Stem cell transplantation may repair the injured heart, but tissue regeneration is limited by death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, anoikis and inflammation. Interventions known to enhance transplanted cell survival include heat shock, over-expressing anti-apoptotic proteins, free radical scavengers, anti-inflammatory therapy and co-delivery of extracellular matrix molecules. Combinatorial use of such interventions markedly enhances graft cell survival, but death still remains a significant problem. We review these challenges to cardiac cell transplantation and present an approach to systematically address them.Most anti-death studies use histology to assess engraftment, which is time-and labor-intensive. To increase throughput, we developed two biochemical approaches to follow graft viability in the mouse heart. The first relies on LacZ enyzmatic activity to track genetically modified cells, and the second quantifies human genomic DNA content using repetitive Alu sequences. Both show linear relationships between input cell number and biochemical signal, but require correction for the time lag between cell death and loss of signal. Once optimized, they permit detection of as few as 1 graft cell in 40,000 host cells. Pro-survival effects measured biochemically at three days predict long-term histological engraftment benefits. These methods permitted identification of carbamylated erythropoietin (CEPO) as a pro-survival factor for human embryonic stem cell-derived cardiomyocyte grafts. CEPO's effects were additive to heat shock, implying independent survival pathways. This system should permit combinatorial approaches to enhance graft viability in a fraction of the time required for conventional histology.
SummaryThe MRL/MpJ mouse has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle. We studied the temporal evolution of infarcts and cryoinjuries in MRL/MpJ and C57BL/6 control mice. Both types of injury in MRL/MpJ mice heal similarly to controls by typical scar formation rather than muscle regeneration, and no differences in cell proliferation, angiogenesis or scar contraction between the two mouse strains were observed.Background-Myocardial infarcts in mammals heal by scar formation rather than formation of new muscle tissue. The MRL/MpJ mouse, however, has been reported to exhibit minimal scarring and subsequent cardiac regeneration after cryoinjury of the right ventricle. Other groups have reported that permanent and temporary ligation of the coronary artery resulted in scarring without regeneration.Methods-To clarify these contradictory results, we studied the temporal evolution of infarcts in MRL/MpJ and C57BL/6 control mice from 1 to 90 days post-injury, and the effects of intrathoracic cryoinjury to 28 days.Results-After infarction, the conversion from necrotic myocardium to granulation tissue and then to scar proceeded identically in the two groups. Infarct DNA synthesis, measured by incorporation of a BrdU pulse, peaked at 4 days in both strains and did not differ between strains at any time point. Endothelial cell and total vascular density in the both the infarcted and non-infarcted cardiac tissue did not differ between groups at any time. Histological analysis of directly cryoinjured right and left ventricular myocardium showed indistinguishable wound healing in both strains, and final scar size was identical in each group.Conclusions-These studies demonstrate that both myocardial infarcts and cryoinjuries in MRL/ MpJ mice heal by typical scar formation rather than muscle regeneration, in a manner very similar to C57BL/6 controls. We conclude that the MRL mouse is not a model for myocardial regeneration.
Intramyocardial injection of therapeutic agents may enhance heart repair after infarction. Incomplete retention of intramyocardial injections has been reported, but modes of loss are undefined. We determined the fate of neutron-activated microspheres injected into acutely ischemic rat myocardium using saline, Pluronic F127, or Matrigel as vehicle. Twenty minutes after injection in saline, 63% +/- 12% of 10-mum microspheres was retained in the heart. Similar retention was observed after 6 days. Injection site leakage accounted for 14% +/- 5% of the microspheres, whereas exit via coronary veins resulted in 11.2% +/- 9.5% collecting in the lungs. Microspheres distribution to other organs was minimal. Retention of 40-mum microspheres was similar to that observed with the 10-mum microspheres. Pluronic F127 and Matrigel reduced immediate leakage to 4% +/- 1% and 2% +/- 1%, respectively. Surprisingly, microsphere retention in the heart was not improved at 20 min using either gelling vehicle, suggesting that leakage occurs over a prolonged period. Thus, most injected particles are retained in the ischemic rat heart following direct injection, but significant fractions are lost from the injection site and through coronary veins. Gelling agents reduced short-term leakage, but failed to enhance longer-term retention. Hydrogels with stiffer mechanical properties might enhance retention and reduce variability.
