Angiogenic factors in women ten years after severe very early onset preeclampsia.

BACKGROUND: Women with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease. METHODS: Twenty women with severe early onset preeclampsia before 24 weeks' gestation, who delivered between 1993-2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA. RESULTS: Sixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43-11.11 pg/mL (0.33), sFlt-1: 102.98-101.92 pg/ml (0.84), PLGF: 3.57-4.20 pg/mL (0.38), VEGF: 64.05-45.72 pg/mL (0.73), E-selectin: 5.11-4.68 ng/mL (0.20), P-selectin: 85.35-71.69 ng/mL (0.69), sICAM-3: 0.42-0.63 ng/mL (0.41) and Thrombomodulin: 0.92-0.93 ng/mL (0.59). CONCLUSION: There were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease.

E-selectin is elevated in cord blood of South Asian neonates compared with Caucasian neonates.

OBJECTIVE: To test the hypothesis that the increased risk of type 2 diabetes mellitus and coronary artery disease in South Asian subjects could be caused by the presence of endothelial dysfunction in early life. We studied markers of endothelial dysfunction in umbilical cord blood of South Asian neonates and compared these with that of Caucasian control subjects. STUDY DESIGN: From South Asian (n = 57) and Caucasian (n = 21) neonates, cord blood was collected and levels of glucose, insulin, lipids, and markers of endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1) and inflammation (C-reactive protein) were measured. RESULTS: Plasma E-selectin levels were significantly higher in South Asian neonates (46.7 versus 33.5 ng/mL, P < .001), and levels of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 did not differ. Furthermore, South Asian neonates had hyperinsulinemia (P = .043), dyslipidemia (with significantly higher triglyceride and lower high-density lipoprotein cholesterol levels), and higher C-reactive protein levels (75.7 versus 43.8 ng/mL, P = .009). CONCLUSIONS: South Asian newborns are characterized by elevated E-selectin levels in line with the hypothesis that endothelial dysfunction is present early in life. In addition, hyperinsulinemia, dyslipidemia, and inflammation are present. Because many pathogenic variables for coronary artery disease and type 2 diabetes are already present at birth in South Asian patients, the question arises whether rigorous childhood lifestyle intervention could be beneficial.

The effect of multidisciplinary lifestyle intervention on the pre- and postprandial plasma gut Peptide concentrations in children with obesity.

Objective. This study aims to evaluate the effect of a multidisciplinary treatment of obesity on plasma concentrations of several gut hormones in fasting condition and in response to a mixed meal in children. Methods. Complete data were available from 36 obese children (age 13.3 ± 2.0 yr). At baseline and after the 3-month multidisciplinary treatment, fasting and postprandial blood samples were taken for glucose, insulin, ghrelin, peptide YY (PYY), and glucagon-like peptide 1 (GLP-1). Results. BMI-SDS was significantly reduced by multidisciplinary treatment (from 4.2 ± 0.7 to 4.0 ± 0.9, P < .01). The intervention significantly increased the area under the curve (AUC) of ghrelin (from 92.3 ± 18.3 to 97.9 ± 18.2 pg/L, P < .01), but no significant changes were found for PYY or GLP-1 concentrations (in fasting or postprandial condition). The insulin resistance index (HOMA-IR) remained unchanged as well. Conclusion. Intensive multidisciplinary treatment induced moderate weight loss and increased ghrelin secretion, but serum PYY and GLP-1 concentrations and insulin sensitivity remained unchanged.

Delayed onset of the diurnal melatonin rise in patients with Huntington's disease.

Sleep disturbances are very prevalent in Huntington's disease (HD) patients and can substantially impair their quality of life. Accumulating evidence suggests considerable dysfunction of the hypothalamic suprachiasmatic nucleus (SCN), the biological clock, in both HD patients and transgenic mouse models of the disease. As melatonin has a major role in the regulation of sleep and other cyclical bodily activities and its synthesis is directly regulated by the SCN, we postulated that disturbed SCN function is likely to give rise to abnormal melatonin secretion in HD. Therefore, we compared 24 h melatonin secretion profiles between early stage HD patients and age-, sex- and body mass index-matched controls. Although mean diurnal melatonin levels were not different between the two groups (p = 0.691), the timing of the evening rise in melatonin levels was significantly delayed by more than 01:30 h in HD patients (p = 0.048). Moreover, diurnal melatonin levels strongly correlated with both motor (r = -0.70, p = 0.036) and functional impairment (r = +0.78, p = 0.013). These findings suggest a delayed sleep phase syndrome-like circadian rhythm disorder in early stage HD patients and suggest that melatonin levels may progressively decline with advancing disease.

