Structural identification of oxidized acyl-phosphatidylcholines that induce platelet activation

Oxidation of low-density lipoprotein (LDL) generates proinflammatory and prothrombotic mediators that may play a crucial role in cardiovascular and inflammatory diseases. In order to study platelet-activating components of oxidized LDL 1-stearoyl-2-arachidonoyl-sn-glycero-3- phosphocholine, a representative of the major phospholipid species in LDL, the 1-acyl-phosphatidylcholines (PC), was oxidized by CuCl2 and H2O2. After separation by high-performance liquid chromatography, three compounds were detected which induced platelet shape change at low micromolar concentrations. Platelet activation by these compounds was distinct from the pathways stimulated by platelet-activating factor, lysophosphatidic acid, lyso-PC and thromboxane A(2), as evidenced by the use of specific receptor antagonists. Further analyses of the oxidized phospholipids by electrospray ionization mass spectrometry structurally identified them as 1-stearoyl-2-azelaoyl-sn-glycero-3-phosphocholine (m/z 694; SAzPC), 1-stearoyl-2-glutaroyl-snglycero-3- phosphocholine (m/z 638; SGPC), and 1-stearoyl-2-( 5-oxovaleroyl)-sn-glycero-3-phosphocholine (m/z 622; SOVPC). These observations demonstrate that novel 1-acyl-PC which had previously been found to stimulate interaction of monocytes with endothelial cells also induce platelet activation, a central step in acute thrombogenic and atherogenic processes. Copyright (C) 2005 S. Karger AG, Basel

The Genetics Journey: A Case Report of a Genetic Diagnosis Made 30 Years Later

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re‐evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family’s clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that “the patient” can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient’s daughter’s pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient’s husband’s internet search of his wife’s clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re‐evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147210/1/jgc40894.pd

Exploiting unexpected situations in the mathematics classroom

The professional development of mathematics teachers needs to support teachers in orchestrating the mathematics classroom in ways that enable them to respond flexibly and productively to the unexpected. When a situation arises in the classroom which is not connected in an obvious way to the mathematical learning intentions of the lesson, it can be challenging for the teacher to improvise so as to craft this situation into an opportunity for doing and learning mathematics. In this study, as teacher-researcher I maintained a record of unexpected situations as they arose in my own secondary mathematics classroom. Details are given of four unexpected situations which I found ways to exploit mathematically, and these are analysed to highlight factors which may enhance a mathematics teacher’s preparedness for dealing with the unexpected. The results of this study indicate that deviating from the intended lesson to exploit an unexpected situation in which students have shown some interest can lead them into enjoyable and worthwhile mathematical engagement

A Role for VEGFR2 Activation in Endothelial Responses Caused by Barrier Disruptive OxPAPC Concentrations

Introduction: Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2) is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation

A hierarchical Bayesian model for understanding the spatiotemporal dynamics of the intestinal epithelium

Our work addresses two key challenges, one biological and one methodological. First, we aim to understand how proliferation and cell migration rates in the intestinal epithelium are related under healthy, damaged (Ara-C treated) and recovering conditions, and how these relations can be used to identify mechanisms of repair and regeneration. We analyse new data, presented in more detail in a companion paper, in which BrdU/IdU cell-labelling experiments were performed under these respective conditions. Second, in considering how to more rigorously process these data and interpret them using mathematical models, we use a probabilistic, hierarchical approach. This provides a best-practice approach for systematically modelling and understanding the uncertainties that can otherwise undermine the generation of reliable conclusions-uncertainties in experimental measurement and treatment, difficult-to-compare mathematical models of underlying mechanisms, and unknown or unobserved parameters. Both spatially discrete and continuous mechanistic models are considered and related via hierarchical conditional probability assumptions. We perform model checks on both in-sample and out-of-sample datasets and use them to show how to test possible model improvements and assess the robustness of our conclusions. We conclude, for the present set of experiments, that a primarily proliferation-driven model suffices to predict labelled cell dynamics over most time-scales

All-sky search for gravitational-wave bursts in the second joint LIGO-Virgo run

We present results from a search for gravitational-wave bursts in the data collected by the LIGO and Virgo detectors between July 7, 2009 and October 20, 2010: data are analyzed when at least two of the three LIGO-Virgo detectors are in coincident operation, with a total observation time of 207 days. The analysis searches for transients of duration < 1 s over the frequency band 64-5000 Hz, without other assumptions on the signal waveform, polarization, direction or occurrence time. All identified events are consistent with the expected accidental background. We set frequentist upper limits on the rate of gravitational-wave bursts by combining this search with the previous LIGO-Virgo search on the data collected between November 2005 and October 2007. The upper limit on the rate of strong gravitational-wave bursts at the Earth is 1.3 events per year at 90% confidence. We also present upper limits on source rate density per year and Mpc^3 for sample populations of standard-candle sources. As in the previous joint run, typical sensitivities of the search in terms of the root-sum-squared strain amplitude for these waveforms lie in the range 5 10^-22 Hz^-1/2 to 1 10^-20 Hz^-1/2. The combination of the two joint runs entails the most sensitive all-sky search for generic gravitational-wave bursts and synthesizes the results achieved by the initial generation of interferometric detectors.Comment: 15 pages, 7 figures: data for plots and archived public version at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=70814&version=19, see also the public announcement at http://www.ligo.org/science/Publication-S6BurstAllSky

