Prenatal arsenite exposure alters maternal cardiac remodeling during late pregnancy.

Exposure to inorganic arsenic through drinking water is widespread and has been linked to many chronic diseases, including cardiovascular disease. Arsenic exposure has been shown to alter hypertrophic signaling in the adult heart, as well as in utero offspring development. However, the effect of arsenic on maternal cardiac remodeling during pregnancy has not been studied. As such, there is a need to understand how environmental exposure contributes to adverse pregnancy-related cardiovascular events. This study seeks to understand the impact of trivalent inorganic arsenic exposure during gestation on maternal cardiac remodeling in late pregnancy, as well as offspring outcomes. C57BL/6 J mice were exposed to 0 (control), 100 or 1000 µg/L sodium arsenite (NaAsO2) beginning at embryonic day (E) 2.5 and continuing through E17.5. Maternal heart function and size were assessed via transthoracic echocardiography, gravimetric measurement, and histology. Transcript levels of hypertrophic markers were probed via qRT-PCR and confirmed by western blot. Offspring outcomes were assessed through echocardiography and gravimetric measurement. We found that maternal heart size was smaller and transcript levels of Esr1 (estrogen receptor alpha), Pgrmc1 (progesterone receptor membrane component 1) and Pgrmc2 (progesterone receptor membrane component 2) reduced during late pregnancy with exposure to 1000 µg/L iAs vs. non-exposed pregnant controls. Both 100 and 1000 µg/L iAs also reduced transcription of Nppa (atrial natriuretic peptide). Akt protein expression was also significantly reduced after 1000 µg/L iAs exposure in the maternal heart with no change in activating phosphorylation. This significant abrogation of maternal cardiac hypertrophy suggests that arsenic exposure during pregnancy can potentially contribute to cardiovascular disease. Taken together, our findings further underscore the importance of reducing arsenic exposure during pregnancy and indicate that more research is needed to assess the impact of arsenic and other environmental exposures on the maternal heart and adverse pregnancy events.

Prenatal Arsenite Exposure Alters Maternal Cardiac Remodeling During Late Pregnancy.

Exposure to inorganic arsenic through drinking water is widespread and has been linked to many chronic diseases, including cardiovascular disease. Arsenic exposure has been shown to alter hypertrophic signaling in the adult heart, as well as in-utero offspring development. However, the effect of arsenic on maternal cardiac remodeling during pregnancy has not been studied. As such, there is a need to understand how environmental exposure contributes to adverse pregnancy-related cardiovascular events. This study seeks to understand the impact of trivalent inorganic arsenic exposure during gestation on maternal cardiac remodeling in late pregnancy, as well as offspring outcomes. C57BL/6J mice were exposed to 0 (control), 100 or 1000 µg/L sodium arsenite (NaAsO 2 ) beginning at embryonic day (E) 2.5 and continuing through E17.5. Maternal heart function and size were assessed via transthoracic echocardiography, gravimetric measurement, and histology. Transcript levels of hypertrophic markers were probed via qRT-PCR and confirmed by western blot. Offspring outcomes were assessed through echocardiography and gravimetric measurement. We found that exposure to 1000 µg/L iAs abrogated normal physiologic growth of the maternal heart during late pregnancy and reduced transcript levels of estrogen receptor alpha (ERα), progesterone receptor membrane component 1 (Pgrmc1) and progesterone receptor membrane component 2 (Pgrmc2). Both 100 and 1000 µg/L iAs also reduced transcription of protein kinase B (Akt) and atrial natriuretic peptide (ANP). Akt protein expression was also significantly reduced after 1000 µg/L iAs exposure in the maternal heart with no change in activating phosphorylation. This significant abrogation of maternal cardiac hypertrophy suggests that arsenic exposure during pregnancy can potentially contribute to cardiovascular disease. Taken together, our findings further underscore the importance of reducing arsenic exposure during pregnancy and indicate that more research is needed to assess the impact of arsenic and other environmental exposures on the maternal heart and adverse pregnancy events.

Educator's blueprint: A guide for clinician-educators to achieve promotion in emergency medicine.

Promotion and tenure (P&T) can be a complex process, which many junior faculty in academic emergency medicine may struggle navigating. This paper presents perspectives and key considerations to guide faculty through the promotions process. We explore tips through three key phases: plotting the course for a successful academic career, collecting data to support academic advancement, and packaging materials into a compelling application portfolio. This resource can inform faculty and faculty developers when planning for P&T.

