BACKGROUND:We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying ...mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein–coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein–coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
METHODS:Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein–coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg · min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV).
RESULTS:G-protein–coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product2,186 ± 1,783 n = 7 vs. 11,607 ± 4,347 n = 8; left ventricular developed pressure22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = −443 ± 262 vs. −1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR302 ± 17 vs. 312 ± 38; ejection fraction69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%).
CONCLUSIONS:G-protein–coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including ...15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell–mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE–fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE–fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE–induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell–dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.
Objectives. To evaluate the self-perceived knowledge and confidence of inpatient and outpatient pharmacists in applying pharmacogenomics information to clinical practice.
Methods. A 19-question ...multiple-choice, electronic needs-assessment survey instrument was distributed to 480 inpatient and outpatient pharmacists in a large, academic, multi-campus healthcare system.
Results. The survey response rate was 64% (303). Most respondents (85%) agreed that pharmacists should be required to be knowledgeable about pharmacogenomics, and 65% agreed that pharmacists should be capable of providing information on the appropriate use of pharmacogenomics testing. Sixty-three percent felt they could not accurately apply the results of pharmacogenomics tests to drug-therapy selection, dosing, or monitoring.
Conclusion. Pharmacists believe pharmacogenomics knowledge is important to the profession, but they lack the knowledge and self-confidence to act on the results of pharmacogenomics testing and may benefit from pharmacogenomics education.
New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement ...was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype–phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
•NIH convened work groups and a conference to address research and treatment for PKU.•Sapropterin may allow liberalization of a Phe-restricted diet for those who respond.•New therapies are needed to optimize quality of life across the lifespan.•Research is needed on strategies to improve access to and compliance with treatment.•Management guidelines must be based on rigorous study design and outcome measures.
Teaching Engineering Practices Cunningham, Christine M.; Carlsen, William S.
Journal of science teacher education,
03/2014, Volume:
25, Issue:
2
Journal Article
Peer reviewed
Engineering is featured prominently in the Next Generation Science Standards (NGSS) and related reform documents, but how its nature and methods are described is problematic. This paper is a ...systematic review and critique of that representation, and proposes that the disciplinary core ideas of engineering (as described in the NGSS) can be disregarded safely if the practices of engineering are better articulated and modeled through student engagement in engineering projects. A clearer distinction between science and engineering practices is outlined, and prior research is described that suggests that precollege engineering design can strengthen children's understandings about scientific concepts. However, a piecemeal approach to teaching engineering practices is unlikely to result in students understanding engineering as a discipline. The implications for science teacher education are supplemented with lessons learned from a number of engineering education professional development projects.
Pulmonary hypertension secondary to pulmonary fibrosis (PF‐PH) is one of the most common causes of PH, and there is no approved therapy. The molecular signature of PF‐PH and underlying mechanism of ...why pulmonary hypertension (PH) develops in PF patients remains understudied and poorly understood. We observed significantly increased vascular wall thickness in both fibrotic and non‐fibrotic areas of PF‐PH patient lungs compared to PF patients. The increased vascular wall thickness in PF‐PH patients is concomitant with a significantly increased expression of the transcription factor Slug within the macrophages and its target prolactin‐induced protein (PIP), an extracellular matrix protein that induces pulmonary arterial smooth muscle cell proliferation. We developed a novel translational rat model of combined PF‐PH that is reproducible and shares similar histological features (fibrosis, pulmonary vascular remodeling) and molecular features (Slug and PIP upregulation) with human PF‐PH. We found Slug inhibition decreases PH severity in our animal model of PF‐PH. Our study highlights the role of Slug/PIP axis in PF‐PH.
Synopsis
Pulmonary hypertension (PH) is a major complication of pulmonary fibrosis (PF), yet it is poorly understood. This study highlights the Slug/PIP axis as a key driver of vascular remodeling in pulmonary hypertension secondary to pulmonary fibrosis (PF‐PH) patients.
