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Silver Spring, United States
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News Article | May 3, 2017
Site: www.eurekalert.org

Sudden cardiac death resulting from fibrillation - erratic heartbeat due to electrical instability - is one of the leading causes of death in the United States. Now, researchers have discovered a fundamentally new source of that electrical instability, a development that could potentially lead to new methods for predicting and preventing life-threatening cardiac fibrillation. A steady heartbeat is maintained by electrical signals that originate deep within the heart and travel through the muscular organ in regular waves that stimulate the coordinated contraction of muscle fibers. But when those waves are interrupted by blockages in electrical conduction - such as scar tissue from a heart attack - the signals can be disrupted, creating chaotic spiral-shaped electrical waves that interfere with one another. The resulting electrical turbulence causes the heart to beat ineffectively, quickly leading to death. Scientists have known that instabilities at the cellular level, especially variation in the duration of each electrical signal - known as an action potential - are of primary importance in creating chaotic fibrillation. By analyzing electrical signals in the hearts of an animal model, researchers from the Georgia Institute of Technology and the U.S. Food and Drug Administration have found an additional factor - the varying amplitude of the action potential - that may also cause dangerous electrical turbulence within the heart. The research, supported by the National Science Foundation, was reported April 20 in the journal Physical Review Letters. "Mathematically, we can now understand some of these life-threatening instabilities and how they develop in the heart," said Flavio Fenton, a professor in Georgia Tech's School of Physics. "We have proposed a new mechanism that explains when fibrillation will occur, and we have a theory that can predict, depending on physiological parameters, when this will happen." The voltage signal that governs the electrically-driven heartbeat is mapped by doctors from the body surface using electrocardiogram technology, which is characterized by five main segments (P-QRS-T), each representing different activations in the heart. T waves occur at the end of each heartbeat, and indicate the back portion of each wave. Researchers have known that abnormalities in the T wave can signal an increased risk of a potentially life-threatening heart rhythm. Fenton and his collaborators studied the cellular action potential amplitude, which is controlled by sodium ion channels that are part of the heart's natural regulatory system. Sodium ions flowing into the cells boost the concentration of cations - which carry a positive charge - leading to a phenomena known as depolarization, in which the action potential of the cell rises above its resting level. The sodium channels then close at the peak of the action potential. While variations in the duration of the action potential indicate problems with the heart's electrical system, the researchers have now associated dynamic variations in the amplitude of the action potential with conduction block and the onset of fibrillation. "We have shown for the first time that a fundamentally different instability related to amplitude may underlie or additionally affect the risk of cardiac instabilities leading to fibrillation," said Richard Gray, one of the study's co-authors and a biomedical engineer in the Office of Science and Engineering Laboratories in the U.S. Food and Drug Administration. "You can have one wave with a long amplitude followed by one wave with a short amplitude, and if the short one becomes too short, the next wave will not be able to propagate," said Diana Chen, a Georgia Tech graduate student and first author of the study. "The waves going through the heart have to move together to maintain an effective heartbeat. If one of them breaks, the first wave can collide with the next wave, initiating the spiral waves." If similar results are found in human hearts, this new understanding of how electrical turbulence forms could allow doctors to better predict who would be at risk of fibrillation. The information might also lead to the development of new drugs for preventing or treating the condition. "One next scientific step would be to investigate pharmaceuticals that would reduce or eliminate the cellular amplitude instability," said Gray. "At the present time, most pharmaceutical approaches are focused on the action potential duration." The critical role of electrical waves in governing the heart's activity allows physics - and mathematics - to be used for understanding what is happening in this most critical organ, Fenton said. "We have derived a mathematical explanation for how this happens, why it is dangerous and how it initiates an arrhythmia," he explained. "We now have a mechanism that provides a better understanding of how these electrical disturbances originate. It's only when you have these changes in wave amplitude that the signals cannot propagate properly." Chen studied at the FDA's Center for Devices and Radiological Health through the NSF/FDA Scholar-in- Residence Program. Operated in collaboration with the National Science Foundation's Directorate for Engineering's Chemical, Bioengineering, Environmental, and Transport Systems, the program enables investigators in science, engineering and mathematics to develop research collaborations within the intramural research environment at the FDA. In addition to those already mentioned, the paper included work from Ilija Uzelac, a postdoctoral fellow, and Conner Herndon, a graduate research assistant. All are from the Georgia Tech School of Physics. This material is based upon work supported by the National Science Foundation under awards CNS-1347015 and CNS-1446675. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. CITATION: Diandian Diana Chen, et al., "A Mechanism for QRS Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos," (Physical Review Letters, 2017). https:/


