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Pharmacologic therapy is an integral component in the management of most cardiovascular emergencies. This article reviews the pharmacotherapy involved in the treatment of acute coronary syndromes, acute heart failure, and various arrhythmias. The focus will be to provide practical pearls that can be applied at the bedside in the Emergency Department.

Acute aortic dissection is a serious and life-threatening condition that requires prompt, effective management. The purpose of this study was to evaluate the efficacy and safety of esmolol for heart rate control in patients with acute aortic dissection in the Emergency Department (ED).This was a retrospective, descriptive analysis of patients treated for type A or type B acute aortic dissection in the ED at an academic medical center. The primary outcome was the proportion of patients achieving strict (≤60 bpm) or lenient (≤80 bpm) heart rate control within the first 60 min of therapy at the study site. The primary safety endpoint was the incidence of hypotension, defined as a systolic blood pressure of90 mmHg or a mean arterial pressure of ≤60 mmHg.Of 266 patients screened, 40 patients met inclusion criteria. Thirty-three patients (82.5%) attained lenient rate control within the first 60 min of esmolol therapy. Eleven patients (27.5%) achieved a strict heart rate goal within the first 60 min of esmolol therapy. Five patients (12.5%) experienced an episode of hypotension during the first 3 h of esmolol therapy.In patients treated with esmolol infusion for acute aortic dissection, a lenient HR goal was achieved in most patients. In contrast, esmolol was not associated with attainment of strict HR control in most patients included in this sample. Further studies are warranted to evaluate the exact role of esmolol in acute aortic dissection in a larger patient population.

Small diagnostic tissue samples can be inadequate in testing an expanding list of validated oncogenic driver alterations and fail to reflect intratumour heterogeneity (ITGH) in lung cancer. Liquid biopsies are non-invasive and may better reflect ITGH. Most liquid biopsies are performed in the context of circulating tumour DNA (ctDNA) in plasma but Exhaled Breath Condensate (EBC) shows promise as a lung-specific liquid biopsy.In this prospective, proof-of-concept study we carried out targeted Next Generation Sequencing (NGS) on diagnostic tissue samples from 125 patients with lung cancer and compared results to plasma and EBC for 5 oncogenic driver mutations (EGFR, KRAS, PIK3CA, ERBB2, BRAF) using an ultrasensitive PCR technique (UltraSEEK™ Lung Panel on the MassARRAY® System, Agena Bioscience, San Diego, CA, USA).There was a significantly higher failure rate due to unamplifiable DNA in tissue NGS (57/125, 45.6%) compared to plasma (27/125, 21.6%, p 0.001 and EBC (26/125,20.8%, p ≤ 0.001. Consequently, both plasma and EBC identified higher number of mutations compared to tissue NGS. Specifically, there were significantly higher numbers of mutations detected in EGFR, KRAS and PIK3CA in plasma (p = 9.82 × 10The results suggest that EBC is effective in identifying clinically relevant alterations in patients with lung cancer using UltraSEEK™ and has a potential role as an adjunct to plasma testing.

Bupropion overdose can produce seizures, arrhythmias, and shock. The toxicokinetics of massive bupropion ingestions are not well characterized.A 22-year-old female ingested an estimated 40.5 g (644...

Background Elastin breakdown and the resultant loss of lung elastic recoil is a hallmark of pulmonary emphysema in susceptible individuals as a consequence of tobacco smoke exposure. Systemic alterations to the synthesis and degradation of elastin may be important to our understanding of disease phenotypes in chronic obstructive pulmonary disease. We investigated the association of skin elasticity with pulmonary emphysema, obstructive lung disease, and blood biomarkers of inflammation and tissue protease activity in tobacco-exposed individuals. Methods Two hundred and thirty-six Caucasian individuals were recruited into a sub-study of the University of Pittsburgh Specialized Center for Clinically Orientated Research in chronic obstructive pulmonary disease, a prospective cohort study of current and former smokers. The skin viscoelastic modulus (VE), a determinant of skin elasticity, was recorded from the volar forearm and facial wrinkling severity was determined using the Daniell scoring system. Results In a multiple regression analysis, reduced VE was significantly associated with cross-sectional measurement of airflow obstruction (FEV1/FVC) and emphysema quantified from computed tomography (CT) images, β = 0.26, p = 0.001 and β = 0.24, p = 0.001 respectively. In emphysema-susceptible individuals, elasticity-determined skin age was increased (median 4.6 years) compared to the chronological age of subjects without emphysema. Plasma biomarkers of inflammation (TNFR1, TNFR2, CRP, PTX3, and SAA) and matrix metalloproteinase activity (MMP1, TIMP1, TIMP2, and TIMP4) were inversely associated with skin elasticity. Conclusions We report that an objective non-invasive determinant of skin elasticity is independently associated with measures of lung function, pulmonary emphysema, and biomarkers of inflammation and tissue proteolysis in tobacco-exposed individuals. Loss of skin elasticity is a novel observation that may link the common pathological processes that drive tissue elastolysis in the extracellular matrix of the skin and lung in emphysema-susceptible individuals. Electronic supplementary material The online version of this article (10.1186/s12931-019-1098-7) contains supplementary material, which is available to authorized users.