Vascular walls were thickened in both fibrotic and non‐fibrotic areas in the lungs of PF‐PH patients, but wall thickening was mainly restricted to fibrotic areas of PF patients.
In PF‐PH patients, the transcriptional factor Slug was up‐regulated in macrophages and led to increased vascular wall thickness through its target PIP.
Inhibition of Slug ameliorated PH in an animal model that recapitulates human histological and molecular characteristics of PF‐PH.
Pulmonary hypertension (PH) is a major complication of pulmonary fibrosis (PF), yet it is poorly understood. This study highlights the Slug/PIP axis as a key driver of vascular remodeling in pulmonary hypertension secondary to pulmonary fibrosis (PF‐PH) patients.
The Framework for K‐12 Science Education and the Next Generation Science Standards propose that students learn core ideas and practices related to engineering as well as science. To do so, students ...will need high‐quality curricular materials designed to meet these goals. We report an efficacy study of an elementary engineering curriculum, Engineering is Elementary (EiE) that includes a set of hypothesized critical components designed to encourage student engagement in practices, connect engineering and science learning, and reach diverse students. To measure the impact of the curriculum, we conducted a cluster randomized controlled trial in 604 classrooms in 152 schools in three states. Schools were randomly assigned to either the treatment curriculum or to a comparison curriculum that addressed the same learning goals but did not include several critical components. Results show that students who used the treatment curriculum (EiE) regardless of demographic characteristics outperformed students in the comparison group on outcome measures of both engineering and science content learning. The results show that curriculum design affects student‐learning outcomes.
Technology is important to all aspects of our lives, so helping students develop an accurate understanding of technology should be an educational goal at the K-12 level. Assessments are important ...tools in reaching this goal. We developed an instrument to measure the technology conceptions of children ages 8-11, the 'What is Technology' (WT) instrument. We gathered evidence for the validity of using the WT instrument to measure children's conceptions of technology, including changes due to an intervention, and we describe those changes. We used exploratory factor analysis (EFA) to establish scales, and confirmatory factor analysis (CFA) with new samples of subjects to confirm our hypothesised model of children's conceptions. For further evidence, we analyzed and coded the written responses children gave to open-ended questions asking them to explain their understanding of technology, then calculated correlations between these codes and the CFA-confirmed scale measures. We found that children tend to think of technology as artifacts that are powered by electrical energy; however, after instruction most children's conceptions become more consistent with definitions given in educational standards. The instrument is shown to be valid and reliable for its intended use, to assess preadolescent children's conceptions of technology, and evaluate the impact of an intervention.
•As a new discipline in most elementary classrooms, engineering provides a unique opportunity to examine how disciplinary affinity can be developed through purposeful activity and metadiscourse about ...participation.•Identity work among students and teachers occurred at two levels: at the epistemological level—development of knowledge of engineering, and at the ontological level—recognition of being a member.•Multiple texts in the instructional units played roles in providing opportunities for identity work: The storybooks, posters, student data sheets, and notebooks, provided ways of building affiliation, framing actions, offering reference for discussions, and creating intertextual links to verbal discourse.•Classroom chronotopes were relevant to the ways that identity and participation were constructed in this classroom.•A key dimension of identity work for engineering concerns the collective sense of being.
This article examines the emergence of identity work in engineering among elementary school students. Engineering has only recently been added to state and national standards in the United States. The purpose of the study was to examine ways that engaging in engineering practices transforms students’ views of engineering and themselves. Video of two teachers, each teaching one engineering unit, was analyzed. Across the lessons of these engineering units (designing a parachute and designing a mortar mixture for a stone wall), a sociolinguistic perspective was taken to show how engagement in engineering provides opportunities for identity work among the students and teachers. Analyses of the classroom discourse identified the epistemological and ontological constructions of identity, uses of intertextuality and chronotopes to build identity over time, and ways that collective understandings supported student take-up of an engineering identity. Because engineering is a new discipline in most classrooms, it provides a unique opportunity to examine how disciplinary affinity can be developed through purposeful activity and metadiscourse about participation.
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