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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Terahertz spectroscopy techniques for explosives detection.

Spectroscopy in the terahertz frequency range has demonstrated unique identification of both pure and military-grade explosives. There is significant potential for wide applications of the technology for nondestructive and nonintrusive detection of explosives and related devices. Terahertz radiation can penetrate most dielectrics, such as clothing materials, plastics, and cardboard. This allows both screening of personnel and through-container screening. We review the capabilities of the technology to detect and identify explosives and highlight some of the critical works in this area.

Faculty physicians and new physicians disagree about which procedures are essential to learn in medical school.

BACKGROUND: Clinical procedures taught in the undergraduate medical curriculum are important for subsequent residency training and clinical practice. Published reports suggest that medical schools may not be adequately teaching procedures. This study identifies procedures considered essential by residents completing internship and by medical school faculty, and determines agreement on their importance for medical student education. METHODS: Two hundred and thirty-five physicians (184 new physicians who recently completed internship and 51 medical school teaching faculty) categorized 31 clinical procedures based on the importance for internship. New physicians who had completed internship reported the level of training received in medical school for each procedure. RESULTS: Survey responses were 76% (faculty) and 70% (new physicians who had completed internship). The faculty majority identified 14 procedures as 'Must Know.' New physicians disagreed on 8 of these and categorized an additional 5 as essential. There was 32% concordance for the 19 procedures identified by either group. New physicians reported 'Limited Hands-On Training' for all 19 procedures but 'Comprehensive Hands-On Training' for only two. CONCLUSIONS: New physicians who have completed internship and medical school faculty do not agree on procedures essential for internship. A core educational list of 19 procedures was identified using the responses from these two groups.

Large group high-fidelity simulation enhances medical student learning.

BACKGROUND: Previous work shows feasibility for large group high-fidelity simulation with correlation to basic science in the preclinical curriculum. AIMS: This project studies whether large group simulation leads to enhanced basic science learning. METHODS: This was an educational performance study before and after high-fidelity simulation for first-year medical students. Basic neuroscience concepts were reinforced with simulation, and pretesting and posttesting were analysed along with summative exam results. The number correct was compared on a contingency table using the Mantel-Haenszel chi-squared test and same student correlation was accounted for with a 'Generalized Estimating Equations' model. RESULTS: The study included 112 students; three were excluded for missing data. Students showed statistically significant improvement on two of the four questions, and a nonsignificant improvement or equivalent performance on two questions. Students were significantly more likely to get all four responses correct on the posttest than on the pretest. Summative testing 11 days later had >80% correct responses for three factual recall questions and 58% correct responses for a single knowledge application question. CONCLUSIONS: Simulation is an effective teaching method for preclinical basic science education. Students demonstrated significant improvements after participating in a live interactive simulation scenario.

A case of intrauterine molar pregnancy with coexistent ectopic pregnancy.

We describe a woman who presented to the Emergency Department (ED) with vaginal bleeding and abdominal pain. She was initially diagnosed by the emergency physician with a molar pregnancy by transvaginal ultrasound, which was confirmed and treated by the consulting obstetrical service with a dilatation and curettage the following day. The patient was discharged home later that same day and subsequently returned to the ED after several hours complaining of an acute worsening of her abdominal pain with associated fatigue and lightheadedness. Transabdominal ultrasound performed by the emergency physician demonstrated intra-abdominal free fluid, and the obstetrical service was immediately contacted. Subsequent operative management identified a separate ruptured ectopic pregnancy in the fallopian tube that was confirmed by pathologic analysis after laparoscopic removal.

Emergency department management of meningitis and encephalitis.

Bacterial meningitis and viral encephalitis are infectious disease emergencies that can cause significant patient morbidity and mortality. Clinicians use epidemiologic, historical, and physical examination findings to identify patients at risk for these infections, and central nervous system (CNS) imaging and lumbar puncture (LP) may be needed to further evaluate for these diagnoses. The diagnosis of bacterial meningitis can be challenging, as patients often lack some of the characteristic findings of this disease with presentations that overlap with more common disorders seen in the emergency department. This article addresses considerations in clinical evaluation, need for CNS imaging before LP, interpretation of cerebrospinal fluid results, standards for and effects of timely antibiotic administration, and recommendations for specific antimicrobial therapy and corticosteroids.

Drug Insight: steroids in CNS infectious diseases--new indications for an old therapy.

Infectious diseases of the CNS lead to overwhelming inflammatory processes within the brain and spinal cord that contribute substantially to patient morbidity and mortality. Pharmacological strategies to modulate inflammation have been investigated, although the resulting guidelines have sometimes been contradictory. Steroids have been proposed as adjunctive treatments for bacterial meningitis, tuberculous meningitis and herpes simplex virus encephalitis. Well-designed randomized controlled trials have established dexamethasone as an adjunctive therapy for adult patients receiving antibiotics for bacterial meningitis, and physicians prescribing the initial antibiotics need to be aware of current guidelines. Morbidity and mortality in patients with tuberculous meningitis exceeds 50%. Steroid treatments reduce mortality through an as yet unknown mechanism, although their effects on morbidity are less clear. Herpes simplex virus encephalitis is also associated with considerable morbidity and mortality. Despite a lack of randomized trials, there is some evidence that steroids used alongside antiviral therapy might be beneficial in this condition. As we discuss in this Review, systemic steroid treatment is an important aspect of treatment regimens for CNS infectious diseases, and the recent literature provides guidelines for the use of steroids in combination with appropriate antimicrobial therapy.

A skin abscess model for teaching incision and drainage procedures.

BACKGROUND: Skin and soft tissue infections are increasingly prevalent clinical problems, and it is important for health care practitioners to be well trained in how to treat skin abscesses. A realistic model of abscess incision and drainage will allow trainees to learn and practice this basic physician procedure. METHODS: We developed a realistic model of skin abscess formation to demonstrate the technique of incision and drainage for educational purposes. The creation of this model is described in detail in this report. RESULTS: This model has been successfully used to develop and disseminate a multimedia video production for teaching this medical procedure. Clinical faculty and resident physicians find this model to be a realistic method for demonstrating abscess incision and drainage. CONCLUSION: This manuscript provides a detailed description of our model of abscess incision and drainage for medical education. Clinical educators can incorporate this model into skills labs or demonstrations for teaching this basic procedure.