DIRAS3 regulates autophagy in an endometriosis epithelial cell line.

RESEARCH QUESTION: What is the role of DIRAS3 in endometriosis pathogenesis? DESIGN: Prospective patient cohort study combined with experiments in the 12Z human endometriosis epithelial cell line model to determine the role of DIRAS3 in endometriosis. Endometrium and endometriosis lesion samples were collected from premenopausal women from 24 control and 40 endometriosis patients by laparoscopic surgery. The role of DIRAS3 in endometriosis was assessed by siRNA knockdown in 12Z cells followed by proliferation, apoptosis, invasion and autophagy assays. Autophagy was induced by serum starvation and the levels of autophagy determined by assessing changes in the expression levels and localization of autophagy marker proteins, such as LC3. RESULTS: DIRAS3 mRNA showed a large increase in expression in ectopic endometriosis lesions compared with endometrium from control patients, with expression largely localized to the epithelium. DIRAS3 knockdown in 12Z endometriosis epithelial cells caused a significant reduction in the number of proliferating cells (1.6-fold, adjusted P = 0.0007) and increased apoptosis (AnnexinV/7AAD double-positive cells +48%, P = 0.01), indicating an effect on cell proliferation. Induction of autophagy by serum starvation caused significant upregulation in DIRAS3 expression after 24 h (mRNA +2.4-fold [adjusted P = 0.017], protein +8.1-fold (adjusted P = 0.029), reduced LC3I/LC3II ratio (-2.2-fold, adjusted P = 0.044) and an increase in the number of double positive LC3/DIRAS3 puncta (+2.3-fold, P = 0.02). Knockdown of DIRAS3 in serum-starved cells led to a reduction in autophagy, indicated by an overall decrease in LC3 expression and significant increase in LC3I/LC3II ratio. CONCLUSIONS: DIRAS3 is highly upregulated in endometriosis lesions. Studies in an endometriosis epithelial cell line indicate that DIRAS3 facilitates cell survival in this context by inducing autophagy.

Fertility preserving management of ovarian torsion.

OBJECTIVE: To analyze characteristics of acute and chronic ovarian torsion, review treatment recommendations, and present possible surgical techniques for fertility preservation in young women. DESIGN: Literature review and demonstration of perioperative management of ovarian torsion using radiologic images and intraoperative video footage. Ovarian torsion is mostly mentioned in context of gynecologic emergencies, where acute ovarian torsion with arterial obstruction leads to ovarian ischemia and necrosis. However, ovarian torsion can also occur as a partial or intermittent torsion with venous and lymphatic obstruction, followed by ovarian swelling. In both cases, surgical management of ovarian torsion commonly includes oophorectomy, although leading guidelines recommend preservation of the ovary. We here aimed to raise awareness for the clinical features of ovarian torsion and demonstrate adequate perioperative management, thereby avoiding surgical overtreatment in young women. SETTING: Medical University of Vienna, Department of Obstetrics and Gynecology. PATIENT(S): We present a case of acute ovarian torsion with a consequently ischemic ovary as well as a case of chronic ovarian torsion with related massive ovarian edema. The patients included in this video gave consent for publication of the video and posting of the video online, including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc.), and other applicable sites. INTERVENTION(S): Laparoscopic management with detorsion of the torquated ovaries, cystectomy on an ischemic ovary and oophoropexy to the pelvic side wall and utero-ovarian ligament to prevent recurrence. MAIN OUTCOME MEASURES: Postoperative relief of pain and normalization of ovarian size and morphology on ultrasound imaging. RESULTS: The current cases show successful conservative surgical management of ovarian torsion, hence preserving hormonal function and fertility in young women. CONCLUSION: Although it is recommended to preserve fertility in young women affected by ovarian torsion, surgical overtreatment by means of oophorectomy is still common in clinical routine. Increasing awareness for the clinical characteristics of acute and chronic ovarian torsion, as well as for the importance of preservation of the ovary, is crucial. We therefore believe that ovarian torsion and its surgical management deserve increased attention in the future.

Does the Use of the "Proseek® Multiplex Inflammation I Panel" Demonstrate a Difference in Local and Systemic Immune Responses in Endometriosis Patients with or without Deep-Infiltrating Lesions?