Cadmium exposure induces a sex-dependent decline in left ventricular cardiac function.

AIMS: Cadmium exposure is a worldwide problem that has been linked to the development of cardiovascular disease. This study aimed to elucidate mechanistic details of chronic cadmium exposure on the structure and function of the heart. MAIN METHODS: Male and female mice were exposed to cadmium chloride (CdCl2) via drinking water for eight weeks. Serial echocardiography and blood pressure measurements were performed. Markers of hypertrophy and fibrosis were assessed, along with molecular targets of Ca2+-handling. KEY FINDINGS: Males exhibited a significant reduction in left ventricular ejection fraction and fractional shortening with CdCl2 exposure, along with increased ventricular volume at end-systole, and decreased interventricular septal thickness at end-systole. Interestingly, no changes were detected in females. Experiments in isolated cardiomyocytes revealed that CdCl2-induced contractile dysfunction was also present at the cellular level, showing decreased Ca2+ transient and sarcomere shortening amplitude with CdCl2 exposure. Further mechanistic investigation uncovered a decrease in sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) protein expression and phosphorylated phospholamban levels in male hearts with CdCl2 exposure. SIGNIFICANCE: The findings of our novel study provide important insight into how cadmium exposure may act as a sex-specific driver of cardiovascular disease, and further underscore the importance of reducing human exposure to cadmium.

Physiological and metabolic characteristics of novel double-mutant female mice with targeted disruption of both growth hormone-releasing hormone and growth hormone receptor.

Mice with disruptions of growth hormone-releasing hormone (GHRH) or growth hormone receptor (GHR) exhibit similar phenotypes of prolonged lifespan and delayed age-related diseases. However, these two models respond differently to calorie restriction indicating that they might carry different and/or independent mechanisms for improved longevity and healthspan. In order to elucidate these mechanisms, we generated GHRH and GHR double-knockout mice (D-KO). In the present study, we focused specifically on the characteristics of female D-KO mice. The D-KO mice have reduced body weight and enhanced insulin sensitivity compared to wild-type (WT) controls. Growth retardation in D-KO mice is accompanied by decreased GH expression in pituitary, decreased circulating IGF-1, increased high-molecular-weight (HMW) adiponectin, and leptin hormones compared to WT controls. Generalized linear model-based regression analysis, which controls for body weight differences between D-KO and WT groups, shows that D-KO mice have decreased lean mass, bone mineral density, and bone mineral content, but increased adiposity. Indirect calorimetry markers including oxygen consumption, carbon dioxide production, and energy expenditure were significantly lower in D-KO mice relative to the controls. In comparison with WT mice, the D-KO mice displayed reduced respiratory exchange ratio (RER) values only during the light cycle, suggesting a circadian-related metabolic shift toward fat utilization. Interestingly, to date survival data suggest extended lifespan in D-KO female mice.

The Coexistence of Carpal Tunnel Syndrome in Workers With Trigger Digit.

Background: The objective of this study was to investigate the prevalence of carpal tunnel syndrome (CTS) in workers with trigger digit. There are few cross-sectional studies that assess this relationship. Methods: A baseline examination of 1216 workers from 17 diverse manufacturing facilities was conducted. Worker demographics, medical history, and symptoms of trigger digit were assessed. Age, sex, and body mass index were obtained. Biomechanical factors were individually measured using the Strain Index (SI). Prevalence was assessed with univariate and multivariate logistic regression. Results: Unadjusted prevalence of trigger digit was 12.0%, and among those workers, there was an unadjusted CTS prevalence of 26.7%. The adjusted multivariate model found an odds ratio (OR) of CTS of 1.56 (95% confidence interval [CI], 1.03-2.36) among the workers with trigger digit. The ORs of CTS for SI (OR = 1.53 [95% CI, 1.04-2.23]), age (OR = 1.03 [95% CI, 1.01-1.04]), and current smoking (OR = 1.76 [95% CI, 1.12-2.75]) were also significant. Sex and diabetes were not statistically significant covariates. Conclusion: The prevalence of CTS is higher among workers with trigger digit.

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer.

