Magnetic resonance imaging detects placental hypoxia and acidosis in mouse models of perturbed pregnancies

Endothelial dysfunction as a result of dysregulation of anti-angiogenic molecules secreted by the placenta leads to the maternal hypertensive response characteristic of the pregnancy complication of preeclampsia. Structural abnormalities in the placenta have been proposed to result in altered placental perfusion, placental oxidative stress, cellular damage and inflammation and the release of anti-angiogenic compounds into the maternal circulation. The exact link between these factors is unclear. Here we show, using Magnetic Resonance Imaging as a tool to examine placental changes in mouse models of perturbed pregnancies, that T2 contrast between distinct regions of the placenta is abolished at complete loss of blood flow. Alterations in T2 (spin-spin or transverse) relaxation times are explained as a consequence of hypoxia and acidosis within the tissue. Similar changes are observed in perturbed pregnancies, indicating that acidosis as well as hypoxia may be a feature of pregnancy complications such as preeclampsia and may play a prominent role in the signalling pathways that lead to the increased secretion of anti-angiogenic compounds

Perceptions of preparedness for the first medical clerkship : a systematic review and synthesis

Background: The transition from university-based to clerkship-based education can be challenging. Medical schools have introduced strategies to ease the transition, but there has been no systematic review synthesizing the evidence on the perceptions of preparedness of medical students for their first clerkship to support these interventions. This study therefore aimed to (1) identify and synthesize the published evidence on medical students’ perceptions of preparedness for their first clerkship, and (2) identify factors that may impact on preparedness for clerkship, to better inform interventions aimed at easing this transition. Methods: Electronic databases (Medline, Journals@Ovid, CINAHL, ERIC, Web of Science, Embase) were searched without restriction and secondary searching of reference lists of included studies was also conducted. Included studies used quantitative or qualitative methodologies, involved medical students and addressed student/supervisor perceptions of preparedness for first clerkship. The first clerkship was defined as the first truly immersive educational experience during which the majority of learning was vocational and self-directed, as per the MeSH term ‘clinical clerkship’ and associated definition. Using an inductive thematic synthesis approach, 2 researchers independently extracted data, coded text (from results and discussion sections), and identified themes related to preparedness. Any disagreements were resolved by discussion and findings were then narratively synthesized. Results: The initial search identified 1214 papers. After removing duplicates and assessing abstracts and full articles against the inclusion criteria, 8 articles were included in the review. In general, the body of evidence was of sound methodological quality. Ten themes relating to perceptions of preparedness of medical students for their first clerkship were identified; competence, disconnection, links to the future, uncertainty, part of the team, time/workload, adjustment, curriculum, prior life experiences and learning. Conclusions: Eight of the ten themes related to perceptions of preparedness are potentially amenable to curricula strategies to improve the transition experience. The evidence supports clinical skills refreshers, clarification of roles and expectations, demystification of healthcare hierarchy and assessment processes and student-student handovers. Evidence also supports preclinical educational strategies such as enhancing content contextualization, further opportunities for the application of knowledge and skills, and constructive alignment of assessment tasks and pedagogical aims

Placental regulation of inflammation and hypoxia after TNF-α infusion in mice

Problem: Increased levels of inflammatory cytokines are demonstrated in the serum of women with pre-eclampsia. TNF-α infusion in animal models induces proteinuric hypertension similar to human pre-eclampsia. The effect of TNF-α on regulation of the immune and hypoxic pathways in the developing placenta and their relationship with experimental pre-eclampsia remains unexamined. Method of Study: TNF-α was infused into pregnant mice, and the effects on maternal hypertension, proteinuria, circulating levels of sFlt-1 and corresponding placental changes in molecules responding to inflammation (TLR-3 and TLR-4) and hypoxia (HIF-1α) were examined. Results: TNF-α infusion resulted in maternal hypertension and proteinuria. Molecular changes in the placenta involved upregulation of TLR-3, TLR-4 and HIF-1α. Serum levels of sFlt-1 were high in pregnant animals, but not further upregulated by TNF-α infusion. Conclusion: A role for maladaptive regulation of TLR and HIF-1α induced by an imbalance in inflammatory cytokines is implicated in the pathogenesis of pre-eclampsia