Endometriotic lesions are able to infiltrate surrounding tissue. This is made possible partly by an altered local and systemic immune response that helps achieve neoangiogenesis, cell proliferation and immune escape. Deep-infiltrating endometriosis (DIE) differs from other subtypes through the invasion of its lesions over 5 mm into affected tissue. Despite the invasive nature of these lesions and the wider range of symptoms they can trigger, DIE is described as a stable disease. This elicits the need for a better understanding of the underlying pathogenesis. We used the "Proseek® Multiplex Inflammation I Panel" in order to simultaneously detect 92 inflammatory proteins in plasma and peritoneal fluid (PF) of controls and patients with endometriosis, as well as in particular patients with DIE, in order to gain a better insight into the systemically and locally involved immune response. Extracellular newly identified receptor for advanced gycation end-products binding protein (EN-RAGE), C-C motif Chemokine ligand 23 (CCL23), Eukaryotic translation initiation factor 4-binding protein 1 (4E-BP1) and human glial cell-line derived neurotrophic factor (hGDNF) were significantly increased in plasma of endometriosis patients compared to controls, whereas Hepatocyte Growth factor (HGF) and TNF-related apoptosis inducing ligand (TRAIL) were decreased. In PF of endometriosis patients, we found Interleukin 18 (IL-18) to be decreased, yet Interleukin 8 (IL-8) and Interleukin 6 (IL-6) to be increased. TNF-related activation-induced cytokine (TRANCE) and C-C motif Chemokine ligand 11 (CCL11) were significantly decreased in plasma, whereas C-C motif Chemokine ligand 23 (CCL23), Stem Cell Factor (SCF) and C-X-C motif chemokine 5 (CXCL5) were significantly increased in PF of patients with DIE compared to endometriosis patients without DIE. Although DIE lesions are characterized by increased angiogenetic and pro-inflammatory properties, our current study seems to support the theory that the systemic immune system does not play a major role in the pathogenesis of these lesions.

The latest advances in the pharmacological management of endometriosis.

INTRODUCTION: Endometriosis is a benign disease, characterized by a wide range of symptoms and different degrees of severity, which is why therapy should be individually adapted to the patient's needs. Over the years, a lot of research has gone into finding new therapeutic approaches for this enigmatic disease. AREAS COVERED: This review presents the latest advances in pharmacological management of endometriosis and is solely focused on studies published from 2010 to 2021. EXPERT OPINION: Clinicians and researchers are constantly searching for new therapeutic strategies for endometriosis patients. As there are well-established treatments, however, any new medication should fulfill at least one of the three criteria: increased efficacy, comparable efficacy but a better safety profile, or treatments that have a lack of accompanying contraceptive effects that are seen in most endometriosis treatments. While some new substances show promising results, further studies are needed to demonstrate the fulfillment of one of the above-mentioned criteria.

Vaginal transisthmic myomectomy: a step by step video tutorial.

OBJECTIVE: To provide a video tutorial on vaginal transisthmic myomectomy in women with large submucosal fibroids. DESIGN: Stepwise demonstration of the technique, with a narrated video footage. SETTING: Submucosal fibroids protrude into the uterine cavity and can cause numerous symptoms, including abnormal uterine bleeding, dysmenorrhea, subfertility, and obstetric complications. Over the last decades, hysteroscopic resection has become the preferred surgical approach for submucosal fibroids because it provides significant advantages regarding perioperative morbidity and postoperative recovery time when compared with laparotomy or laparoscopy with complete transection of the uterine wall. However, in large or multiple fibroids, longer surgery durations of hysteroscopic resection can lead to higher complication rates and incomplete resection. In some cases, hysteroscopic resection might even be impossible to perform. Furthermore, in many regions, special equipment for hysteroscopic myomectomy might not be available. Herein, we present a minimally invasive surgical alternative for approaching submucosal fibroids. PATIENT(S): A 26-year-old woman presenting with hypermenorrhea and dysmenorrhea (on a numeric rating scale from 0-10) caused by a recurrent International Federation of Gynaecology and Obstetrics (FIGO) type 0 fibroid measuring 5 cm in diameter. INTERVENTION(S): Vaginal transisthmic myomectomy performed with a longitudinal transection of the uterine cervix and isthmus, morcellation of the fibroid with a scalpel, and multilayer reconstruction. MAIN OUTCOME MEASURE(S): Vaginal transisthmic myomectomy is a fast and relatively simple, minimally invasive surgical technique suitable for large or multiple FIGO 0 and some FIGO 1 fibroids, necessitating the use of only basic surgical equipment. RESULT(S): Vaginal transisthmic myomectomy provides an additional minimally invasive surgical approach for submucosal fibroids. CONCLUSION(S): This surgical option for selected patients may help prevent complications resulting from prolonged hysteroscopic surgery, repeated hysteroscopic procedures owing to incomplete resection, and the morbidity of transabdominal approaches for myomectomy. With this video, we aim to expedite the clinical learning curve of this technique, which should be investigated on a broader scale in the future.

