Correlation of the circadian rhythm of blood pressure with renal function, vascular endothelial damage and melatonin secretion in patients with preeclampsia

The aim of this study was to correlate the disorders of the circadian rhythm of blood pressure with abnormalities in renal function, vascular endothelium, as well as serum melatonin levels before and after delivery in patients with preeclampsia. Subjects and methods A total of 91 women divided in four groups were enrolled in this perspective study. Group A consisted of patients with preeclampsia (n=31), group B of women with gestational hypertension without proteinuria (n=20) and group C included normotensive pregnant women (n=20). Healthy non-pregnant women of a reproductive age formed group D (n=20). From group A, 21 women were diagnosed with mild preeclampsia while the other 10 met at least one of the criteria of heavy preeclampsia. Renal function was assessed by 24h urine protein excretion, serum creatinine, urea, uric acid and cystatin C. Endothelial function was assessed by markers of endothelial activation (von Willebrand factor) and damage (soluble adhesive molecules sVCAM-1 and sICAM-2). Serum melatonin and its major urine metabolite 6-sulfatoxymelatonine (6-SMT) levels were also evaluated in daytime and nighttime measurements. Subjects from group A and group B before the initiation of antihypertensive therapy underwent 24h blood pressure monitoring. Moreover, in all women from both groups A and B, 24h urine samples were collected and blood samples were obtained at 10:00 a.m. and at 00:00 of the same day. In women from group A, all sample collections mentioned above and blood pressure monitoring were repeated 2 months postpartum. Ιn women from group C and group D the 24h urine collection as well as the collection of morning and nocturnal blood and urine samples was performed only once at their recruitment in the study. Results Women with preeclampsia had significantly higher body mass index (BMI), serum cystatin C and endothelial damage markers (vWf and sVCAM-1) compared to women from the other groups in our study. On the contrary, nocturnal serum melatonin concentrations and morning urine 6-SMT concentrations were significantly lower in the group of preeclampsia. Elimination of the circadian rhythm of blood pressure was defined as a decrease of the mean arterial pressure (MAP) during the night by less than 10% compared to the MAP during the day (6:00 a.m. to 9:00 p.m.). According to that definition, 21 out of 31 women with preeclampsia (68%), 8 out of 20 with gestational hypertension (40%) and 2 out of 20 normotensive pregnant women (10%) were considered as non-dippers. In group A (women with preeclampsia), non-dippers had significantly higher BMI and significantly elevated serum cystatin C, sVCAM-1 and vWf compared to dippers. Serum uric acid levels and 24h urine protein excretion were elevated in non-dippers but the differences were not statistically significant. In addition, serum nocturnal melatonin and morning urine 6-SMT levels were significantly reduced in non-dippers with preeclampsia. Two months postpartum, 11 women out of 21 non-dippers (52%) with preeclampsia continued to be non-dippers while the other 10 restored blood pressure circadian rhythm. In these new subgroup of dippers and non-dippers, it was demonstrated that non-dippers had higher proteinuria and serum cystatin C levels compared to dippers, while endothelial damage markers (vWf, sVCAM-1 and sICAM-1) were decreased in non-dippers. Serum nocturnal melatonin and morning urine 6-SMT concentrations were still higher in non-dippers compared to dippers, while nocturnal melatonin secretion was normalized in dippers.