Breast cancer is the second most commonly diagnosed malignancy among women globally. Past MRI studies have linked a high animal fat diet (HAFD) to increased mammary cancer risk in the SV40Tag mouse model of triple-negative breast cancer. Here, serial MRI examines tumor progression and measures the arterial blood volume feeding mammary glands in low fat diet (LFD) or HAFD fed mice. Virgin female C3(1)SV40Tag mice (n = 8), weaned at 3 weeks old, were assigned to an LFD (n = 4, 3.7 kcal/g, 17.2% kcal from vegetable oil) or an HAFD (n = 4, 5.3 kcal/g, 60% kcal from lard) group. From ages 8 to 12 weeks, weekly fast spin echo MR images and time-of-flight (TOF) MR angiography of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed. Inguinal mammary glands were excised and fixed for ex vivo MRI and histology. Tumor, blood, and mammary gland volumes for each time point were measured from manually traced regions of interest; tumors were classified as invasive by histopathology-blinded observers. Our analysis confirmed a strong correlation between total tumor volume and blood volume in the mammary gland. Tumor growth rates from weeks 8-12 were twice as high in HAFD-fed mice (0.42 ± 0.14/week) as in LFD-fed mice (0.21 ± 0.03/week), p < 0.004. Mammary gland blood volume growth rate was 2.2 times higher in HAFD mice (0.29 ± 0.11/week) compared with LFD mice (0.13 ± 0.06/week), p < 0.02. The mammary gland growth rate of HAFD-fed mice (0.071 ± 0.011/week) was 2.7 times larger than that of LFD-fed mice (0.026 ± 0.009/week), p < 0.01. This is the first non-invasive, in vivo MRI study to demonstrate a strong correlation between an HAFD and increased cancer burden and blood volume in mammary cancer without using contrast agents, strengthening the evidence supporting the adverse effects of an HAFD on mammary cancer. These results support the potential future use of TOF angiography to evaluate vasculature of suspicious lesions.

Insulin sensitivity in long-lived growth hormone-releasing hormone knockout mice.

Our previous studies showed that loss-of-function mutation of growth hormone releasing hormone (GHRH) results in increased longevity and enhanced insulin sensitivity in mice. However, the details of improved insulin action and tissue-specific insulin signaling are largely unknown in this healthy-aging mouse model. We conducted hyperinsulinemic-euglycemic clamp to investigate mechanisms underlying enhanced insulin sensitivity in growth hormone (GH) deficient mice. Further, we assessed in vivo tissue-specific insulin activity via activation of PI3K-AKT and MAPK-ERK1/2 cascades using western blot. Clamp results showed that the glucose infusion rate required for maintaining euglycemia was much higher in GHRH-/- mice compared to WT controls. Insulin-mediated glucose production was largely suppressed, whereas glucose uptake in skeletal muscle and brown adipose tissue were significant enhanced in GHRH-/- mice compared to WT controls. Enhanced capacity of insulin-induced activation of the PI3K-AKT and MAPK-ERK1/2 signaling were observed in a tissue-specific manner in GHRH-/- mice. Enhanced systemic insulin sensitivity in long-lived GHRH-/- mice is associated with differential activation of insulin signaling cascades among various organs. Improved action of insulin in the insulin sensitive tissues is likely to mediate the prolonged longevity and healthy-aging effects of GH deficiency in mice.

Physiological and metabolic features of mice with CRISPR/Cas9-mediated loss-of-function in growth hormone-releasing hormone.

Our previous study demonstrated that the loss of growth hormone releasing hormone (GHRH) results in increased lifespan and improved metabolic homeostasis in the mouse model generated by classical embryonic stem cell-based gene-targeting method. In this study, we targeted the GHRH gene using the CRISPR/Cas9 technology to avoid passenger alleles/mutations and performed in-depth physiological and metabolic characterization. In agreement with our previous observations, male and female GHRH-/- mice have significantly reduced body weight and enhanced insulin sensitivity when compared to wild type littermates. Dual-energy X-ray absorptiometry showed that there were significant decreases in lean mass, bone mineral content and density, and a dramatic increase in fat mass of GHRH-/- mice when compared to wild type littermates. Indirect calorimetry measurements showed dramatic reductions in oxygen consumption, carbon dioxide production and energy expenditure in GHRH-/- mice compared to wild type mice in both light and dark cycles. Respiratory exchange ratio was significantly lower in GHRH-/- mice during the light cycle, but not during the dark cycle, indicating a circadian related metabolic shift towards fat utilization in the growth hormone deficient mice. The novel CRISPR/Cas9 GHRH-/- mice are exhibiting the consistent and unique physiological and metabolic characteristics, which might mediate the longevity effects of growth hormone deficiency in mice.