Risk of Venous Thromboembolism: The Prothrombin-G20210A Mutation and Combined Oral Contraceptives

The risk of venous thromboembolism in oral contraceptive pill users becomes dramatically increased in patients with inherited thrombophilias. The often undiscovered prothrombotic genetic conditions pose a potentially deadly threat to its generally young demographic. When thrombosis is discovered in oral contraceptive pill users with a strong family history of related events, it becomes essential to screen for prothrombotic genetic conditions and further mitigate any associated modifiable risk factors. Here we present a case of pulmonary embolism requiring cardiopulmonary resuscitation in 30-year-old female found to have a Prothrombin G20210A on oral contraceptive pills. The emergent management of the critical case, as well as the subsequent evaluation for prothrombotic conditions and the role of potential screening is discussed

Modular Knee Arthrodesis as Definitive Treatment for Periprosthetic Infection, Bone Loss, and Failure of the Extensor Mechanism After Total Knee Arthroplasty

Background: Periprosthetic joint infection (PJI) after total knee arthroplasty (TKA) can result in bone and soft-tissue loss, leg length discrepancies, and dysfunctional extensor mechanisms. While above-knee amputation (AKA) is an established salvage treatment, modular knee arthrodesis (MKA) is a viable option that provides rigid stability and maintains leg length even in patients with severe bone and soft-tissue loss. We sought to report the outcomes of patients with an MKA as the definitive treatment. Methods: We retrospectively reviewed 8 patients implanted with an MKA at 2 institutions between 2016 and 2022. The mean age was 69.63 years, and 50.0% of patients were women. All patients were indicated for conversion to an MKA as the definitive treatment in the setting of treated chronic PJI after TKA, severe bone loss, and failure of the extensor mechanism not amenable to repair. Medical records and radiographs were reviewed. Results: No patients required incision and drainage or exchange of their MKA for PJI at mean 2-year follow-up. One patient required 2 revisions for mechanical failure of his implant at 5.0 and 6.4 years postoperatively. Conclusions: MKA is a viable permanent alternative to AKA for patients with treated chronic PJI and dysfunctional extensor mechanism after TKA. The procedure restores leg lengths in the setting of severe bone and soft-tissue loss, therefore allowing patients to ambulate independently. Still, surgeons should be aware of the potential for mechanical failure requiring revision

Mortality After Complex Displaced Proximal Humerus Fractures in Elderly Patients: Conservative Versus Operative Treatment With Reverse Total Shoulder Arthroplasty

Introduction: Proximal humerus fractures (PHFs) are a common fragility fracture and have been shown to increase mortality in elderly patients. In the last decade, reverse total shoulder arthroplasty (RTSA) was introduced as a reliable operative treatment option for this indication. In other fragility fractures, most notably hip fractures, urgent surgical treatment can reduce mortality. The purpose of this study is to evaluate whether treatment with RTSA can reduce 1-year mortality in elderly patients with complex displaced PHFs. Materials and Methods: A retrospective study was performed to compare 1-year mortality between 2 groups of elderly patients (>75 years old) who presented to a level 1 trauma center emergency department with complex displaced PHFs. The conservative treatment group (n = 83; mean age, 83.7 years) presented from 2008 to 2010 when RTSA was not yet available, and treatment was nonoperative. The surgical treatment group (n = 62; mean age, 82.2 years) presented from 2012 to 2015 and underwent RTSA. Results: One-year mortality was 8.1% (male 7.1%; female 8.3%) in the surgical treatment group and 10.8% (male 18.8%; female 9.0%) in the conservative treatment group. The reduction in mortality in the surgical treatment group was not significant (entire cohort P = .56; males P = .35; females P = .59). Discussion: Recent studies failed to show better functional results after surgical treatment with RTSA when compared to conservative treatment. This study suggests that a benefit of surgical treatment with RTSA that was not examined until now might exist—a reduction in the increased mortality risk associated with PHFs. Conclusions: There was no significant difference in 1-year mortality between the groups, although there was a trend showing lower mortality with RTSA, mostly in men. Further studies with larger populations and longer follow-up times are needed to determine whether this trend is of clinical significance