Hsa-mir-135a Shows Potential as A Putative Diagnostic Biomarker in Saliva and Plasma for Endometriosis.

Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the need for diagnostic biomarkers. The correlation of circulating miRNAs with altered inflammatory signals seen in patients with endometriosis has raised the possibility that miRNAs can serve as biomarkers for the disease. In our study, we analyzed miRNA expression in saliva of women with and without endometriosis using a FireFly custom multiplex circulating miRNA assay. This focused panel included 28 human miRNAs, 25 of which have been previously found to be differentially expressed either in plasma, serum, and/or blood of women with endometriosis, compared to controls. We found that hsa-mir-135a was expressed significantly higher in the saliva of women with endometriosis, independent of disease stage and menstrual cycle phase. We confirmed that hsa-mir-135a also showed significantly elevated expression in the plasma of endometriosis patients. This indicates that hsa-mir-135a is a putative noninvasive biomarker of endometriosis in both saliva and plasma, but further validation studies are required to assess its clinical value as a biomarker.

Myomectomy for a large uterine fibroid via mini-laparotomy: a step-by-step video tutorial.

OBJECTIVE: To provide a video tutorial on myomectomy via mini-laparotomy in women with large uterine fibroids. DESIGN: Stepwise demonstration of the technique with narrated video footage. SETTING: Uterine fibroids represent the most common benign gynecologic disease, and myomectomy is a frequent reproductive surgery aiming to preserve or improve fertility. Abdominal and laparoscopic myomectomy are common treatments, but over the last decades, laparoscopy has become the preferred surgical approach because it provides significant advantages, such as shorter recovery time and a lower overall risk of complications. However, removal of large fibroids by laparoscopy is often technically challenging or even impossible. PATIENT(S): A 29-year-old woman presenting with urinary frequency and lower abdominal pressure due to a 14-cm diameter FIGO type 4 uterine fibroid in the anterior uterine wall. INTERVENTION(S): Myomectomy via mini-laparotomy using a 4-cm transverse skin incision and morcellation with a scalpel using an atraumatic circular self-retaining wound retractor. MAIN OUTCOME MEASURE(S): Mini-laparotomy represents a safe and simple approach combining the benefits of laparoscopy, such as reduced postoperative pain, reduced morbidity, and shorter hospitalization time, and the benefits of laparotomy, such as shorter duration of surgery, cost-effectiveness, and no need for advanced laparoscopic skills. RESULT(S): Mini-laparotomy can provide preferable cosmesis compared with alternative approaches. CONCLUSION(S): Mini-laparotomy represents an alternative minimally-invasive approach for large uterine fibroids, resulting in good overall outcome and no need for special surgical skills or equipment including power-morcellators. With this video, we aim to expedite the clinical learning curve of this technique and believe that selected patients desiring fertility could benefit from its application on a broader scale in the future.

Comparison of a practice-based versus theory-based training program for conducting vacuum-assisted deliveries: a randomized-controlled trial.