Pediatric Needle Cricothyrotomy: A Case for Simulation in Prehospital Medicine.

INTRODUCTION: A patient that cannot be oxygenated or ventilated requires immediate and effective assessment, treatment, and transportation. Pediatric needle cricothyrotomy is used infrequently, therefore providers have a tendency to lose proficiency. Simulation training and evaluation are valuable tools to improve provider experience and skill. METHODS: A case was designed involving a 3-year-old male with a peanut allergy that presents with rash, swelling, and severe respiratory distress. The patient's respiratory distress and swelling worsens despite treatment with epinephrine and other allergic reaction medications. The patient then becomes unresponsive and impossible to oxygenate or ventilate. The primary objective of this case is airway management with needle cricothyrotomy in the pediatric population. A secondary objective is appropriate postprocedure management including appropriate ventilation rates and emergency medical transportation methods. RESULTS: This case was initially presented to 45 paramedics. Provider comfort with managing airway emergencies in young children improved from 47% to 89%. Confidence in performing pediatric needle cricothyrotomy improved from 16% to 87%. All providers felt the exercise was valuable and 98% felt the simulation provided appropriate realism. DISCUSSION: This scenario provides an outstanding opportunity for paramedic evaluation and training in pediatric needle cricothyrotomy and significantly improved the comfort level of providers' management of a failed pediatric airway. As we reflected on the use of this module, it was apparent that this was a very beneficial opportunity to spend one-on-one time between participants and their medical director. The training staff also benefited from the repeated emphasis of good assessment and treatment of a complex patient scenario.

Preclinical medical student observations associated with later professionalism concerns.

PURPOSE: Professionalism is a core physician competency and identifying students at risk for poor professional development early in their careers may allow for mentoring. This study identified indicators in the preclinical years associated with later professionalism concerns. METHODS: A retrospective analysis of observable indicators in the preclinical and clinical years was conducted using two classes of students (n = 226). Relationships between five potential indicators of poor professionalism in the preclinical years and observations related to professional concerns in the clinical years were analyzed. RESULTS: Fifty-three medical students were identified with at least one preclinical indicator and one professionalism concern during the clinical years. Two observable preclinical indicators were significantly correlated with unprofessional conduct during the clinical years: Three or more absences from attendance-required sessions (odds ratio 4.47; p=.006) and negative peer assessment (odds ratio 3.35; p=.049). CONCLUSIONS: We identified two significant observable preclinical indicators associated with later professionalism concerns: excessive absences and negative peer assessments. Early recognition of students at risk for future professionalism struggles would provide an opportunity for proactive professional development prior to the clinical years, when students' permanent records may be affected. Peer assessment, coupled with attention to frequent absences, may be a method to provide early recognition.

Platform for induction and maintenance of transgene-free hiPSCs resembling ground state pluripotent stem cells.

Cell banking, disease modeling, and cell therapy applications have placed increasing demands on hiPSC technology. Specifically, the high-throughput derivation of footprint-free hiPSCs and their expansion in systems that allow scaled production remains technically challenging. Here, we describe a platform for the rapid, parallel generation, selection, and expansion of hiPSCs using small molecule pathway inhibitors in stage-specific media compositions. The platform supported efficient and expedited episomal reprogramming using just OCT4/SOX2/SV40LT combination (0.5%-4.0%, between days 12 and 16) in a completely feeder-free environment. The resulting hiPSCs are transgene-free, readily cultured, and expanded as single cells while maintaining a homogeneous and genomically stable pluripotent population. hiPSCs generated or maintained in the media compositions described exhibit properties associated with the ground state of pluripotency. The simplicity and robustness of the system allow for the high-throughput generation and rapid expansion of a uniform hiPSC product that is applicable to industrial and clinical-grade use.

Recurrent spontaneous globe subluxation: a case report and review of manual reduction techniques.

BACKGROUND: Spontaneous globe subluxation is an uncommon problem that develops acutely and can present with significant patient distress from ocular pain and vision loss. OBJECTIVES: To present an unusual case of recurrent spontaneous globe subluxation and describe several methods emergency physicians can use to reduce a subluxation. CASE REPORT: We describe a patient with recurrent spontaneous globe subluxation who presented to the Emergency Department with acute ocular pain and vision loss. The subluxation was emergently reduced, resolving the pain and restoring normal vision. Various manual reduction techniques are discussed. CONCLUSION: There are a number of manual reduction techniques used for treating spontaneous globe subluxation.