Στόχος της παρούσης μελέτης είναι να συσχετιστεί η διαταραχή του κιρκάδιου ρυθμού της αρτηριακής πίεσης με τις μεταβολές της λειτουργίας των νεφρών, των αγγειακών ενδοθηλιακών κυττάρων και των επιπέδων της μελατονίνης σε ασθενείς με προεκλαμψία πριν και μετά τον τοκετό. Υλικό και μέθοδοι Συνολικά έλαβαν μέρος 91 γυναίκες, οι οποίες χωρίστηκαν σε 4 ομάδες: A. Έγκυες με προεκλαμψία (n=31), Β. Έγκυες με υπέρταση της κύησης χωρίς λευκωματουρία (n=20), Γ. Έγκυες με φυσιολογική αρτηριακή πίεση (n=20), Δ. Γυναίκες υγιείς, μή κυοφορούσες, αναπαραγωγικής ηλικίας (n=20). Από την ομάδα Α (n=31), 21 γυναίκες παρουσίασαν ήπια προεκλαμψία, ενώ οι υπόλοιπες 10 πληρούσαν τουλάχιστον ένα από τα κριτήρια της σοβαρής προεκλαμψίας. Οι παράμετροι που προσδιορίστηκαν διακρίνονται σε 3 κατηγορίες. Η πρώτη κατηγορία περιλαμβάνει δείκτες νεφρικής λειτουργίας όπως το λεύκωμα ούρων 24ώρου, η κρεατινίνη, η ουρία, το ουρικό οξύ και η συστατίνη-C. Η δεύτερη κατηγορία περιλαμβάνει δείκτες ενδοθηλιακής δυσλειτουργίας όπως ο vWf και τα διαλυτά μόρια προσκόλλησης sVCAM-1 και sICAM-1, ενώ στην τρίτη κατηγορία περιλαμβάνεται ο προσδιορισμός των συγκεντρώσεων της μελατονίνης στoν ορό και της 6-sulfatoxymelatonin (6-SMT), που αποτελεί τον κύριο μεταβολίτη της μελατονίνης στα ούρα, πρωί και βράδυ. Στις γυναίκες των ομάδων Α και Β πριν την έναρξη αντιυπερτασικής αγωγής, έγινε 24ωρη καταγραφή της αρτηριακής πίεσης, συλλογή ούρων 24ώρου και αιμοληψίες που πραγματοποιούνταν σταθερά στις 10.00 π.μ. και 00.00 τις ίδιας ημέρας. Όλη η παραπάνω διαδικασία επαναλήφθηκε στις γυναίκες της ομάδας Α και 2 μήνες μετά τον τοκετό. Στις γυναίκες της ομάδας Γ και Δ όλη η παραπάνω διαδικασία έγινε εφ΄άπαξ. Αποτελέσματα Από την ανάλυση των αποτελεσμάτων προέκυψε ότι οι γυναίκες με προεκλαμψία εμφάνισαν στατιστικά σημαντικά υψηλότερα επίπεδα ΒΜΙ (body mass index), συστατίνης-C καθώς και των δεικτών ενδοθηλιακής βλάβης vWf και sVCAM-1 σε σχέση με τις άλλες ομάδες της μελέτης. Αντίθετα, οι βραδινές συγκεντρώσεις της μελατονίνης ορού και οι πρωινές συγκεντρώσεις της 6-SMT ούρων εμφανίστηκαν σημαντικά χαμηλότερες στην ομάδα της προεκλαμψίας. Ως κατάργηση του κιρκάδιου ρυθμού της αρτηριακής πίεσης (non-dipping) θεωρήθηκε πτώση της μέσης αρτηριακής πίεσης (ΜΑP) κατά τη διάρκεια της νύχτας (9.00μμ εως 6.00πμ) μικρότερη από 10% σε σχέση με τη ΜΑP κατά τη διάρκεια της ημέρας (6.00πμ εως9.00μμ). Με βάση τον παραπάνω ορισμό, 21 από τις 31 γυναίκες με προεκλαμψία (68%), 8 από τις 20 γυναίκες με υπέρταση της κύησης (40%) και 2 από τις 20 νορμοτασικές έγκυες (10% ) χαρακτηρίστηκαν ως non-dippers. Στην ομάδα της προεκλαμψίας οι non-dippers εμφάνισαν σημαντικά υψηλότερο BMI καθώς και υψηλότερες συγκεντρώσεις συστατίνης-C, sVCAM-1 και vWf και σε σχέση με τις dippers. Τα επίπεδα του ουρικού οξέος ορού καθώς του λευκώματος ούρων 24ώρου παρουσιάστηκαν αυξημένα στις non-dippers αλλά οι διαφορές δεν ήταν στατιστικά σημαντικές. Επίσης, παρατηρήθηκε ότι τα επίπεδα της βραδινής μελατονίνης ορού και της πρωινής 6-SMT ούρων ήταν σημαντικά χαμηλότερα στις non-dippers έγκυες με προεκλαμψία. Δύο μήνες μετά τον τοκετό από τις 21 γυναίκες με προεκλαμψία που χαρακτηρίστηκαν non-dippers, οι 11 (52%) παρέμειναν non-dippers ενώ στις υπόλοιπες 10 επανήλθε ο κιρκάδιος ρυθμός της αρτηριακής πίεσης (dippers). Σε αυτή τη νέα υποομάδα των dippers και non-dippers, διαπιστώθηκε ότι οι non-dippers είχαν υψηλότερα επίπεδα λευκωματουρίας και συστατίνης-C σε σχέση με τις dippers ενώ οι δείκτες ενδοθηλιακής βλάβης, vWf, sVCAM-1 και sICAM-1 εμφάνισαν χαμηλότερα επίπεδα στις non-dippers. Τέλος, οι συγκεντρώσεις της βραδινής μελατονίνης ορού και της πρωινής 6-SMT ούρων εξακολουθούσαν να είναι χαμηλότερες στις non-dippers σε σχέση με τις dippers, ενώ στις dippers η νυχτερινή έκκριση της μελατονίνης εξομαλύνθηκε