PURPOSE: Vacuum-assisted deliveries (VAD) are complex procedures that require training and experience to be performed proficiently. We aimed to evaluate if a more resource intensive practice-based training program for conducting VAD is more efficient compared to a purely theory-based training program, with respect to immediate training effects and persistence of skills 4-8 weeks after the initial training. METHODS: In this randomized-controlled study conducted in maternity staff, participants performed a simulated low-cavity non-rotational vacuum delivery before (baseline test) and immediately after the training (first post-training test) as well as 4-8 weeks thereafter (second post-training test). The study's primary endpoint was to compare training effectiveness between the two study groups using a validated objective structured assessment of technical skills (OSATS) rating scale. RESULTS: Sixty-two participants were randomized to either the theory-based group (n = 31) or the practice-based group (n = 31). Total global and specific OSATS scores, as well as distance of cup application to the flexion point improved significantly from baseline test to the first post-training test in both groups (pall < 0.007). Skill deterioration after 4-8 weeks was only found in the theory-based group, whereas skills remained stable in the practice-based group. CONCLUSION: A practice-based training program for conducting VAD results in comparable immediate improvement of skills compared to a theory-based training program, but the retention of skills 4-8 weeks after training is superior in a practice-based program. Future studies need to evaluate, whether VAD simulation training improves maternal and neonatal outcome after VAD.

The Role of Long Non-Coding RNAs in Endometriosis.

Endometriosis is a chronic gynecological disorder affecting the quality of life and fertility of many women around the world. Heterogeneous and non-specific symptoms may lead to a delay in diagnosis, with treatment options limited to surgery and hormonal therapy. Hence, there is a need to better understand the pathogenesis of the disease to improve diagnosis and treatment. Long non-coding RNAs (lncRNAs) have been increasingly shown to be involved in gene regulation but remain relatively under investigated in endometriosis. Mutational and transcriptomic studies have implicated lncRNAs in the pathogenesis of endometriosis. Single-nucleotide polymorphisms (SNPs) in lncRNAs or their regulatory regions have been associated with endometriosis. Genome-wide transcriptomic studies have identified lncRNAs that show deregulated expression in endometriosis, some of which have been subjected to further experiments, which support a role in endometriosis. Mechanistic studies indicate that lncRNAs may regulate genes involved in endometriosis by acting as a molecular sponge for miRNAs, by directly targeting regulatory elements via interactions with chromatin or transcription factors or by affecting signaling pathways. Future studies should concentrate on determining the role of uncharacterized lncRNAs revealed by endometriosis transcriptome studies and the relevance of lncRNAs implicated in the disease by in vitro and animal model studies.

Performing central venous catheters in neonates and small infants undergoing cardiac surgery using a wireless transducer for ultrasound guidance: a prospective, observational pilot study.

BACKGROUND: Neonates and small infants with congenital cardiac disease undergoing cardiac surgery represent major challenges facing paediatric anaesthesia and perioperative medicine. AIMS: We here aimed to investigate the success rates in performing ultrasound (US) guided central venous catheter insertion (CVC) in neonates and small infants undergoing cardiac surgery, and to evaluate the practicability and feasibility of thereby using a novel wireless US transducer (WUST). METHODS: Thirty neonates and small infants with a maximum body weight of 10 kg and need for CVC before cardiac surgery were included in this observational trial and were subdivided into two groups according to their weight: < 5 kg and ≥ 5 kg. Cannulation success, failure rate, essential procedure related time periods, and complications were recorded and the clinical utility of the WUST was assessed by a 5-point Likert scale. RESULTS: In total, CVC-insertion was successful in 27 (90%) of the patients and the first attempt was successful in 24 (78%) of patients. Success rates of CVC were 80% < 5 kg and 100% ≥5 kg. Comparing the two groups we found a clear trend towards longer needle insertion time in patients weighing < 5 kg (33 [28-69] vs. 24 [15-37]s, P = .07), whereas, the total time for catheter insertion and the duration of the whole procedure were similar in both groups (199 [167-228] vs. 178 [138-234] and 720[538-818] vs. 660 [562-833]s. In total, we report 3 (10%) cases of local hematoma as procedure-related complications. Assessments of the WUST revealed very good survey results for all parameters of practicability and handling (all ratings between 4.5 and 5.0). CONCLUSION: Although difficulties in CVC-placement seem to relate to vessel size and patient's weight, US guided CVC-insertion represents a valuable, fast, and safe intervention in neonates and small children undergoing cardiac surgery. Using the WUST is feasible for this clinical application and may aid in efforts aiming to optimize perioperative care. TRIAL REGISTRATION: Wireless US-guided CVC placement in infants; Clinicaltrials.gov: NCT04597021 ; Date of Registration: 21October, 2020; retrospectively registered.

