INTRODUCTION:Preeclampsia (PE) has been considered to be a maternal inflammatory response to pregnancy and may be hazardous for mother and child. Soluble urokinase Plasminogen Activator receptor (suPAR) is a non-specific marker that reflects overall systemic inflammation and immune activation. OBJECTIVES:We examined the levels of suPAR in first and third trimesters of normal- and preeclamptic pregnancies. METHODS:Two clinical studies were conducted. The first study included 43 women who subsequently developed PE and 86 control women not developing PE. Blood samples were collected during the first trimester. The two groups were matched with respect to gestational age. In the second study, 13 cases of PE and 8 controls were enrolled and blood samples were collected during the third trimester. Serum suPAR were analyzed by the commercially availably suPARnostic® assay kit (ELISA, Virogates, Copenhagen, Denmark). RESULTS:There were no significant differences in first trimester suPAR level between women who subsequently developed PE and those who completed a normal pregnancy (4.5 [3.7-5.4] ng/mL versus 4.3 [3.8-5.0] ng/mL, p=0.49, median [interquartile range]). In the third trimester, suPAR levels were significantly elevated in the preeclamptic group compared to the control group (2.5 [2.2-3.5] ng/mL versus 1.9 [1.5-2.1] ng/mL, p=0.008). After adjustment for gestational age (38.6 (0.7) and 31 (3.1) weeks in the control- and the PE-group respectively, p<0.001, mean (SD)), the group difference did not remain statistically significant (p=0.064). CONCLUSION:suPAR is not a suitable marker for detecting the systemic maternal inflammatory response in women with established PE nor a useful pre-clinical marker of the disorder. The observation of the higher suPAR level in first trimester of pregnancy compared to third trimester suPAR level alludes to a possible physiological function that needs to be clarified.

The aim was to determine plasma levels of sFlt-1 and sEng on the arterial and venous side of the uteroplacental circulation in preeclamptic patients and healthy controls. Preeclamptic patients had higher arterial concentrations than controls of sFlt-1 (17,450 vs. 5055 pg/ml, p = 0.003) and sEng (68.7 vs. 28.7 ng/ml, p = 0.003). In the preclampsia group sFlt-1 was higher in the uterine vein than in the radial artery (22,450 vs. 17,450 pg/ml, p = 0.005). We found no gradient for sEng. Our results support the hypothesis that excess sFlt-1 at least partly originates in placenta, while excess sEng appears to have a different origin.

Please cite this paper as: Yu Y, Hanssen K, Kalyanaraman V, Chirindel A, Jenkins A, Nankervis A, Torjesen P, Scholz H, Henriksen T, Lorentzen B, Garg S, Menard M, Hammad S, Scardo J, Stanley J, Wu M, Basu A, Aston C, Lyons T. Reduced soluble receptor for advanced glycation end‐products (sRAGE) scavenger capacity precedes pre‐eclampsia in Type 1 diabetes. BJOG 2012;119:1512–1520. Objective Increased advanced glycation end‐products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre‐eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four‐fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM ( n = 118; 26 developed PE) and healthy nondiabetic pregnant controls ( n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N ε ‐(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal‐modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE−). Results In DM PE+ versus DM PE−, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE ( P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester ( P < 0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester ( P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

1 BETA-BLOCKING DRUG USE IN COCAINE ABUSERS: IS IT SAFE AND EFFECTIVE THERAPY IN HOSPITALIZED PATIENTS? GD. Everett, N. Uddin, A. Java, A. Klotchko, A. Velazquez, S. Singapuri, A. Prevost, R. Rostorfer, E. Benzaquen, K. Patel, V. Patel, P. Fotso, L. Ramos Florida Hospital Medical Center, Orlando, FL; University of Central Florida, Orlando, FL and Orlando Health, Orlando, FL. Purpose of Study: Case reports have suggested that beta-blockers may unpredictably exacerbate hypertension and tachycardia in concurrent cocaine abusers. Physicians avoid beta-blockers in these patients despite the chest pain and hypertension that cocaine may cause. This study was designed to assess the physiological effect of beta-blockers given to cocaine abusers during emergency room and hospital stays when their symptoms warrented beta-blockers but before their use of cocaine was discovered. Methods Used: A cohort consisting of every patient admitted to a large, urban hospital during a single calendar year, whose urine contained cocaine metabolites, was created. Subjects were included if they had blood pressure and heart rate measurements recorded before and after beta-blockers or other medications were given. 114 subjects met the criteria. Multivariate regression analysis was used to assess the independent effect of beta-blockers on the blood pressure and heart rate. The regression analysis controlled for the effect of each vasoactive medication given to the subjects. Summary of Results: The subjects were 33% female, 64% black, 27% white and 9% other race. The median age was 43(23Y74). Chest pain (30%) was the most common admission complaint. 5% of subjects had a troponin level of more than 1.0. 14% and 4% of subjects had creatinine values that exceeded 3.0 and 9.0 respectively. The table displays the results of the main analysis: unadjusted and multivariate adjusted effects of beta-blockers on systolic BP, diastolic BP, and heart rate. Conclusions: There was no evidence of a deleterious or paradoxical effect of beta blockers when administered to patients documented to be using cocaine.