Stages of competency for medical procedures.

BACKGROUND: Basic medical procedures have historically been taught at the bedside, without a formal curriculum. The supervision of basic procedures is often provided by the next most senior member of the health care team, who themselves may have very little experience. This approach does not allow for preparatory reading or deliberate practise of the procedure, and trainees often track the number of completed procedures as the only evidence of competency, without documented assessments of quality. CONTEXT: The conscious competence model is a learning paradigm for acquiring a new skill that can be applied to teaching medical procedures. There are multiple stages for effectively learning how to competently perform a procedure, which should not be distilled down into bedside demonstration alone. Learners can be guided through these stages to allow progression towards competency to perform a procedure unsupervised. INNOVATION: We propose a novel approach that divides procedural education into a four-step process that covers knowledge, experience, technical skill development and competency evaluation. The stages of competency outlined here can be tailored, with incremental expectations for any medical procedure and any level of learner. IMPLICATIONS: This educational paradigm alters the current structure of teaching procedures at any level of medical education, with the goals of better comprehension, skill retention and decreased adverse outcomes. Graded objectives based on learner level can be determined by educators for each clinical procedure. This four-step framework for teaching medical procedures will make the adage 'see one, do one, teach one' obsolete.

Evaluating educational interventions in emergency medicine.

This article presents the proceedings of the 2012 Academic Emergency Medicine consensus conference breakout group charged with identifying areas necessary for future research regarding effectiveness of educational interventions for teaching emergency medicine (EM) knowledge, skills, and attitudes outside of the clinical setting. The objective was to summarize both medical and nonmedical education literature and report the consensus formation methods and results. The authors present final statements to guide future research aimed at evaluating the best methods for understanding and developing successful EM curricula using all types of educational interventions.

Simulation in medical student education: survey of clerkship directors in emergency medicine.

INTRODUCTION: The objective of this study is to identify (1) the current role of simulation in medical student emergency medicine (EM) education; (2) the challenges to initiating and sustaining simulation-based programs; and (3) educational advances to meet these challenges. METHODS: We solicited members of the Clerkship Directors in Emergency Medicine (CDEM) e-mail list to complete a Web-based survey addressing the use of simulation in both EM clerkships and preclinical EM curricula. Survey elements addressed the nature of the undergraduate EM clerkship and utilization of simulation, types of technology, and barriers to increased use in each setting. RESULTS: CDEM members representing 60 EM programs on the list (80%) responded. Sixty-seven percent of EM clerkships are in the fourth year of medical school only and 45% are required. Fewer than 25% of clerkship core curriculum hours incorporate simulation. The simulation modalities used most frequently were high-fidelity models (79%), task trainers (55%), and low-fidelity models (30%). Respondents identified limited faculty time (88.7%) and clerkship hours (47.2%) as the main barriers to implementing simulation training in EM clerkships. Financial resources, faculty time, and the volume of students were the main barriers to additional simulation in preclinical years. CONCLUSION: A focused, stepwise application of simulation to medical student EM curricula can help optimize the ratio of student benefit to faculty time. Limited time in the curriculum can be addressed by replacing existing material with simulation-based modules for those subjects better suited to simulation. Faculty can use hybrid approaches in the preclinical years to combine simulation with classroom settings for either small or large groups to more actively engage learners while minimizing identified barriers.

Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7.

Epidermal growth factor-like domain 7 (Egfl7) is important for regulating tubulogenesis in zebrafish, but its role in mammals remains unresolved. We show here that endothelial overexpression of Egfl7 in transgenic mice leads to partial lethality, hemorrhaging, and altered cardiac morphogenesis. These defects are accompanied by abnormal vascular patterning and remodeling in both the embryonic and postnatal vasculature. Egfl7 overexpression in the neonatal retina results in a hyperangiogenic response, and EGFL7 knockdown in human primary endothelial cells suppresses endothelial cell proliferation, sprouting, and migration. These phenotypes are reminiscent of Notch inhibition. In addition, our results show that EGFL7 and endothelial-specific NOTCH physically interact in vivo and strongly suggest that Egfl7 antagonizes Notch in both the postnatal retina and in primary endothelial cells. Specifically, Egfl7 inhibits Notch reporter activity and down-regulates the level of Notch target genes when overexpressed. In conclusion, we have uncovered a critical role for Egfl7 in vascular development and have shown that some of these functions are mediated through modulation of Notch signaling.