IntroductionMuscle loss is an important extrapulmonary manifestation of COPD. Dual energy X-ray absorptiometry (DXA) is the method of choice for body composition measurement but is not widely used for muscle mass evaluation. The pectoralis muscle area (PMA) is quantifiable by CT and predicts cross-sectional COPD-related morbidity. There are no studies that compare PMA with DXA measures or that evaluate longitudinal relationships between PMA and lung disease progression.MethodsParticipants from our longitudinal tobacco-exposed cohort had baseline and 6-year chest CT (n=259) and DXA (n=164) data. Emphysema was quantified by CT density histogram parenchymal scoring using the 15th percentile technique. Fat-free mass index (FFMI) and appendicular skeletal mass index (ASMI) were calculated from DXA measurements. Linear regression model relationships were reported using standardised coefficient (β) with 95% CI.ResultsPMA was more strongly associated with DXA measures than with body mass index (BMI) in both cross-sectional (FFMI: β=0.76 (95% CI 0.65 to 0.86), pConclusionsPMA is an accessible measure of muscle mass and may serve as a useful clinical surrogate for assessing skeletal muscle loss in smokers. Decreased PMA correlated with emphysema progression but not lung function decline, suggesting a difference in the pathophysiology driving emphysema, airflow obstruction and comorbidity risk.

FBXL2 is an important ubiquitin E3 ligase component that modulates inflammatory signaling and cell cycle progression, but its molecular regulation is largely unknown. Here, we show that tumor necrosis factor alpha (TNF-α), a critical cytokine linked to the inflammatory response during skeletal muscle regeneration, suppressed Fbxl2 mRNA expression in C2C12 myoblasts and triggered significant alterations in cell cycle, metabolic, and protein translation processes. Gene silencing of Fbxl2 in skeletal myoblasts resulted in increased proliferative responses characterized by activation of mitogen-activated protein (MAP) kinases and nuclear factor kappa B and decreased myogenic differentiation, as reflected by reduced expression of myogenin and impaired myotube formation. TNF-α did not destabilize the Fbxl2 transcript (half-life [t(1/2)], ∼10 h) but inhibited SP1 transactivation of its core promoter, localized to bp −160 to +42 within the proximal 5′ flanking region of the Fbxl2 gene. Chromatin immunoprecipitation and gel shift studies indicated that SP1 interacted with the Fbxl2 promoter during cellular differentiation, an effect that was less pronounced during proliferation or after TNF-α exposure. TNF-α, via activation of JNK, mediated phosphorylation of SP1 that impaired its binding to the Fbxl2 promoter, resulting in reduced transcriptional activity. The results suggest that SP1 transcriptional activation of Fbxl2 is required for skeletal muscle differentiation, a process that is interrupted by a key proinflammatory myopathic cytokine. IMPORTANCE Skeletal muscle regeneration and repair involve the recruitment and proliferation of resident satellite cells that exit the cell cycle during the process of myogenic differentiation to form myofibers. We demonstrate that the ubiquitin E3 ligase subunit FBXL2 is essential for skeletal myogenesis through its important effects on cell cycle progression and cell proliferative signaling. Further, we characterize a new mechanism whereby sustained stimulation by a major proinflammatory cytokine, TNF-α, regulates skeletal myogenesis by inhibiting the interaction of SP1 with the Fbxl2 core promoter in proliferating myoblasts. Our findings contribute to the understanding of skeletal muscle regeneration through the identification of Fbxl2 as both a critical regulator of myogenic proliferative processes and a susceptible gene target during inflammatory stimulation by TNF-α in skeletal muscle. Modulation of Fbxl2 activity may have relevance to disorders of muscle wasting associated with sustained proinflammatory signaling.