Objectives: This qualitative study aimed to characterize the barriers to informed discussions between patients and emergency physicians (EPs) about radiation risk from computed tomography (CT) and to identify future interventions to improve patient understanding of CT radiation risk.Methods: This study used a focus group approach to collect concepts about radiation risk exposure from a national sample of EPs and a local sample of emergency department (ED) patients. A directed content analysis used an a priori medical ethics framework to explore themes from the focus groups while a subsequent normative ethics analysis compared these results with existing perceptions about discussing CT radiation risk.Results: Focus groups (three each for a total of 19 EPs and 27 patients) identified concepts consistent with core medical ethics principles: patients emphasized autonomy and nonmaleficence more than physicians, while physicians emphasized beneficence. Subjects' knowledge of radiation dose and risk were equivalent to previously published reports. When asked about whether they should talk about radiation with patients, 74% of EPs reported that radiation exposure should be discussed, but the study EPs self-reported doing so with only an average of 24% of patients. Patients reported wanting to hear about radiation from their physicians the next time they need CT scans and thought that a written handout would work better than any other method. When presented with options for how to discuss risk with patients, EPs reported needing easy access to risk information and preferred discussion over other communications approaches, but had mixed support of distributing patient handouts. Conclusions:The normative view that radiation from diagnostic CT should be discussed in the ED is shared by patients and physicians, but is challenged by the lack of a structured method to communicate CT radiation risk to ED patients. Our analysis identifies promising interest among physicians and patients to use information guides and electronic order prompts as potential informational tools to overcome this barrier.ACADEMIC EMERGENCY MEDICINE 2014; 21:122-129
Background Fibrosis around cardiac cell injections represents an obstacle to graft integration in cell-based cardiac repair. Thrombospondin-2 (TSP-2) is a pro-fibrotic, anti-angiogenic matricellular protein and an attractive target for therapeutic knockdown to improve cardiac graft integration and survival. Methods We used a TSP-2 knockout (KO) mouse in conjunction with a fetal murine cardiomyocyte grafting model to evaluate the effects of a lack of TSP-2 on fibrosis, vascular density and graft size in the heart. Results Two weeks after grafting in the uninjured heart, fibrosis area was reduced 4.5-fold in TSP-2 KO mice and the thickness of the peri-graft scar capsule was reduced 7-fold compared to wild-type (WT). Endothelial cell density in the peri-graft region increased 2.5-fold in the absence of TSP-2, and cardiomyocyte graft size increased by 46% in TSP-2 KO hearts. Conclusions TSP-2 is a key regulator of fibrosis and angiogenesis following cell grafting in the heart, and its absence promotes better graft integration, vascularization and survival.
Rare earth metal magnets (Buckyballs and similar products) remain an important public health risk for children. We report the presentation, course, and treatment of a boy who inserted a string of 30 magnets through his urethra into his bladder and review the diagnostic as well as the therapeutic options for foreign bodies inserted into the pediatric urogenital tract.
Researchers have attempted to optimize imaging utilization by describing which clinical variables are more predictive of acute disease and, conversely, what combination of variables can obviate the need for imaging. These results are then used to develop evidence-based clinical pathways, clinical decision instruments, and clinical practice guidelines. Despite the validation of these results in subsequent studies, with some demonstrating improved outcomes, their actual use is often limited. This article outlines a research agenda to promote the dissemination and implementation (also known as knowledge translation) of evidence-based interventions for emergency department (ED) imaging, i.e., clinical pathways, clinical decision instruments, and clinical practice guidelines. We convened a multidisciplinary group of stakeholders and held online and telephone discussions over a 6-month period culminating in an in-person meeting at the 2015 Academic Emergency Medicine consensus conference. We identified the following four overarching research questions: 1) what determinants (barriers and facilitators) influence emergency physicians' use of evidence-based interventions when ordering imaging in the ED; 2) what implementation strategies at the institutional level can improve the use of evidence-based interventions for ED imaging; 3) what interventions at the health care policy level can facilitate the adoption
CONTEXT Cardiac glycosides of plant origin are implicated in toxic ingestions that may result in hospitalization and are potentially lethal. The utility of commonly available digoxin serum assays for detecting foxglove and oleander ingestion has been demonstrated, but no studies have evaluated the structurally similar convallatoxin found in Convallaria majalis (lily of the valley) for rapid laboratory screening, nor has digoxin immune Fab been tested as an antidote for this ingestion. OBJECTIVE We aimed to (1) evaluate multiple digoxin assays for cross-reactivity to convallatoxin, (2) identify whether convallatoxin could be detected in vivo at clinically significant doses and (3) determine whether digoxin immune Fab could be an effective antidote to convallatoxin. MATERIALS AND METHODS Cross-reactivities of purified convallatoxin and oleandrin with five common digoxin immunoassays were determined. Serum from mice challenged with convallatoxin was tested for apparent digoxin levels. Binding of convallatoxin to digoxin immune Fab was determined in vitro. RESULTS Both convallatoxin and oleandrin were detectable by a panel of commonly used digoxin immunoassays, but cross-reactivity was variable between individual assays. We observed measurable apparent digoxin levels in serum of convallatoxin intoxicated mice at sublethal doses. Convallatoxin demonstrated no binding by digoxin immune Fab. CONCLUSION Multiple digoxin immunoassays detect botanical cardiac glycosides including convallatoxin and thus may be useful for rapid determination of severe exposures, but neutralization of convallatoxin by digoxin immune Fab is unlikely to provide therapeutic benefit.
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