Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment

During placentation invasive extravillous trophoblasts (EVTs) migrate into the maternal uterus and modify its vessels. In particular, remodeling of the spiral arteries by EVTs is critical for adapting blood flow and nutrient transport to the developing fetus. Failures in this process have been noticed in different pregnancy complications such as preeclampsia, intrauterine growth restriction, stillbirth, or recurrent abortion. Upon invasion into the decidua, the endometrium of pregnancy, EVTs encounter different maternal cell types such as decidual macrophages, uterine NK (uNK) cells and stromal cells expressing a plethora of growth factors and cytokines. Here, we will summarize development of the EVT lineage, a process occurring independently of the uterine environment, and formation of its different subtypes. Further, we will discuss interactions of EVTs with arteries, veins and lymphatics and illustrate how the decidua and its different immune cells regulate EVT differentiation, invasion and survival. The present literature suggests that the decidual environment and its soluble factors critically modulate EVT function and reproductive success

Maternal Obesity Drives Functional Alterations in Uterine NK Cells

Over one-fifth of North American women of childbearing age are obese, putting these women at risk for a variety of detrimental chronic diseases. In addition, obesity increases the risk for developing major complications during pregnancy. The mechanisms by which obesity contributes to pregnancy complications and loss remain unknown. Increasing evidence indicates that obesity results in major changes to adipose tissue immune cell composition and function; whether or not obesity also affects immune function in the uterus has not been explored. Here we investigated the effect of obesity on uterine natural killer (uNK) cells, which are essential for uterine artery remodeling and placental development. Using a cohort of obese or lean women, we found that obesity led to a significant reduction in uNK cell numbers accompanied with impaired uterine artery remodeling. uNK cells isolated from obese women had altered expression of genes and pathways associated with extracellular matrix remodeling and growth factor signaling. Specifically, uNK cells were hyper-responsive to PDGF, resulting in overexpression of decorin. Functionally, decorin strongly inhibited placental development by limiting trophoblast survival. Together, these findings establish a potentially new link between obesity and poor pregnancy outcomes, and indicate that obesity-driven changes to uterine-resident immune cells critically impair placental development

On the origin of [Ne II] emission in young stars: mid-infrared and optical observations with the Very Large Telescope

{Abridged version for ArXiv}. We provide direct constraints on the origin of the [Ne II] emission in 15 young stars using high-spatial and spectral resolution observations with VISIR at the VLT that allow us to study the kinematics of the emitting gas. In addition we compare the [Ne II] line with optical forbidden lines observed for three stars with UVES. The [Ne II] line was detected in 7 stars, among them the first confirmed detection of [Ne II] in a Herbig Be star, V892 Tau. In four cases, the large blueshifted lines indicate an origin in a jet. In two stars, the small shifts and asymmetric profiles indicate an origin in a photo-evaporative wind. CoKu Tau 1, seen close to edge-on, shows a spatially unresolved line centered at the stellar rest velocity, although cross-dispersion centroids move within 10 AU from one side of the star to the other as a function of wavelength. The line profile is symmetric with wings extending up to about +-80 km/s. The origin of the [Ne II] line could either be due to the bipolar jet or to the disk. For the stars with VLT-UVES observations, in several cases, the optical forbidden line profiles and shifts are very similar to the profile of the [Ne II] line, suggesting that the lines are emitted in the same region. A general trend observed with VISIR is a lower line flux when compared with the fluxes obtained with Spitzer. We found no correlation between the line full-width at half maximum and the line peak velocity. The [Ne II] line remains undetected in a large part of the sample, an indication that the emission detected with Spitzer in those stars is likely extended.Comment: Accepted for publication in Astronomy & Astrophysics; revised version: corrected minor typos, corrected center values (col 3) for CoKuTau1 in Table

Multidimensional models of hydrogen and helium emission line profiles for classical T Tauri Stars: method, tests and examples