To the Editor, A 16-year-old female with medical history of anxiety and depression presented to the emergency department approximately 45 min after reportedly ingesting 450 mg (7.6 mg/kg) of buspir...

Rationale: Gene expression of BAL cells, which samples the cellular milieu within the lower respiratory tract, has not been well studied in severe asthma. Objectives: To identify new biomolecular mechanisms underlying severe asthma by an unbiased, detailed interrogation of global gene expression. Methods: BAL cell expression was profiled in 154 asthma and control subjects. Of these participants, 100 had accompanying airway epithelial cell gene expression. BAL cell expression profiles were related to participant (age, sex, race, and medication) and sample traits (cell proportions), and then severity-related gene expression determined by correlating transcripts and coexpression networks to lung function, emergency department visits or hospitalizations in the last year, medication use, and quality-of-life scores. Measurements and Main Results: Age, sex, race, cell proportions, and medications strongly influenced BAL cell gene expression, but leading severity-related genes could be determined by carefully identifying and accounting for these influences. A BAL cell expression network enriched for cAMP signaling components most differentiated subjects with severe asthma from other subjects. Subsequently, an in vitro cellular model showed this phenomenon was likely caused by a robust upregulation in cAMP-related expression in nonsevere and β-agonist-naive subjects given a β-agonist before cell collection. Interestingly, ELISAs performed on BAL lysates showed protein levels may partly disagree with expression changes. Conclusions: Gene expression in BAL cells is influenced by factors seldomly considered. Notably, β-agonist exposure likely had a strong and immediate impact on cellular gene expression, which may not translate to important disease mechanisms or necessarily match protein levels. Leading severity-related genes were discovered in an unbiased, system-wide analysis, revealing new targets that map to asthma susceptibility loci.

Primary graft dysfunction (PGD) is a major cause of morbidity and mortality after lung transplantation. Ischemia–reperfusion injury (IRI) is a key event that contributes to PGD, though complex interactions affect donor lungs status, such as preceding brain death (BD), hemorrhagic shock (HS), and pre-engraftment lung management, the latter recognized as important risk factors for PGD. We hypothesized that a multi-hit isogenic mouse model of lung transplantation is more closely linked to PGD than IRI alone. Left lung transplants were performed between inbred C57BL/6 mice. A one-hit model of IRI was established by inducing cold ischemia (CI) of the donor lungs at 0°C for 1, 72, or 96 hours before engraftment. Multi-hit models were established by inducing 24 hours of HS and/or 3 hours of BD before 24 hours of CI. The recipients were killed at 24 hours after transplant and lung graft samples were analyzed. In the one-hit model of IRI, up to 72-hour CI time resulted in minimal cellular infiltration near small arteries after 24-hour reperfusion. Extension of CI time to 96 hours led to increased cellular infiltration and necroptotic pathway activation, without evidence of apoptosis, after 24-hour reperfusion. In a multi-hit model of PGD, “HS + BD + IRI” demonstrated increased lung injury, cellular infiltration, and activation of necroptotic and apoptotic pathways compared with IRI alone. Treatment with an inhibitor of receptor-interacting protein kinase 1 kinase, necrostatin-1, resulted in a significant decrease of downstream necroptotic pathway activation in both single- and multi-hit models of IRI. Thus, activation of necroptosis is a central event in IRI after prolonged CI, though it may not be sufficient to cause PGD alone. Pathological evaluation of donor lungs after CI-induced IRI, in conjunction with pre-engraftment donor lung factors in our multi-hit model, demonstrated early evidence of lung injury consistent with PGD. Our findings support the premise that pre-existing donor lung status is more important than CI time alone for inflammatory pathway activation in PGD, which may have important clinical implications for donor lung retrieval.

