The Impact of Prenatal Diagnosis of Selected Central Nervous System Anomalies for Prenatal Counselling Based on Significant Pregnancy Morbidity and Neonatal Outcomes.

BACKGROUND & OBJECTIVES: Prenatal screening and diagnostic imaging advances have led to an increased detection of CNS anomalies, including ventriculomegaly/congenital hydrocephalus (HCP), Dandy-Walker malformation (DWM), and myelomeningocele (MMC). Data on pregnancy outcomes and the impact of prenatal diagnosis on neonatal outcomes is limited. Our study aimed to provide data on obstetric and neonatal outcomes following prenatal diagnosis of one of three CNS anomalies. METHODS: A retrospective search of two databases in Alberta, Canada and NICU chart review of cases between 2001 and 2011was completed. Primary outcomes for each group were pregnancy outcome (live birth, stillbirth, and termination) and detection rate. Secondary outcomes were live and total birth prevalence, mode of delivery, GA at delivery, and length of NICU stay for inborn versus outborn patients. RESULTS: Prenatal detection rates were 91.6% (HCP), 83.4% (DWM), and 92.9 % (MMC). Termination rates were 30.2% (DWM), 34.2% (HCP), and 48.5% (MMC). Median GA (weeks, range) at diagnosis were 22 (17-38), 20 (12-37), and 20.5 (18-34) for HCP, DWM, and MMC, respectively. Rate of Caesarean section for fetal indication was 50.0%, 44.4%, and 42.9% for HCP, DWM, and MMC, respectively. Median NICU length of stay was longer for outborn patients than inborn patients and were as follows: (range) 33.0 (21-38) versus 8.5 (1-49) d (HCP), and 29 (29-57) versus 14 (2-75) d (DWM). CONCLUSION: This study provides termination rates, obstetric interventions, and NICU length of stay for prenatally-identified CNS anomalies. Collectively, this study assists prenatal counselling women with a fetus affected by a described CNS anomaly.

A mechanism for suppression of the CDP-choline pathway during apoptosis.

Inhibition of the CDP-choline pathway during apoptosis restricts the availability of phosphatidylcholine (PtdCho) for assembly of membranes and synthesis of signaling factors. The N-terminal nuclear localization signal (NLS) in CTP:phosphocholine cytidylyltransferase (CCT)α is removed during apoptosis but the caspase(s) involved and the contribution to suppression of the CDP-choline pathway is unresolved. In this study we utilized siRNA silencing of caspases in HEK293 cells and caspase 3-deficient MCF7 cells to show that caspase 3 is required for CCTα proteolysis and release from the nucleus during apoptosis. CCTα-Δ28 (a caspase-cleaved mimic) expressed in CCTα-deficient Chinese hamster ovary cells was cytosolic and had increased in vitro activity. However, [³H]choline labeling experiments in camptothecin-treated MCF7 cells and MCF7 cells expressing caspase 3 (MCF7-C3) revealed a global suppression of the CDP-choline pathway that was consistent with inhibition of a step prior to CCTα. In camptothecin-treated MCF7 and MCF7-C3 cells, choline kinase activity was unaffected; however, choline transport into cells was reduced by 30 and 60%, respectively. We conclude that caspase 3-mediated removal of the CCTα NLS contributes minimally to the inhibition of PtdCho synthesis during DNA damage-induced apoptosis. Rather, the CDP-choline pathway is inhibited by caspase 3-independent and -dependent suppression of choline transport into cells.

Impact of preoperative angiotensin-converting enzyme inhibitor use on clinical outcomes after cardiac surgery.

BACKGROUND: Controversy exists about whether preoperative angiotensin-converting enzyme inhibitor (ACEi) therapy is associated with adverse outcomes after coronary artery bypass grafting (CABG). METHODS: We analyzed the outcomes of consecutive patients who underwent isolated CABG between 1998 and 2007 at a single institution. We used multivariable models to examine the association between preoperative ACEi therapy and in-hospital and long-term outcomes. RESULTS: Of the 5946 patients undergoing isolated CABG during the study period, 3,262 (54.9%) were treated with an ACEi preoperatively and 2,684 (45.1%) were not. Median follow-up was 3.8 years. Patients treated with an ACEi preoperatively were more likely to have diabetes, hypertension, an ejection fraction of less than 40%, and recent myocardial infarction (all p<0.0001). They were less likely to have pre-existing renal failure (p=0.004) or require an urgent or emergent CABG (p=0.03). Postoperative use of an inotrope (26% vs 20%, p<0.0001) or intra-aortic balloon pump (1.8% vs 1.1%, p=0.03) was more frequent in patients treated preoperatively with an ACEi; however, preoperative ACEi use was not an independent predictor of in-hospital mortality (odds ratio [OR], 1.1; p=0.76), prolonged length of stay in the intensive care unit (OR, 0.9; p=0.09), or new-onset renal failure (OR, 0.7; p=0.09). Furthermore, preoperative use of an ACEi had no independent association with long-term survival (p=0.54) or freedom from acute coronary syndrome (p=0.07). However, it was associated with an increased risk of readmission for heart failure over time (hazard ratio, 1.2; p=0.007). CONCLUSIONS: We found no association between preoperative ACEi therapy and adverse in-hospital outcomes or long-term survival after CABG. Preoperative ACEi therapy appears to be safe in patients undergoing CABG.

Nuclear export of the rate-limiting enzyme in phosphatidylcholine synthesis is mediated by its membrane binding domain.

CTP:phosphocholine cytidylyltransferase alpha (CCTalpha), the rate-limiting enzyme in the CDP-choline pathway for phosphatidylcholine (PtdCho) synthesis, is activated by translocation to nuclear membranes. However, CCTalpha is cytoplasmic in cells with increased capacity for PtdCho synthesis and following acute activation, suggesting that nuclear export is linked to activation. The objective of this study was to identify which CCTalpha domains were involved in nuclear export in response to the lipid activators farnesol (FOH) and oleate. Imaging of CCT-green fluorescent protein (GFP) mutants expressed in CCTalpha-deficient CHO58 cells showed that FOH-mediated translocation to nuclear membranes and export to the cytoplasm required the membrane binding amphipathic helix (domain M). Nuclear export was reduced by a mutation that mimics constitutive phosphorylation of the CCT phosphorylation (P) domain. However, domain M alone was sufficient to promote translocation to the nuclear envelope and export of a nuclear-localized GFP construct in FOH- or oleate-treated CHO58 cells. In the context of acute activation with lipid mediators, nuclear export of CCT-GFP mutants correlated with in vitro activity but not PtdCho synthesis. This study describes a nuclear export pathway that is dependent on membrane interaction of an amphipathic helix, thus linking lipid-dependent activation to the nuclear/cytoplasmic distribution of CCTalpha.