LINC01133 Inhibits Invasion and Promotes Proliferation in an Endometriosis Epithelial Cell Line.

Endometriosis is a common gynecological disorder characterized by ectopic growth of endometrium outside the uterus and is associated with chronic pain and infertility. We investigated the role of the long intergenic noncoding RNA 01133 (LINC01133) in endometriosis, an lncRNA that has been implicated in several types of cancer. We found that LINC01133 is upregulated in ectopic endometriotic lesions. As expression appeared higher in the epithelial endometrial layer, we performed a siRNA knockdown of LINC01133 in an endometriosis epithelial cell line. Phenotypic assays indicated that LINC01133 may promote proliferation and suppress cellular migration, and affect the cytoskeleton and morphology of the cells. Gene ontology analysis of differentially expressed genes indicated that cell proliferation and migration pathways were affected in line with the observed phenotype. We validated upregulation of p21 and downregulation of Cyclin A at the protein level, which together with the quantification of the DNA content using fluorescence-activated cell sorting (FACS) analysis indicated that the observed effects on cellular proliferation may be due to changes in cell cycle. Further, we found testis-specific protein kinase 1 (TESK1) kinase upregulation corresponding with phosphorylation and inactivation of actin severing protein Cofilin, which could explain changes in the cytoskeleton and cellular migration. These results indicate that endometriosis is associated with LINC01133 upregulation, which may affect pathogenesis via the cellular proliferation and migration pathways.

Is Chronic Endometritis Associated with Tubal Infertility? A Prospective Cohort Study.

STUDY OBJECTIVE: Chronic endometritis (CE), which often presents asymptomatically, is associated with recurrent pregnancy loss, recurrent implantation failure after in vitro fertilization, and endometriosis. Data connecting CE with fallopian tubal occlusion are limited. The aim was to assess a potential association of CE, defined by the presence of syndecan-1 (CD138)-positive plasma cells in endometrial tissue samples, with fallopian tube patency and other factors for infertility, including endometriosis, adenomyosis, and hydrosalpinges. DESIGN: Prospective, monocentral pilot study. SETTING: Tertiary care center. PATIENTS: A cohort of 100 women who were infertile was enrolled from July 2019 to December 2020. INTERVENTIONS: Hysteroscopy with endometrial biopsy and laparoscopy with chromopertubation. MEASUREMENTS AND MAIN RESULTS: CE was found in 13 women (13.0%) and was associated with endometriosis (p = .034) and unilateral/bilateral fallopian tube blockage (p = .013). In women with endometriosis, the mean number of CD138-positive cells was positively correlated with the revised American Society for Reproductive Medicine score (r = .302, p = .028). In a binary regression model, the presence of a hydrosalpinx on one or both sides (odds ratio 15.308; 95% confidence interval, 1.637-143.189; p = .017) and the finding of CE in the endometrial tissue sample (odds ratio 5.273; 95% confidence interval, 1.257-22.116; p = .023) were significantly associated with fallopian tubal occlusion. CONCLUSION: CE was significantly associated with blockage of the fallopian tubes and endometriosis. Endometriosis stage was associated with the number of CD138-positive cells in endometrial biopsies.

Does the Use of the "Proseek® Multiplex Oncology I Panel" on Peritoneal Fluid Allow a Better Insight in the Pathophysiology of Endometriosis, and in Particular Deep-Infiltrating Endometriosis?