Background The ubiquitin-proteasome pathway, mediated in part, by ubiquitin E3 ligases, is critical in regulating cellular processes such as cell proliferation, apoptosis, and migration. FBXO17 was recently identified as an F-box protein that targets glycogen synthase kinase-3β to the E3 ubiquitin ligase protein complex for polyubiquitination and proteasomal degradation. Here, we identified that in several lung adenocarcinoma cell lines, FBXO17 cellular protein was detected at relatively high levels, as was expression in a subset of lung cancers. Hence, we investigated the effects of FBXO17 on cell proliferation. Methods Single cell RNA sequencing analysis was performed on a resection of a non-small cell lung carcinoma tumor to examine FBXO17 expression. Multiple lung cancer cell lines were immunoblotted, and The Cancer Genome Atlas was analyzed to determine if FBXO17 expression was amplified in a subset of lung cancers. A549 cells were transfected with empty vector or FBXO17-V5 plasmid and immunoblotted for Akt pathway mediators including PDK1, ERK1/2, ribosomal protein S6, and CREB. Cell proliferation and viability were analyzed by trypan blue exclusion, BrdU incorporation and an MTS-based fluorometric assay. Studies were also performed after transfecting with sifbxo17. Samples were used in an RNA microarray analysis to evaluate pathways affected by reduced FBXO17 gene expression. Results We observed that overexpression of FBXO17 increased A549 cell proliferation coupled with Akt activation. Ectopically expressed FBXO17 also increased ERK1/2 kinase activation and increased phosphorylation of RPS6, a downstream target of mTOR. We also observed an increased number of cells in S-phase and increased metabolic activity of lung epithelial cells expressing FBXO17. FBXO17 knockdown reduced Akt Ser 473 phosphorylation approaching statistical significance with no effect on Thr 308. However, ERK1/2 phosphorylation, cellular metabolic activity, and overall cell numbers were reduced. When we analyzed RNA profiles of A549 cells with reduced FBXO17 expression, we observed downregulation of several genes associated with cell proliferation and metabolism. Conclusions These data support a role for FBXO17 abundance, when left unchecked, in regulating cell proliferation and survival through modulation of Akt and ERK kinase activation. The data raise a potential role for the F-box subunit in modulating tumorigenesis. Electronic supplementary material The online version of this article (10.1186/s12931-018-0910-0) contains supplementary material, which is available to authorized users.

Data collected by 3D Laser Radar (Lidar) systems, which utilize arrays of avalanche photo-diode detectors operating in either Linear or Geiger mode, may include a large number of false detector counts or noise from temporal and spatial clutter. We present an improved algorithm for noise removal and signal detection, called Multiple-Peak Spatial Coincidence Processing (MPSCP). Field data, collected using an airborne Lidar sensor in support of the 2010 Haiti earthquake operations, were used to test the MPSCP algorithm against current state-of-the-art, Maximum A-posteriori Coincidence Processing (MAPCP). Qualitative and quantitative results are presented to determine how well each algorithm removes image noise while preserving signal and reconstructing the best estimate of the underlying 3D scene. The MPSCP algorithm is shown to have 9x improvement in signal-to-noise ratio, a 2-3x improvement in angular and range resolution, a 21% improvement in ground detection and a 5.9x improvement in computational efficiency compared to MAPCP.

A study of several unimolecular photochemical rearrangements in poly(methyl methacrylate) glass was carried out with the intent of comparing the behavior of excited-state species trapped in a polymer matrix with both the corresponding solution photochemistry and that in crystal lattices. Three reactants were studied: (a) 4,5,5-triphenylcyclohex-2-en-1-one, (b) 1,1-dicyano-3,3,5,5-tetraphenyl-1,4-pentadiene, and (c) 2,2-dimethyl-1,1-diphenyl-3-(2,2-diphenylvinyl)cyclopropane. The solution photochemistry of the three compounds had previously been studied in our laboratory, and the photochemistry in the crystal lattice had been similarly investigated for the first two. The crystal lattice photochemistry of the last of the three was investigated in the present study

