Angela Makris

Tumor necrosis factor α induces a model of preeclampsia in pregnant baboons (Papio hamadryas).

Preeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control.

Soluble Flt-1 as a diagnostic marker of pre-eclampsia

Backgound: Serum levels of soluble fms‐like tyrosine kinase (sFlt‐1) increase in pre‐eclampsia (PE).

Animal Models of Pre-eclampsia

Citation Sunderland N, Hennessy A, Makris A. Animal models of pre‐eclampsia. Am J Reprod Immunol 2010; 65: 533–541

High-Sensitivity Troponin as a Predictor of Cardiac Events and Mortality in the Stable Dialysis Population

BACKGROUND High-sensitivity cardiac troponin T (hs-cTnT) is a biomarker used in diagnosing myocardial injury. The clinical utility and the variation of this biomarker over time remain unclear in hemodialysis (HD) and peritoneal dialysis (PD) patients. We sought to determine whether hs-cTnT concentrations were predictive of myocardial infarction (MI) and death and to examine hs-cTnT variability over a 1-year period. METHODS A total of 393 nonacute HD and PD patients (70% HD and 30% PD) were followed in a prospective observational study for new MI and death. RESULTS Median hs-cTnT was 57 ng/L (interquartile range, 36-101 ng/L) with no observed difference between HD and PD patients (P = 0.11). Incremental increases in mortality (P = 0.024) and MI (P = 0.001) were observed with increasing hs-cTnT quartiles. MI incidence increased significantly across quartiles in both HD and PD patients (P = 0.012 and P = 0.025, respectively), whereas mortality increased only in HD patients (P = 0.015). For every increase of 25 ng/L in hs-cTnT, the unadjusted hazard ratio (HR) was 1.10 for mortality in the whole group (95% CI, 1.04-1.16, P = 0.001) and 1.16 for MI (95% CI, 1.08-1.23, P < 0.001). Adjusted HR for mortality was 1.07 (95% CI, 1.01-1.15, P = 0.04) and 1.14 for MI (95% CI, 1.06-1.22, P < 0.001). Changes in hs-cTnT from baseline concentrations after 1 year were minimal (55 ng/L vs 53 ng/L, P = 0.22) even in patients who had an MI (P = 0.53). CONCLUSIONS hs-cTnT appears to have a useful role in predicting MI and death in the dialysis population. Over a 1-year period concentrations remained stable even in patients who sustained a new cardiac event.

Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy.

Background Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines. Objective To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy. Design Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-α) were examined by enzyme-linked immunosorbent assay. Results Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 ± 2.7% [16.3 pg/ml (range 6.1–21.5 pg/ml)] to 24.5 ± 3.3% [30.4 pg/ml (range 16.9–34.8 pg/ml)] with increasing concentrations of clonidine (0.08–1.3 μg/ml), and by 8.8 ± 3.5% [4.1 pg/ml (range 3.0–17.8 pg/ml)] and 17.2 ± 1.9% [22.6 pg/ml (range 13.2–23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 μg/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-α and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies. Conclusion Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-α and IL-6 by placentas and PBMCs.

Weight and Metabolic Outcomes After 2 Years on a Low- Carbohydrate Versus Low-Fat Diet:

Previous studies have demonstrated that low-carbohydrate diets achieve greater short-term (6 months) weight loss than low-fat diets. Longer-term (1 to 2 years) data have been inconsistent. Weight loss obtained with either diet is generally minimal. Some investigators have attributed this suboptimal weight loss to the uniform lack of inclusion in most studies of behavioral interventions to change lifestyle. This randomized, parallel-group, controlled trial compared the effects of 2-year treatment with either a low-carbohydrate or low-fat diet combined with a behavioral intervention program on body weight and several other clinical endpoints. Between 2003 and 2007, 307 adults at a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m 2 (SD, 3.5 kg/m 2 ) were enrolled. A total of 153 of the study subjects (group 1) were assigned to a low-carbohydrate diet, which limited carbohydrate intake to 20 g/d for 3 months; unrestricted consumption of fat and protein was allowed. Carbohydrate intake after the first 12 weeks was gradually increased (5 g/d per week) until the desired weight was reached. Group 2 was comprised of 154 participants who were assigned to receive a low-fat diet limiting energy intake to 1200 to 1800 kcal/d, with ≤30% of the calories from fat. All participants received comprehensive behavioral treatment. Weight loss and most secondary outcomes (serum lipoproteins, blood pressure, urinary ketones, and symptoms were assessed at 3, 6, 12, and 24 months. Secondary outcomes of bone mineral density and body composition were evaluated at 6, 12, and 24 months. Both diet groups achieved clinically significant and almost identical weight loss at 1 year (11 kg [11%]) and at 2 years (7 kg [7%]. No differences were found between the groups in weight, bone mineral density, or body composition over the 2 years of the study. At 3 and 6 months, however, significantly greater reductions were found in the low-carbohydrate diet group than in the low-fat diet group for triglyceride levels, diastolic pressure, and very-low-density as well as low-density lipoprotein cholesterol levels. More adverse symptoms were observed in the first 6 months in the low-carbohydrate diet group. An increase of approximately 20% in high-density lipoprotein cholesterol levels was observed in the low-carbohydrate diet group at 6 months and persisted throughout the study; this increase was more than twice that found in the low-fat diet group. The investigators conclude from these findings that either a low-carbohydrate or a low-fat diet can achieve successful long-term weight loss if combined with a behavioral intervention program.

Acute Pulmonary Oedema as a Complication of Hypertension During Pregnancy

Objective. To determine rates of and potential causative factors for acute pulmonary oedema (APO) in hypertensive women. Methods. Statistical analysis, including logistic regression, was applied to the individual patient data (IPD) of all hypertensive women who delivered in 2005 at two comparable units. Results. Of 880 cases analysed, there were no women with APO in unit one and 19 women in unit two. The women with APO received larger quantities of intravenous fluids, delivered at earlier gestations, via Caesarean section, following failed induction of labour and had a longer hospital stay. Conclusion. The development of APO in women with hypertension during pregnancy is associated with high levels of intravenous fluid administration.

Role of proteinuria in defining pre-eclampsia: clinical outcomes for women and babies.

1. The presence of proteinuria is not essential to the diagnosis of pre‐eclampsia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre‐eclampsia compared with other non‐proteinuric disease presentations.

Fetal–Maternal Alignment of Regulatory T Cells Correlates with IL-10 and Bcl-2 Upregulation in Pregnancy

Transplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10–dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL-10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor α and that Treg cell IL-10 receptor α expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL-10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation.

A randomised comparison of hydralazine and mini-bolus diazoxide for hypertensive emergencies in pregnancy: The PIVOT trial

Aims:  Diazoxide is one of few available agents for treatment of hypertensive emergencies in pregnancy. From previous studies, there is a question concerning safety after moderate‐dose administration caused episodes of hypotension. Rapid control of severe hypertension is necessary to reduce maternal morbidity, for example, stroke and placental abruption. This study was designed to compare the efficacy of mini‐bolus diazoxide with intravenous (i.v.) hydralazine.