Endometriosis appears to share certain cancer-related processes, such as cell attachment, invasion, proliferation and neovascularization, some of which can also be found in other healthy tissues. In order to better understand the altered milieu of the peritoneal cavity, while acknowledging the reported similarities between endometriosis and neoplastic processes, we applied a multiplex oncology panel to search for specific biomarker signatures in the peritoneal fluid of women with endometriosis, women with deep-infiltrating endometriosis (DIE), as well as controls. In total, 84 patients were included in our study, 53 women with endometriosis and 31 controls. Ninety-two proteins were measured in prospectively collected peritoneal fluid (PF) samples, using the "Proseek® Multiplex Oncology I Panel". We first compared patients with endometriosis versus controls, and in a second step, DIE versus endometriosis patients without DIE. Out of the 92 analyzed proteins, few showed significant differences between the groups. In patients with endometriosis, ICOS ligand, Endothelial growth factor, E-selectin, Receptor tyrosine-protein kinase erbB-2, Interleukin-6 receptor alpha, Vascular endothelial growth factor receptor 2, Fms-related tyrosine kinase 3 ligand, C-X-C motif chemokine 10, Epididymal secretory protein E4 and Folate receptor-alpha were decreased, while Interleukin-6 and Interleukin-8 were increased compared to controls. Looking at patients with DIE, we found Chemokine ligand 19, Stem cell factor, Vascular endothelial growth factor D, Interleukin-6 receptor alpha and Melanoma inhibitory activity to be increased compared to endometriosis patients without DIE. We have shown a distinct regulation of the immune response, angiogenesis, cell proliferation, cell adhesion and inhibition of apoptosis in PF of patients with endometriosis compared to controls. The specific protein pattern in the PF of DIE patients provides new evidence that DIE represents a unique entity of extrauterine endometriosis with enhanced angiogenetic and pro-proliferative features.

Endometriosis Patients Show an Increased M2 Response in the Peritoneal CD14+low/CD68+low Macrophage Subpopulation Coupled with an Increase in the T-helper 2 and T-regulatory Cells.

Endometriosis is a chronic inflammatory disease associated with an impaired immune response at the site of lesion implantation. The ability of macrophages to respond to changes in their environment is critical for an effective immune response. However, the existing knowledge of the peritoneal immune cell populations, their activation state and contribution to the immunological changes that occur in endometriosis are still controversial and inconclusive. In this study, we have examined the relative abundance of peritoneal macrophage subtypes, in women with (n = 21) versus without (n = 18) endometriosis and disease-associated changes in the adaptive T cell response. Using flow cytometry, we showed that peritoneal fluid monocyte/macrophages are composed of two populations of cells that exhibit major differences in the levels of the CD14 and CD68 markers, which we classified as the CD14+low/CD68+low and CD14+high/CD68+high subpopulations. Moreover, endometriosis-associated changes in the macrophage subtypes occurred only in the CD14+low/CD68+low subpopulation. In this subpopulation, we found an increased macrophage type 2 response that was coupled with an increase in peritoneal T-helper 2 and T-regulatory cell populations in women with endometriosis, compared with controls. In summary, this study resolves conflicting data in the literature regarding changes in the peritoneal immune cell population in endometriosis and identifies CD14+low/CD68+low macrophages as the subpopulation that changes in response to the disease.

Basic Laparoscopic Skills Training Is Equally Effective Using 2D Compared to 3D Visualization: A Randomized Controlled Trial.

Reduced depth perception due to two-dimensional (2D) visualization of a three-dimensional (3D) space represents a main challenge in acquiring basic laparoscopic skills (BLS); 3D visualization might increase training efficiency. This study aimed to assess whether BLS training on a standard box trainer using 2D is at least equally effective compared to 3D. Medical students were randomized to training of Fundamentals of Laparoscopic Surgery (FLS) tasks using either 2D or 3D for four weeks. Baseline and post-training tests were performed using the assigned visualization modality. Data of 31 participants were analyzed (n = 16 2D, n = 15 3D). Baseline test scores did not differ significantly between groups; only at the peg transfer task and total scores, the 3D group performed better than the 2D group. All scores improved significantly in both groups, with post training scores not differing significantly between groups. Non-inferiority of 2D compared to 3D was demonstrated for total score improvement and improvement in all individual FLS tasks except for suturing with extracorporeal knot tying. Post training test performance did not change significantly when changing to the unfamiliar modality. In conclusion, BLS training using standard 2D is at least equally effective as with 3D, without significant disadvantages when changing to the other modality.

The Prognostic Value of Angiogenic Markers in Twin Pregnancies to Predict Delivery Due to Maternal Complications of Preeclampsia.

