Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

Endothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner.     

Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.     

A nursing partnership for better outcomes in Aboriginal mental health, including substance use

This article draws on our participatory action research findings and interventions, such as advocacy and professional education, as applied during and after a large project focusing on Aboriginal mental health and safe medication management. The project was conducted by our research team and partners, community-controlled Aboriginal health services, and community leaders. The paper provides a discussion of major Aboriginal mental health issues gleaned from the literature, along with a discussion, and a conceptual model for conducting ethical Aboriginal health research, that has both evolved and guided us. It is hoped that this paper will assist nurses and other professional colleagues to work more effectively with Aboriginal peoples.     

Atlanto-occipital dislocation: case report and discussion

Atlanto-occipital dislocation (AOD) is a devastating condition that frequently results in prehospital cardiorespiratory arrest and accounts for 15% of fatal spinal trauma. Atlanto-occipital dislocation occurs 5 times more commonly in children than adults, and is believed to be caused by hyperextension. Because of improvements in prehospital resuscitation, more victims with AOD now survive to reach the emergency department. Neurologic injury is usually severe secondary to ligamentous disruption that allows the cranium to move with respect to the cervical spine, and associated facial and head injuries are common. There are, however, reports of survivors without neurologic deficits. We present the case of a 46-year-old woman who suffered an AOD after a motor vehicle crash and we discuss the diagnosis of this condition. The signs of AOD are often subtle, and the possibility of this diagnosis must be kept in mind in all patients with a neck injury, even in the absence of neurologic signs. A systematic approach to assessing the cranio-cervical relationship on the lateral cervical x-ray and the appropriate use of CT scanning is essential to identifying AOD. Through this case report we hope to familiarize clinicians with mechanisms of injury and appropriate imaging interpretation that will assist in the diagnosis of AOD.     

Non-resuscitative first aid training and assessment for junior secondary school students: A pre-post study

School-based first aid interventions can contribute to the number of adults trained in first aid in the community over time but few studies have examined the effectiveness of teaching non-resuscitative first aid on knowledge, attitudes and skills. Currently, there is no consensus on the optimal content and duration of first aid training for junior secondary students. The aim of this study was to evaluated the effectiveness of a 2.5 hour introductory non-resuscitative first aid course for junior secondary students.This prospective, single-centre, pre-post study included 140 students (11–13 years old). Students completed a questionnaire on first aid knowledge, attitude towards first aid and self-confidence to perform first aid before and after a training session. Six emergency medicine physicians taught practical first aid skills training. A game-based formative assessment was undertaken where the instructors assessed small teams of students’ role-playing injured classmates and first aid responders (and vice-versa) treating abrasions, ankle sprain, choking and a scald injury.Few students had prior first aid training (14%). After adjusting for student''s age, sex, prior first aid training and format delivery, the course was associated with increased mean knowledge score (pre-training 53%, post-training 88%; mean difference [MD] 35%, 95% CI: 32% to 38%), positive attitudes and more confidence in performing first aid after training (all P < .001). All teams showed a good level of competency in treating simulated injuries with first aid kits.This brief non-resuscitative first aid course was associated with noticeable and valuable changes in knowledge score and self-confidence level in performing first aid. The game-based formative assessment facilitated a positive learning environment for skill competency evaluation.     

First Series of Exeter Small Stem Primary Total Hip Arthroplasty Minimum 5 Years of Follow-Up

We carried out a prospective study of 47 Exeter (Stryker Inc, Warsaw, Ind) small stem total hip arthroplasty in 42 patients with an average age of 58 years and a mean follow-up of 8.5 years. The Oxford hip score improved from a preoperative mean of 47 to 17 at last follow-up. More than 87% patients had excellent or good Harris hip scores, and 90% were able to walk with little or no pain. Stem subsidence within the cement mantle was observed in 26% of cases, and none showed evidence of aseptic loosening or implant failure. Two stems were removed due to infection. The survival rate of this implant was 95.7% at 10 years. This first series of Exeter small stem showed excellent medium-term results, comparable to its larger counterparts.     

Essential thrombocythemia with deleted 5q - a genetic and morphologic hybrid?

A 66-year-old man who presented with progressive and marked thrombocytosis but normal hemoglobin was diagnosed to have essential thrombocythemia upon the demonstration of JAK2 V617F mutation. Bone marrow examination, however, showed the presence of monolobulated megakaryocytes and conventional cytogenetic analysis revealed an isolated interstitial deletion of the long arm of chromosome 5, characteristic of 5q− syndrome. A literature review indicated that isolated deletion of 5q is uncommon in essential thrombocythemia but that, when this isolated deletion is present, the disease often shows mixed features of both essential thrombocythemia and 5q− syndrome.     

Copy Number Variation in Tumor Cells and Extracellular DNA in Patients with Lung Adenocarcinoma

Bulletin of Experimental Biology and Medicine - Copy number variation of some gene loci in lung tumor cells extracted by laser capture microdissection and in cell-free DNA in the plasma of patients...