Magnetic resonance imaging measurements of T2 relaxation times within contrasting regions of murine placenta is dependent upon blood flow

Introduction: It has been postulated that reduced placental perfusion as a result of abnormal placental implantation is the initiating event that leads to the maternal symptoms of preeclampsia. To be able to directly measure blood flow and perfusion in the placenta in experimental models of preeclampsia would provide valuable insight into the structural abnormalities of this syndrome. Magnetic resonance imaging (MRI) offers visualization of anatomy and analysis of changes in tissue morphology and function including blood flow and perfusion. The major source of image contrast in MRI comes from the variation in relaxation times between tissues. Previously, human placenta has appeared as fairly homogeneous in studies of T1 and T2 relaxation times, with no internal morphology apparent. Objectives: The aim of this study was to investigate, using much higher field strengths (11.7 Tesla) and much higher resolution than have been used previously, whether structural inhomogeneities in the placenta can be discerned by T2 mapping and whether T2 mapping is capable of detecting structural abnormalities that may affect blood flow in a preeclamptic placenta

Morphological differences in murine placenta detected by magnetic resonance imaging measurements of T2 relaxation times in mouse models of preeclampsia

Introduction: We have demonstrated that morphologically distinct regions of the murine placenta can be detected by magnetic resonance imaging (MRI), with image contrast arising from the variation in T2 relaxation times between regions and dependent upon blood flow. Previous studies of human placenta by other groups have shown a homogeneous tissue with correlation of relaxation times with gestational age and a trend for shorter relaxation times in pregnancies complicated by preeclampsia and fetal growth restriction. The ability to detect morphological changes and alterations in blood flow in experimental models of preeclampsia would be a significant boost in understanding the relationship between abnormal placental implantation, reduced placental perfusion, inflammatory cytokines, angiogenic molecules and other factors that may play a role in the syndrome. Objectives: The aim of this study was to investigate whether morphological changes or abnormalities can be detected by T2 mapping in the placenta of mice subject to two experimental models of preeclampsia (reduced uterine perfusion pressure (RUPP) model and TNF-a induced model)

Application of Cytoscape to the analysis of diagrams of mechanisms underlying patient problems

In problem based learning (PBL) tutorials in a medical context, students solve authentic patient problems with the educational aim to develop their reasoning capacity. A key activity to facilitate development of their reasoning capacity in a tutorial is the construction of diagrams of mechanisms that explain patient problems. These diagrams are networks of discrete elements (such as headache) of patient problems. Analysis of these diagrams may yield insights into students’ reasoning styles. To achieve this aim, we employed an application called Cytoscape, which is capable of visualising and analysing networks, to study these diagrams. In this preliminary study, we showed that Cytoscape can be used to analyze these diagrams of mechanisms produced in PBL tutorials. We found that students tend to reason in a hierarchical manner. Parameters are also defined that can be used to identify incorrect and missing links in their reasoning processes

The expression of placental soluble fms-like tyrosine kinase 1 in mouse placenta varies significantly across different litters from normal pregnant mice

Objective: Gene expression studies often pool tissues from multiple placentas when using animal models of preeclampsia without accounting for the potential confounders of litter origin or pup sex. We aimed to determine whether placental gene expression differs based on sex or litter. Methods: We examined the differential expression of soluble fms-like tyrosine kinase 1 (Flt-1) using 35 pups from six normal pregnant mice. Results: Expression of sFlt-1 (p = 0.003) was significantly different between litters but not between sexes (p = 0.17). Conclusions: These findings highlight the importance of adequate sampling from multiple litters in expression studies when using animal models in clinical research