The sFlt-1 (soluble fms-like tyrosine kinase-1), PlGF (placental growth factor), and their ratio are useful for predicting delivery because of preeclampsia in singleton pregnancies. Evidence on the utility of sFlt-1/PlGF ratio in twin pregnancies is lacking. We aimed to evaluate the predictive value of sFlt-1/PlGF ratio for delivery because of preeclampsia in twins. A retrospective data analysis of 164 twin pregnancies with suspected preeclampsia was performed. The sFlt-1/PlGF ratio, which was known to clinicians, was significantly higher in women who delivered within 1 and 2 weeks compared with those who did not (median: 98.9 and 84.2 versus 23.5 pg/mL, respectively; P<0.001). The area under the curve values sFlt-1/PlGF ratio levels were 0.88 (95% CI, 0.83-0.84) and 0.88 (95% CI, 0.83-0.93) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling, respectively. The predictive accuracy of sFlt-1/PlGF was independent of gestational age at sampling and chorionicity (P>0.100 for interaction). The area under the curve values of sFlt-1/PlGF were significantly higher than for PlGF alone (mean 0.88 and 0.88 versus 0.81 and 0.80) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling (P=0.055 and 0.001, respectively). sFlt-1/PlGF ratio lower than 38 was able to rule-out delivery within 1 and 2 weeks with a negative predictive value of 98.8% and 96.4% for delivery because of preeclampsia within 1 and 2 weeks, respectively. A cutoff of 38 is applicable for ruling out delivery because of preeclampsia in twin pregnancies.

Investigating selected adhesion molecules as urinary biomarkers for diagnosing endometriosis.

RESEARCH QUESTION: Are selected cell adhesion molecules useful as urinary biomarkers for diagnosing endometriosis? DESIGN: Prospective, longitudinal study (the Endometriosis Marker Austria) in patients who underwent laparoscopic surgery for benign gynaecological pathologies. A total of 149 patients not receiving hormonal treatment for at least 3 months prior to recruitment were included and preoperative urine protein levels of soluble vascular adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), E-selectin and P-selectin were measured using a magnetic bead-based multiplex assay, normalized to creatinine levels of each sample. Levels were correlated with endometriosis status, menstrual cycle phase, body mass index, cigarette smoking and severity and entity of the lesions. RESULTS: Urine levels of sVCAM-1, sICAM-1, E-selectin and P-selectin did not differ between women with (n = 84) and without (n = 65) endometriosis and among subgroups. Accordingly, receiver operating characteristic analysis to examine the value of using sVCAM-1, sICAM-1, E-selectin and P-selectin levels and sVCAM/sICAM ratio to diagnose endometriosis were not significant. Whether the serum sVCAM-1 levels correlated with the urine levels of the protein in the same women was also investigated, which revealed no significant correlations for sVCAM or sICAM. CONCLUSION: Although a previous study had suggested that serum sVCAM is a promising biomarker for diagnosing endometriosis, no significant differences were found in urine levels of sVCAM-1, sICAM-1, E-selectin and P-selectin between women with and without endometriosis. Other markers should be studied in an effort to establish a truly non-invasive urinary test for diagnosing endometriosis.

Regulation of histamine and diamine oxidase in patients undergoing orthotopic liver transplantation.

Increased concentrations of the vasodilator histamine have been observed in patients undergoing abdominal surgery. The role of histamine during orthotopic liver transplantation (OLT) has only been studied in animals. The aim of this study was to measure plasma concentrations of histamine and its degrading enzyme diamine oxidase (DAO) in patients undergoing orthotopic liver transplantation, and assess whether histamine or DAO correlate with intraoperative noradrenaline requirements. Histamine and DAO concentrations were measured in 22 adults undergoing liver transplantation and 22 healthy adults. Furthermore, norepinephrine requirements during liver transplantation were recorded. Baseline concentrations of histamine and DAO were greater in patients, who underwent liver transplantation, than in healthy individuals (Histamine: 6.4 nM, IQR[2.9-11.7] versus 4.3 nM, IQR[3.7-7.1], p = 0.029; DAO: 2.0 ng/mL, IQR[1.5-4.1] versus <0,5 ng/mL, IQR[<0.5-1.1], p < 0.001). During liver transplantation, histamine concentrations decreased to 1.8 nM, IQR[0.5-4.9] in the anhepatic phase (p < 0.0001 versus baseline), and to 1.5 nM, IQR[0.5-2.9] after reperfusion (p < 0.0001 versus baseline). In contrast, DAO concentrations increased to 35.5 ng/ml, IQR[20-50] in the anhepatic phase (p = 0.001 versus baseline) and to 39.5 ng/ml, IQR[23-64] after reperfusion (p = 0.001 versus baseline), correlating inversely with histamine. Norepinephrine requirements during human liver transplantation correlated significantly with DAO concentrations in the anhepatic phase (r = 0.58, p = 0.011) and after reperfusion (r = 0.56; p = 0.022). In patients undergoing orthotopic liver transplantation, histamine concentrations decrease whereas DAO concentrations increase manifold. Diamine oxidase correlates with intraoperative norepinephrine requirements in patients undergoing OLT.

