and long after pregnancy. Herein, we investigate the possibility that the placental syncytiotrophoblast and deported trophoblastic debris serve as sources of fetal mHAgs. We mapped the expression of four mHAgs (human mHAg 1, pumilio domain-containing protein KIAA0020, B-cell lymphoma 2-related protein A1, and ribosomal protein S4, Y linked) in the placenta. Each of these proteins was expressed in several placental cell types, including the syncytiotrophoblast. These antigens and two additional Y chromosome-encoded antigens [DEAD box polypeptide 3, Y linked (DDX3Y), and lysine demethylase5D] were also identified by RT-PCR in the placenta, purified trophoblast cells, and cord blood cells. Finally, we used a proteomic approach to investigate the presence of mHAgs in the syncytiotrophoblast and trophoblast debris shed from first-trimester placenta. By this method, four antigens (DDX3Y; ribosomal protein S4, Y linked; solute carrier 1A5; and signal sequence receptor 1) were found in the syncytiotrophoblast, and one antigen (DDX3Y) was found in shed trophoblast debris. The finding of mHAgs in the placenta and in trophoblast debris provides the first direct evidence that fetal antigens are present in debris shed from the human placenta. The data, thus, suggest a mechanism by which the maternal immune system is exposed to fetal alloantigens, possibly explaining the relationship between parity and graft-versus-host disease.