Celecoxib enhances doxorubicin-induced cytotoxicity in MDA-MB231 cells by NF-kappaB-mediated increase of intracellular doxorubicin accumulation.

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX) inhibitors are anti-inflammatory agents that have also shown to be useful in anticancer therapy. In the present study, we show that the specific COX-2 inhibitor celecoxib enhances the inhibitory effect of doxorubicin (dox) on human MDA-MB231 breast tumour growth in vivo and in vitro. We also found that celecoxib increased the intracellular accumulation and retention of dox in vitro. Since the NSAID indomethacin and the specific COX-2 inhibitor NS398 did not affect the in vitro actions of dox, these effects are likely to be mediated via a COX-independent mechanism. It has been suggested that some COX-inhibitors can enhance the actions of cytostatics by overcoming multidrug resistance through the inhibition of ABC-transporter proteins. However, we found that the three main ATP-binding cassette (ABC)-transporter proteins, implicated in dox transport, were inactive in MDA-MB231 cells. Therefore, the finding that the P-glycoprotein (P-gp) blocker PSC833 also increased cellular accumulation of dox was unexpected. In order to unravel the molecular mechanisms involved in dox accumulation, we examined the involvement of NF-kappaB, as this transcription factor has been implicated in celecoxib action as well as in chemoresistance. We found that celecoxib and PSC833, but not indomethacin or NS398, almost completely inhibited basal- and dox induced NF-kappaB gene-reporter activity and p65 subunit nuclear translocation. Furthermore, the NF-kappaB inhibitor PDTC mimicked the actions of celecoxib and PSC833 on cell growth and on intracellular accumulation of dox, suggesting that NF-kappaB is functionally involved in the actions of these compounds. In conclusion, we show that structurally different compounds, among which are celecoxib and PSC833, increase the intracellular accumulation of dox and enhance dox induced cytotoxicity in MDA-MB231 breast cancer cells most likely via the modulation of NF-kappaB activity.

Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A.

During bone formation and fracture healing there is a cross-talk between endothelial cells and osteoblasts. We previously showed that vascular endothelial growth factor A (VEGF-A) might be an important factor in this cross-talk, as osteoblast-like cells produce this angiogenic factor in a differentiation-dependent manner. Moreover, exogenously added VEGF-A enhances osteoblast differentiation. In the present study we investigated, given the coupling between angiogenesis and bone formation, whether bone morphogenetic proteins (BMPs) stimulate osteoblastogenesis and angiogenesis through the production of VEGF-A. For this we used the murine preosteoblast-like cell line KS483, which forms mineralized nodules in vitro, and an angiogenesis assay comprising 17-d-old fetal mouse bone explants that have the ability to form tube-like structures in vitro. Treatment of KS483 cells with BMP-2, -4, and -6 enhanced nodule formation, osteocalcin mRNA expression, and subsequent mineralization after 18 d of culture. This was accompanied by a dose-dependent increase in VEGF-A protein levels throughout the culture period. BMP-induced osteoblast differentiation, however, was independent of VEGF-A, as blocking VEGF-A activity by a VEGF-A antibody or a VEGF receptor 2 tyrosine kinase inhibitor did not affect BMP-induced mineralization. To investigate whether BMPs stimulate angiogenesis through VEGF-A, BMPs were assayed for their angiogenic activity. Treatment of bone explants with BMPs enhanced angiogenesis. This was inhibited by soluble BMP receptor 1A or noggin. In the presence of a VEGF-A antibody, both unstimulated and BMP-stimulated angiogenesis were arrested. Conditioned media of KS483 cells treated with BMPs also induced a strong angiogenic response, which was blocked by antimouse VEGF-A but not by noggin. These effects were specific for BMPs, as TGF beta inhibited osteoblast differentiation and angiogenesis while stimulating VEGF-A production. These findings indicate that BMPs stimulate angiogenesis through the production of VEGF-A by osteoblasts. In conclusion, VEGF-A produced by osteoblasts in response to BMPs is not involved in osteoblast differentiation, but couples angiogenesis to bone formation.