Glycocalyx Damage Within Human Liver Grafts Correlates With Graft Injury and Postoperative Graft Function After Orthotopic Liver Transplantation.

BACKGROUND: Destruction of the endothelial glycocalyx has been observed within lung and kidney grafts during ischemic organ preservation. We aimed to quantify glycocalyx damage within human liver grafts after organ preservation and correlate the results with graft injury and postoperative graft function in patients undergoing orthotopic liver transplantation (OLT). METHODS: Syndecan-1 (Sdc-1) was measured as indicator of glycocalyx degradation in effluents of 38 liver grafts and serum of patients undergoing OLT. Effluent Sdc-1 concentrations were correlated with hepatic injury markers from the effluent. Furthermore, we assessed the association of Sdc-1 with early allograft dysfunction (EAD), 1-year graft survival, and 1-year patient survival. RESULTS: Effluent Sdc-1 concentrations correlated with effluent concentrations of hepatocellular injury markers, including alkaline phosphatase (R = 0.543, P = 0.003), aspartate aminotransferase (R = 0.420, P = 0.029), and lactate (R = 0.574, P = 0.002). Sdc-1 effluent concentrations were greater in patients who developed EAD compared with those without EAD (4720 [4374-5133] vs 3838 [3202-4240] ng/mL, P = 0.015). Furthermore, receiver operating characteristics analyses revealed that effluent Sdc-1 concentrations (AUC = 0.82, P = 0.017) and serum Sdc-1 concentrations (AUC = 0.84, P = 0.006) were associated with the development of EAD. These results were confirmed by regression analyses. No association was found between Sdc-1 and 1-year graft survival or 1-year patient survival. CONCLUSIONS: Our data suggest that the glycocalyx is damaged within human liver grafts during preservation and the extent of glycocalyx damage correlates with the severity of hepatocellular injury. Recipients of livers grafts with greater glycocalyx damage might be at higher risk for development of EAD after OLT.

Dynamics of soluble syndecan-1 in maternal serum during and after pregnancies complicated by preeclampsia: a nested case control study.

Background We investigated the dynamics and the predictive value of soluble syndecan-1 (Sdc-1), a biomarker of endothelial dysfunction, in uneventful pregnancies and pregnancies complicated by preeclampsia (PE). Methods Serum levels of Sdc-1 were measured at sequential time points during and after uneventful pregnancies (control, n = 95) and pregnancies developing PE (PE_long, n = 12). Levels were further measured in women with symptomatic PE (PE_state, n = 46) at a single time point. Results Sdc-1 levels increased consistently throughout pregnancy. In the PE_long group Sdc-1 levels were lower at all visits throughout pregnancy, and reached significance in weeks 18-22 (p = 0.019), 23-27 (p = 0.009), 28-32 (p = 0.006) and 33-36 (p = 0.008). After delivery, Sdc-1 levels dropped sharply in all pregnancies but were significantly elevated in the PE_long group. The predictive power of Sdc-1 was evaluated analyzing receiver operating characteristic (ROC) curves. A significant power was reached at weeks 14-17 (area under the curve [AUC] 0.65, p = 0.025), 23-27 (AUC 0.73, p = 0.004) and 33-36 (AUC 0.75, p = 0.013). Conclusions In summary, Sdc-1 levels were lower in women developing PE compared to uneventful pregnancies and Sdc-1 might be useful to predict PE. After delivery, Sdc-1 levels remained higher in women with PE. Additional studies investigating the link between glycocalyx degradation, Sdc-1 levels and placental and endothelial dysfunction in pregnancies affected by PE are warranted.