Endometrial cancer: molecular and therapeutic aspects

Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy. Although early-stage EC is effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent EC. Multi-institutional trials are in progress to better define optimal adjuvant treatment for subsets of patients, as well as the role of surgical staging in reducing both overuse and underuse of radiation therapy. Understanding and identifying the molecular biology and genetics of EC are central to the development of novel therapies. A number of molecular and genetic events have been observed in ECs, which have enabled us to have a better understanding of the biology and development of the disease. For example, the PTEN/AKT pathway and its downstream targets and the mTOR pathway have been shown to play an important role in EC pathogenesis. This review summarizes the background of the known molecular alterations, and the management of patients with EC. (c) 2013 Elsevier Ireland Ltd. All rights reserved

Uterine prolapse in pregnancy: risk factors, complications and management

Presentation of uterine prolapse is a rare event in a pregnant woman, which can be pre-existent or else manifest in the course of pregnancy. Complications resulting from prolapse of the uterus in pregnancy vary from minor cervical infection to spontaneous abortion, and include preterm labor and maternal and fetal mortality as well as acute urinary retention and urinary tract infection. Moreover, affected women may be at particular risk of dystocia during labor that could necessitate emergency intervention for delivery. Recommendations regarding the management of this infrequent but potentially harmful condition are scarce and outdated. This review will examine the causative factors of uterine prolapse and the antepartum, intrapartum and puerperal complications that may arise from this condition as well as therapeutic options available to the obstetrician. While early recognition and appropriate prenatal management of uterine prolapse during pregnancy is imperative, implementation of conservative treatment modalities throughout pregnancy, these applied in accordance with the severity of the uterus prolapse and the patient’s preference, may be sufficient to achieve uneventful pregnancy and normal, spontaneous delivery

Melatonin secretion is impaired in women with preeclampsia and an abnormal circadian blood pressure rhythm

Non-dipping circadian blood pressure (BP) is a common finding in preeclampsia, accompanied by adverse outcomes. Melatonin plays pivotal role in biological circadian rhythms. This study investigated the relationship between melatonin secretion and circadian BP rhythm in preeclampsia. Cases were women with preeclampsia treated between January 2006 and June 2007 in the University Hospital of Larissa. Volunteers with normal pregnancy, matched for chronological and gestational age, served as controls. Twenty-four hour ambulatory BP monitoring was applied. Serum melatonin and urine 6-sulfatoxymelatonin levels were determined in day and night time samples by enzyme-linked immunoassays. Measurements were repeated 2 months after delivery. Thirty-one women with preeclampsia and 20 controls were included. Twenty-one of the 31 women with preeclampsia were non-dippers. Compared to normal pregnancy, in preeclampsia there were significantly lower night time melatonin (48.4 +/- 24.7 vs. 85.4 +/- 26.9 pg/mL, p < 0.001) levels. Adjustment for circadian BP rhythm status ascribed this finding exclusively to non-dippers (p < 0.01). Two months after delivery, in 11 of the 21 non-dippers both circadian BP and melatonin secretion rhythm reappeared. In contrast, in cases with retained non-dipping status (n=10) melatonin secretion rhythm remained impaired: daytime versus night time melatonin (33.5 +/- 13.0 vs. 28.0 +/- 13.8 pg/mL, p=0.386). Urinary 6-sulfatoxymelatonin levels were, overall, similar to serum melatonin. Circadian BP and melatonin secretion rhythm follow parallel course in preeclampsia, both during pregnancy and, at least 2 months after delivery. Our findings may be not sufficient to implicate a putative therapeutic effect of melatonin, however, they clearly emphasize that its involvement in the pathogenesis of a non-dipping BP in preeclampsia needs intensive further investigation