Aims/hypothesis Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGF beta 1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia.Methods Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial-derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term.Results Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n=26) vs those without hypertensive complications (diabetic normotensive, n=95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p<0.05) and the normal rise of PlGF during pregnancy was blunted (p<0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2)=42%, p<0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p<0.0001).Conclusions/interpretation Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

Background. To investigate the effect of dietary intake of the NO-donor L-arginine on the diastolic blood pressure in women with pre-eclampsia.Methods. A randomized double-blind study was designed to compare the effect of L-arginine and placebo in pre-eclamptic women with gestational length ranging from 28(+0) to 36(+0) weeks. The women received orally 12 g of L-arginine or placebo daily for up to 5 days. The primary end-point was to identify a difference in diastolic blood pressure alteration between the two groups after 2 days of intervention. Secondary end-points included the interval from study start to delivery, the proportion of women delivered after 2, 5 or 10 days from treatment start and mean birth weight.Results. There was no statistically significant alteration in diastolic blood pressure in the L-arginine group compared with the placebo group after 2 days of treatment (p = 0.4). No differences in the proportions of women delivered by day 2, 5 or 10 after study start, in the mean interval from study start to delivery, or in mean birth weight percentile were observed between the two groups.Conclusions. Oral L-arginine supplementation did not reduce mean diastolic blood pressure after 2 days of treatment compared with placebo in pre-eclamptic patients with gestational length varying from 28 to 36 weeks. Whether L-arginine treatment could be clinically beneficial for the mother or the fetus if started earlier in the disease process than for the women in our study remains to be seen.

The dominating hypothesis of the preeclampsia syndrome (PES) is that placentally derived factors are released to the maternal circulation. These factors are believed to alter endothelial properties resulting in disturbed vasomotor function, increased endothelial permeability, and activation of thrombogenic factors. However, the impact of placentally derived factors on the endothelial cells is influenced by another major variable: the "sensitivity" of the maternal endothelium to the placental factors. Several maternal factors may play a role in determining this sensitivity. They include chronic hypertension, diabetes, and hyperlipidemia. In this article we discuss the possible role of hyperlipidemia (especially high free fatty acids and hypertriglyceridemia) in the pathogenesis of preeclampsia, viewed from this perspective. Pregnancy in general, preeclamptic pregnancy in particular, is associated with a marked hyperlipidemia. We suggest a parallel to atherosclerotic diseases, wherein hyperlipidemia induces endothelial dysfunction, probably by promoting oxidative stress in the arterial wall. The hyperlipidemia of pregnancy may have a similar effect on the endothelial cells. When placentally derived endothelial disturbing factors, like lipid peroxides and trophoblastic components, are released into the maternal circulation, their effects on the endothelium may be enhanced because of hyperlipidemia-mediated activation or "sensitization" of the endothelial cells. Alternatively, placentally derived factors like peroxides may combine with lipoproteins, forming complexes that are more disturbing to cells than the placental factors or lipoproteins are individually. We also discuss the possible role of maternal hyperlipidemia in aggravating placental insufficiency caused by poorly transformed spiral arteries. The hemodynamic flow pattern may be markedly different in completely and incompletely transformed spiral arteries. By analogy to the fundamental role of hemodynamic factors in development of atherosclerosis, we pose the hypothesis that abnormally transformed spiral arteries have an "atherogenic" blood flow pattern that promotes lipid deposition and "acute atherosis".