Situation awareness and accurate Target Identification (TID) are critical requirements for successful battle management. Ground vehicles can be detected, tracked, and in some cases imaged using airborne or space-borne microwave radar. Obscurants such as camouflage net and/or tree canopy foliage can degrade the performance of such radars. Foliage can be penetrated with long wavelength microwave radar, but generally at the expense of imaging resolution. The goals of the DARPA Jigsaw program include the development and demonstration of high-resolution 3-D imaging laser radar (ladar) ensor technology and systems that can be used from airborne platforms to image and identify military ground vehicles that may be hiding under camouflage or foliage such as tree canopy. With DARPA support, MIT Lincoln Laboratory has developed a rugged and compact 3-D imaging ladar system that has successfully demonstrated the feasibility and utility of this application. The sensor system has been integrated into a UH-1 helicopter for winter and summer flight campaigns. The sensor operates day or night and produces high-resolution 3-D spatial images using short laser pulses and a focal plane array of Geiger-mode avalanche photo-diode (APD) detectors with independent digital time-of-flight counting circuits at each pixel. The sensor technology includes Lincoln Laboratory developments of the microchip laser and novel focal plane arrays. The microchip laser is a passively Q-switched solid-state frequency-doubled Nd:YAG laser transmitting short laser pulses (300 ps FWHM) at 16 kilohertz pulse rate and at 532 nm wavelength. The single photon detection efficiency has been measured to be > 20 % using these 32x32 Silicon Geiger-mode APDs at room temperature. The APD saturates while providing a gain of typically > 106. The pulse out of the detector is used to stop a 500 MHz digital clock register integrated within the focal-plane array at each pixel. Using the detector in this binary response mode simplifies the signal processing by eliminating the need for analog-to-digital converters and non-linearity corrections. With appropriate optics, the 32x32 array of digital time values represents a 3-D spatial image frame of the scene. Successive image frames illuminated with the multi-kilohertz pulse repetition rate laser are accumulated into range histograms to provide 3-D volume and intensity information. In this article, we describe the Jigsaw program goals, our demonstration sensor system, the data collection campaigns, and show examples of 3-D imaging with foliage and camouflage penetration. Other applications for this 3-D imaging direct-detection ladar technology include robotic vision, avigation of autonomous vehicles, manufacturing quality control, industrial security, and topography.

Lincoln Laboratory has developed 32×32-pixel ladar focal planes comprising silicon Geiger-mode avalanche photodiodes and high-speed all-digital CMOS timing circuitry in each pixel. In Geiger-mode operation, the APD can detect as little as a single photon, producing a digital CMOS-compatible voltage pulse. This pulse is used to stop a high-speed counter in the pixel circuit, thus digitizing the time of arrival of the optical pulse. This "photon-to-digital conversion" simultaneously achieves single-photon sensitivity and 0.25-ns timing precision. We discuss the development of these focal planes and present imagery from ladar systems that use them.

MIT Lincoln Laboratory continues the development of novel high-resolution 3D imaging laser radar technology and sensor systems. The sensor system described in detail here uses a passively Q-switched solid-state frequency-doubled Nd:YAG laser to transmit short laser pulses (~ 700 ps FWHM) at 532 nm wavelength and derive the range to target surface element by measuring the time-of-flight for each pixel. The single photoelectron detection efficiency has been measured to be > 20 % using these Silicon Geiger-mode APDs at room temperature. The pulse out of the detector is used to stop a > 500 MHz digital clock integrated within the focal-plane array. With appropriate optics, the 32x32 array of digital time values represents a 3D spatial image frame of the scene. Successive image frames from the multi-kilohertz pulse repetition rate laser pulses are accumulated into range histograms to provide 3D volume and intensity information. In this paper, we report on a prototype sensor system, which has recently been developed using new 32x32 arrays of Geiger-mode APDs with 0.35 μm CMOS digital timing circuits at each pixel. Here we describe the sensor system development and present recent measurements of laboratory test data and field imagery.

MIT Lincoln Laboratory is actively developing laser and detector technologies that make it possible to build a 3D laser radar with several attractive features, including capture of an entire 3D image on a single laser pulse, tens of thousands of pixels, few-centimeter range resolution, and small size, weight, and power requirements. The laser technology is base don diode-pumped solid-state microchip lasers that are passively Q-switched. The detector technology is based on Lincoln-built arrays of avalanche photodiodes operating in the Geiger mode, with integrated timing circuitry for each pixel. The advantage of these technologies is that they offer the potential for small, compact, rugged, high-performance systems which are critical for many applications.© (2001) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We have developed a threedimensional imaging laser radar featuring 3-cm range resolution and single-photon sensitivity. This prototype direct-detection laser radar employs compact, all-solid-state technology for the laser and detector array. The source is a Nd:YAG microchip laser that is diode pumped, passively Q-switched, and frequency doubled. The detector is a gated, passively quenched, two-dimensional array of silicon avalanche photodiodes operating in Geigermode. After describing the system in detail, we present a three-dimensional image, derive performance characteristics, and discuss our plans for future imaging three-dimensional laser radars.

A patient with osteomyelitis and supposed osteolysis has been described. Unlike previous cases reported, the osteolysis was observed throughout its entire course and an etiologic factor was present. The surgical excision of the involved bone and immediate restoration with a bone graft was successful. A 3-year follow-up showed no evidence of recurrence.