We present multidimensional non-LTE radiative transfer models of hydrogen and helium line profiles formed in the accretion flows and the outflows near the star-disk interaction regions of classical T Tauri stars (CTTSs). The statistical equilibrium calculations, performed under the assumption of the Sobolev approximation using the radiative transfer code TORUS, has been improved to include He I and He II energy levels. This allows us to probe the physical conditions of the inner wind of CTTSs by simultaneously modelling the robust wind diagnostic line He I (10830) and the accretion diagnostic lines such as Pa-beta, Br-gamma and He I (5876). The code has been tested in 1 and 2-D problems, and we have shown that the results are in agreement with established codes. We apply the model to the complex flow geometries of CTTSs. Example model profiles are computed using the combinations of (1) magnetospheric accretion and disc wind, and (2) magnetospheric accretion and the stellar wind. In both cases, the model produces line profiles which are qualitatively similar to those found in observations. Our models are consistent with the scenario in which the narrow blueshifted absorption component of He I (10830) seen in observations is caused by a disc wind, and the wider blueshifted absorption component (the P-Cygni profile) is caused by a bipolar stellar wind. However, we do not have a strong constraint on the relative importance of the wind and the magnetosphere for the `emission' component. Our preliminary calculations suggest that the temperatures of the disc wind, stellar wind and the magnetosphere cannot be much higher than ~10,000 K, on the basis of the strengths of hydrogen lines. With these low temperatures, we find that the photoionzation by high energy photons (e.g. X-rays) is necessary to produce He I (10830) in emission and to produce the blueshifted absorption components.Comment: 18 pages, 12 figures, accepted for publication in MNRA

Regulated Expression of ADAMTS-12 in Human Trophoblastic Cells: A Role for ADAMTS-12 in Epithelial Cell Invasion?

Metastatic carcinoma cells exploit the same molecular machinery that allows human placental cytotrophoblasts to develop an invasive phenotype. As altered expression levels of ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin repeats) subtypes have been associated with cancer progression, we have examined the function and regulation of members of this gene family in epithelial cell invasion using cultures of highly invasive extravillous cytotrophoblasts and the poorly invasive JEG-3 cytotrophoblast cell line as model systems. Of the multiple ADAMTS subtypes identified in first trimester human placenta and these two trophoblastic cell types, only ADAMTS-12 was preferentially expressed by extravillous cytotrophoblasts. Transforming growth factor-β1 and interleukin-1β, two cytokines that promote and restrain cytotrophoblast invasion in vitro, were also found to differentially regulate trophoblastic ADAMTS-12 mRNA levels. Loss- or gain-of-function studies confirmed that ADAMTS-12, independent of its proteolytic activity, plays a specific, non-redundant role in trophoblast invasion. Furthermore, we demonstrated that ADAMTS-12 regulated cell-extracellular matrix adhesion and invasion through a mechanism involving the αvβ3 integrin heterodimer. This study identifies a novel biological role for ADAMTS-12, and highlights the importance and complexity of its non-proteolytic domain(s) pertaining to its function

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Human placentation : the characterization of novel molecular mechanisms involved in trophoblast invasion

For normal human placental development to occur, cytotrophoblasts located within implanting chorionic villi, differentiate into extravillous cytotrophoblasts that invade into and remodel the maternal stroma and blood vasculature. Extravillous cytotrophoblast invasion is in part regulated by proteolytic and cell-extracellular matrix adhesion mechanisms that have also been shown to play key roles in regulating cancer cell invasion. Trophoblast invasion has therefore been likened to cancer cell invasion, however, unlike tumorigenesis, trophoblast invasion is highly regulated. ADAMTS, a novel gene family of metalloproteinases, have been shown to play important roles in regulating extracellular matrix remodeling events in both physiological and pathological processes. In addition to extracellular matrix remodeling, ADAMTS have the ability to regulate cell-extracellular matrix adhesion, highlighting the possibility that these proteins perform multifunctional roles. To determine whether members of the ADAMTS family play key roles in early placentation, I have characterized the expression of members of this gene family in first trimester placental chorionic villi and in subpopulations of trophoblastic cells. I determined that ADAMTS-12 is expressed in first trimester chorionic villous tissues, and furthermore is preferentially expressed in highly invasive extravillous cytotrophoblasts. Utilizing loss-of and gain-of function studies, I demonstrated that ADAMTS-12 plays a functional role in promoting an invasive phenotype in human trophoblastic cells through a mechanism independent of its proteolyic activity. As cell invasion is also regulated by changes in cell-cell adhesion, I examined the roles that the classical/type-I cadherins, E-cadherin and N-cadherin, play in controlling trophoblast invasion. I determined that E-cadherin and N-cadherin are differentially expressed between poorly-invasive and highly-invasive trophoblastic cells. Additionally, I demonstrated that E-cadherin inhibits trophoblast invasion in a cell adhesion dependent manner, whereas N-cadherin promoted an invasive phenotype through a mechanism dependent upon its extracellular domain. Collectively, these studies describe novel molecular mechanisms that regulate human trophoblast invasion in vitro. These studies are the first to describe a role for N - cadherin in promoting an invasive phenotype in trophoblastic cells, and are the first to describe a role for ADAMTS-12 in regulating cellular invasion. Additionally, these findings shed insight into the cellular mechanisms that regulate cytotrophoblast differentiation along the extravillous cytotrophoblast pathway.Medicine, Faculty ofObstetrics and Gynaecology, Department ofGraduat