Molecular interactions during pregnancy: Association between mannan binding protein deficiency and recurrent miscarriage

The distribution of mannan binding protein (MBP) in blood donorsera was determined by enzyme-linked immunosorbent assay toestablish normal concentrations. Abnormally low MBP concentrationswere found in 16% (21 out of 135) of female partners and 14%(15 out of 108) of male partners of couples experiencing recurrentmiscarriage, compared with <5% of obstetrically normal controls(P < 0.005). This relationship was even stronger (9.5 versus1.0%) and more significant (P < 0.002) when only subjectspresumed to be homozygous for the mutant allele responsiblefor MBP deficiency were considered. By immunohistochemistry,MBP could be demonstrated in first trimester placenta. We suggestthat low concentrations of MBP within the feto-placental unitincrease susceptibility to fetal loss, possibly via an infection-inducedplacental cytokine imbalance.     

Role of Eotaxin-1 (CCL11) and CC chemokine receptor 3 (CCR3) in bleomycin-induced lung injury and fibrosis

Eotaxin-1/CCL11 and its receptor CCR3 are involved in recruitment of eosinophils to diverse tissues, but their role in eosinophil recruitment in pulmonary fibrosis is unclear. The present study examined the pulmonary expression of CCL11 and CCR3 during bleomycin (blm)-induced lung injury and determined their importance in the recruitment of inflammatory cells and the development of lung fibrosis. In mice, blm induced a marked pulmonary expression of CCL11 and CCR3. Immunostaining for CCR3 revealed that this receptor was not only expressed by eosinophils but also by neutrophils. CCL11-deficient (CCL11(-/-)) mice developed significantly reduced pulmonary fibrosis. Expression of profibrotic cytokines such as transforming growth factor-beta1 was diminished in the absence of CCL11. Furthermore, increased lung expression of CCL11 significantly enhanced blm-induced lung fibrosis and production of profibrotic cytokines. These effects were also associated with an increase of eosinophil and neutrophil pulmonary infiltration. In contrast, mice treated with neutralizing CCR3 antibodies developed significantly reduced pulmonary fibrosis, eosinophilia, neutrophilia, and expression of profibrotic cytokines. Together, these data suggest that CCL11 and CCR3 are important in the pulmonary recruitment of granulocytes and play significant pathogenic roles in blm-induced lung fibrosis.     

Heritability and Expression of C-Reactive Protein in Type 2 Diabetes in the Diabetes Heart Study

Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 ± 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.     

The Src kinase Lyn is a negative regulator of mast cell proliferation

Previous investigators have reported that deletion of the protein tyrosine kinase Lyn alters mast cell (MC) signaling responses but does not affect or reduces the cytokine-mediated proliferation of mouse bone marrow-derived MC (BMMC) precursors and of mature MC. We observed that Lyn-deficient mice have more peritoneal MC than wild-type (WT) mice. Studies to explore this unexpected result showed that Lyn(-/-) BM cells expand faster than WT cells in response to interleukin (IL)-3 and stem-cell factor over the 4-5 weeks required to produce a >95% pure population of granular, receptor with high affinity for immunoglobulin E-positive BMMC. Furthermore, differentiated Lyn(-/-) BMMC continue to proliferate more rapidly than WT BMMC and undergo less apoptosis in response to cytokine withdrawal. Additionally, Lyn(-/-) BMMC support greater IL-3-mediated phosphorylation of the prosurvival kinase, Akt, and the proliferative kinase, extracellular-regulated kinase 1/2. These results identify Lyn as a negative regulator of murine MC survival and proliferation.     

Autonomy and developing physicians: Reimagining supervision using self-determination theory

In this article, we address the question, ‘What is the role of autonomy in physician development?’ Medical education is a developmental process, and autonomy plays a motivational role in physician development. Calls for increased supervision of residents have raised concerns that the resulting decreased autonomy might interfere with resident development, leading the authors to explore the relationship between supervision and autonomy. The medical education literature posits a simple inverse relationship between supervision and autonomy. Within competency frameworks, autonomy is operationalised as independence and viewed as the end goal of training. Alternatively, there is emerging empirical literature describing autonomy and supervision as dynamic and developmental constructs and point towards more complex relationship between supervision and autonomy. Self-determination theory (SDT) presents a framework for understanding this dynamic relationship and the role of autonomy in physician development. Within SDT, autonomy is a fundamental psychological need, associated with motivation for learning, self-regulation and an internal locus of control. Supporting learner autonomy can afford learners the opportunity to internalise the values and norms of the profession, leading to an integrated regulation of their behaviours and actions. Conceptualising autonomy through the lens of SDT provides an avenue for education interventions and future research on supervision and autonomy. Educators can integrate supervision and autonomy support in the clinical setting, seeking to motivate learner development by balancing optimal challenge and support and integrating autonomy support with ‘hands-on’ approaches to supervision. SDT also provides a theoretical framework relevant to current discussions regarding feedback conversations and coaching in medical education. Lastly, conceptualising autonomy using SDT opens new avenues for investigation, exploring the complex relationship between supervision and autonomy and developing efforts to integrate autonomy support with clinical supervision.     

Does Perceived Quality of Care Moderate Postpartum Depression? A Secondary Analysis of a Two-Stage Survey

Maternal and Child Health Journal - The purpose of this study was to examine if women’s perceptions of the quality of hospital care during childbirth moderate their risks for symptoms of...     

‘No‐one has listened to anything I’ve got to say before’: Co‐design with people who are sleeping rough

BackgroundDespite policies and programmes aimed at housing people who are homeless, there are still people who live and sleep rough. This project used the skills and knowledge of people in this situation to identify a strategy to mitigate some of the risks.ObjectiveTo describe the development and conduct of a co‐design project involving people who are homeless.Setting/Group MembersA Working Group of 11 was formed following a careful recruitment process from people who had volunteered after consultation by the project team. The co‐design approach was guided by a set of principles.MethodsEight members of the Working Group were interviewed by an external researcher (RM). The approach was primarily deductive, with the principles adopted by the project team used as a framework for data collection and analysis. The co‐design process was captured by the project leaders (BK, PC) supplemented with documentation review and team discussions.ResultsThe group met weekly for 12 weeks, with 8‐10 members present on average. They reviewed information from the survey, contributed ideas for solutions and ultimately decided to provide information via print, a website and an event. Important factors in on‐going involvement were carefully selecting group members and making participation rewarding for them.Discussion/ConclusionsVulnerable people such as those experiencing homelessness can be excluded from decision‐making processes affecting them, as they can be perceived as hard to reach and unable to make a meaningful contribution. This project demonstrated that a carefully managed project, with sufficient resources and commitment, it was possible to involve people who are homeless and maintain involvement over an extended time period.Public ContributionThe Working Group reviewed survey findings and developed an intervention to minimize the health, social and legal harms of sleeping rough. Several members reviewe this paper.