BACKGROUND:We have previously shown that women with proteinuric hypertension of pregnancy (preeclampsia) have increased circulating levels of triglycerides and free fatty acids. Preeclampsia has, therefore, several features in common with the insulin resistance syndrome. The objective of the present study was to investigate the glucose tolerance and insulin response of women with preeclampsia compared to women with normal pregnancy.METHODS:Oral glucose tolerance test was performed in ten women with preeclampsia and eight healthy women with normal pregnancy. The glucose, insulin, C-peptide and free fatty acid responses were calculated.RESULTS:The mean fasting glucose concentration was significantly lower in preeclamptic women (3.3 vs 3.7 mmol/l; p = 0.02). Fasting serum triglycerides were increased in women with preeclampsia compared to normal pregnancy (3.3 vs 1.9 mmol/l; p = 0.003). Women with preeclampsia had also increased serum free fatty acids, 0.52 vs 0.36 mmol/l for normal pregnancy; p = 0.056). Log s-insulin and cholesterol were not different. The incremental area under the curve for the glucose (p = 0.001) and insulin (p = 0.02) responses to oral glucose tolerance test showed higher values for preeclampsia as compared to women with normal pregnancy. For free fatty acids the total area under the suppression curve was higher in women with preeclampsia (p = 0.03).CONCLUSIONS:These results support the concept that preeclampsia is associated with metabolic aberrations found in insulin resistance syndrome.

Activation of coagulation leads to generation of thrombin which in turn is inactivated by the formation of thrombin-antithrombin (TAT) complexes, and thrombin-heparin cofactor complexes (T-HCII). These complexes were measured in plasma by ELISA methods. During normal delivery, the median TAT level in ten women increased from 4.1 to 7.8 times the median normal reference level. There was great individual variation, and levels 42 and 56 times normal median were found in two women shortly after normal delivery. The median T-HCII levels increased only moderately from 2.3 to 3.1 times median normal reference. D-dimer values were elevated in 28 out of the 30 samples. In blood sampled 1-2 days after delivery, the median TAT level was 2.5 times the median normal reference. The median T-HCII level was now 5.6 times the median normal reference value. The values were stable during the first 4 days post partum, and there was little difference between those delivered vaginally or by Caesarean section (C-section). D-dimer values were above normal reference in all women, and higher in women delivered by C-section. In conclusion, increasing TAT levels during labour and delivery indicated generation of thrombin which was mainly inactivated by antithrombin. The T-HCII levels increased less during delivery. In the early post partum period, the T-HCII levels were relatively more increased than the TAT levels. These results suggest that intravascularly generated thrombin is preferably inactivated by antithrombin, even in parturient women. In the post partum period, formation of T-HCII complexes was more evident, possibly reflecting extravascular inactivation of thrombin.

Interest in heat recovery in batch processes is motivated by the fact that a significant part of industrial products (about 50 percent) are produced in batches. The batch mode-of-operation may be required because of limited supply (dairies), because of process requirements (fermentation), or because of tradition and quality consideration (breweries).

Objective To determine the composition of esterified and free fatty acids in sera of women with normal and pre-eclamptic pregnancy.Setting Department of Obstetrics and Gynaecology, Aker Hospital, Oslo, Norway.Subjects Blood samples were taken from 510 healthy nulliparae at a gestational age of 17-19 weeks. Nineteen of these subsequently developed pre-eclampsia, Seventeen of these, for whom blood samples were still available, and a control group of 17 women taken from the same population and matched for age, body mass index, gestational age and parity, were later studied in detail. A further group of 29 women admitted to the hospital with pre-eclampsia were also studied, as was a matched control group of 29 women with normal pregnancies recruited from the antenatal clinic.Methods Blood samples were drawn after 8 to 10 h fasting. The patterns of serum free fatty acids and esterified fatty acids were determined by thin-layer chromatography combined with gas-liquid chromatography. Free fatty acids were also determined enzymatically.Results Among the circulating free fatty acids, the levels of palmitic (16:0), oleic (18:1 n-9) and linoleic acids (18:2 n-6) were significantly higher early in pregnancy in women who later developed pre-eclampsia. The same free fatty acids were also significantly increased in women with pre-eclampsia, The level and composition of the esterified fatty acids in phospholipids, triglycerides and cholesteryl esters did not, however, differ between the two groups early in pregnancy. In contrast, in women with pre-eclampsia, the relative content of oleic acid was increased in the phospholipid fraction, whereas linoleic acid was decreased in the phospholipid and triglyceride fractions.Conclusions We observed that the level and composition of circulating free fatty acids were already altered 10-20 weeks before the clinical onset of pre-eclampsia. When the disease became overt there were changes in both esterified and free fatty acids.

OBJECTIVE:The null hypothesis of this study was that sera of women with preeclampsia are not cytotoxic to endothelial cells in culture. STUDY DESIGN:Endothelial cells were incubated in the presence of sera (30% vol/vol) of either preeclamptic patients (n = 11) or normal pregnant women (n = 11). Release of chromium 51 from prelabeled cells was measured after exposure to the different sera. Viability of the cells was evaluated by trypan blue exclusion and plating efficiencies. Deoxyribonucleic acid and protein synthesis were studied by measuring incorporation of tritiated thymidine and leucine into deoxyribonucleic acid and proteins, respectively. Cell growth was determined by monitoring the number of cells per culture dish during a 5-day incubation period. RESULTS:Release of chromium 51 from endothelial cells incubated in the presence of sera from preeclamptic women was similar to controls (26.3% +/- 4.7% vs 26.7% +/- 2.5%). There was no difference in the number of trypan blue-positive cells in cultures incubated in the presence of sera from preeclamptic women and controls. Seeding the cells in either sera from preeclamptic or control women gave the same percentage of attached cells. Similarly, preincubation of endothelial cells with either one of the two sera resulted in the same number of attached cells when they were reseeded (45% +/- 6% vs 40% +/- 15%, respectively). Incubation of endothelial cells with sera from preeclamptic or control women affected neither deoxyribonucleic acid nor protein synthesis of the endothelial cells. Furthermore, cell proliferation was similar in cultures incubated with sera from preeclamptic women and controls. CONCLUSION:No evidence was found that sera of women with preeclampsia are cytotoxic to endothelial cells in culture.

The waste-heat recovery in batch processes has been studied using the pinch-point method. The aim of the work has been to investigate theoretical and practical approaches to the design of heat-exchanger networks, including heat storage, for waste-heat recovery in batch processes. The study is limited to the incorporation of energy-storage systems based on fixed-temperature variable-mass stores. The background for preferring this to the alternatives (variable-temperature fixed-mass and constant-mass constant-temperature (latent-heat) stores) is given. It is shown that the maximum energy-saving targets as calculated by the pinch-point method (time average model, TAM) can be achieved by locating energy stores at either end of each process stream. This theoretically large number of heat-storage tanks (twice the number of process streams) can be reduced to just a few tanks. A simple procedure for determining a number of heat-storage tanks sufficient to achieve the maximum energy-saving targets as calculated by the pinch-point method is described. This procedure relies on combinatorial considerations, and could therefore be labeled the “combinatorial method” for incorporation of heat storage in heat-exchanger networks. Qualitative arguments justifying the procedure are presented. For simple systems, waste-heat recovery systems with only three heat-storage temperatures (a hot storage, a cold storage, and a heat store at the pinch temperature) often can achieve the maximum energy-saving targets. Through case studies, six of which are presented, it is found that a theoretically large number of heat-storage tanks (twice the number of process streams) can be reduced to just a few tanks. The description of these six cases is intended to be sufficiently detailed to serve as benchmark cases for development of alternative methods.

Recently, we showed that levels of circulating free fatty acids are increased in women who later develop pre-eclampsia long before the clinical onset of the disease. Among the serum free fatty acids, oleic-, linoleic-, and palmitic acid were found to be increased by 37, 25 and 25%, respectively. In the present study we asked if these free fatty acids can interfere with endothelial cell functions. Cultured endothelial cells were exposed to linoleic-, oleic- and palmitic acid in concentrations ranging from 0.016 to 0.133 mumol ml-1, resulting in molar ratios of free fatty acids to albumin of 0.2-1.6. We found that among these fatty acids, linoleic acid reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, whereas palmitic acid had no effect. Endothelial cells incubated in presence of linoleic acid showed a concentration-dependent reduction in prostacyclin release in response to thrombin, and cells incubated with linoleic acid for up to 28 h, showed a reduced thrombin-induced prostacyclin release at every time point. Endothelial level of cGMP mainly reflected the synthesis of endothelium-derived relaxing factor/nitrogen monoxide (EDRF/NO), since blocking of the endogenous production of EDRF/NO with N-omega-nitro-L-arginine, resulted in about 90% reduction in cGMP-content of the endothelial cells. Incubation with linoleic acid reduced the endothelial cGMP level by 70%. Linoleic acid reduced the endothelial cells ability to inhibit platelet aggregation by 10-45%, (p = 0.0019). It was concluded that linoleic acid impedes the ability of the endothelial cells to produce prostacyclin and cGMP, and to inhibit platelet aggregation.