A steady heartbeat is maintained by electrical signals that originate deep within the heart and travel through the muscular organ in regular waves that stimulate the coordinated contraction of muscle fibers. But when those waves are interrupted by blockages in electrical conduction - such as scar tissue from a heart attack - the signals can be disrupted, creating chaotic spiral-shaped electrical waves that interfere with one another. The resulting electrical turbulence causes the heart to beat ineffectively, quickly leading to death. Scientists have known that instabilities at the cellular level, especially variation in the duration of each electrical signal - known as an action potential - are of primary importance in creating chaotic fibrillation. By analyzing electrical signals in the hearts of an animal model, researchers from the Georgia Institute of Technology and the U.S. Food and Drug Administration have found an additional factor - the varying amplitude of the action potential - that may also cause dangerous electrical turbulence within the heart. The research, supported by the National Science Foundation, was reported April 20 in the journal Physical Review Letters. "Mathematically, we can now understand some of these life-threatening instabilities and how they develop in the heart," said Flavio Fenton, a professor in Georgia Tech's School of Physics. "We have proposed a new mechanism that explains when fibrillation will occur, and we have a theory that can predict, depending on physiological parameters, when this will happen." The voltage signal that governs the electrically-driven heartbeat is mapped by doctors from the body surface using electrocardiogram technology, which is characterized by five main segments (P-QRS-T), each representing different activations in the heart. T waves occur at the end of each heartbeat, and indicate the back portion of each wave. Researchers have known that abnormalities in the T wave can signal an increased risk of a potentially life-threatening heart rhythm. Fenton and his collaborators studied the cellular action potential amplitude, which is controlled by sodium ion channels that are part of the heart's natural regulatory system. Sodium ions flowing into the cells boost the concentration of cations - which carry a positive charge - leading to a phenomena known as depolarization, in which the action potential of the cell rises above its resting level. The sodium channels then close at the peak of the action potential. While variations in the duration of the action potential indicate problems with the heart's electrical system, the researchers have now associated dynamic variations in the amplitude of the action potential with conduction block and the onset of fibrillation. "We have shown for the first time that a fundamentally different instability related to amplitude may underlie or additionally affect the risk of cardiac instabilities leading to fibrillation," said Richard Gray, one of the study's co-authors and a biomedical engineer in the Office of Science and Engineering Laboratories in the U.S. Food and Drug Administration. "You can have one wave with a long amplitude followed by one wave with a short amplitude, and if the short one becomes too short, the next wave will not be able to propagate," said Diana Chen, a Georgia Tech graduate student and first author of the study. "The waves going through the heart have to move together to maintain an effective heartbeat. If one of them breaks, the first wave can collide with the next wave, initiating the spiral waves." If similar results are found in human hearts, this new understanding of how electrical turbulence forms could allow doctors to better predict who would be at risk of fibrillation. The information might also lead to the development of new drugs for preventing or treating the condition. "One next scientific step would be to investigate pharmaceuticals that would reduce or eliminate the cellular amplitude instability," said Gray. "At the present time, most pharmaceutical approaches are focused on the action potential duration." The critical role of electrical waves in governing the heart's activity allows physics - and mathematics - to be used for understanding what is happening in this most critical organ, Fenton said. "We have derived a mathematical explanation for how this happens, why it is dangerous and how it initiates an arrhythmia," he explained. "We now have a mechanism that provides a better understanding of how these electrical disturbances originate. It's only when you have these changes in wave amplitude that the signals cannot propagate properly." Explore further: Cause of killer cardiac disease identified by new method More information: Diandian Diana Chen et al, Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos, Physical Review Letters (2017). DOI: 10.1103/PhysRevLett.118.168101


Ardeshirpour Y.,National Institute of Child Health and Human Development | Chernomordik V.,National Institute of Child Health and Human Development | Hassan M.,National Institute of Child Health and Human Development | Hassan M.,Office of Science and Engineering Laboratories | And 4 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. Experimental Design: HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe inj ections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size. Results: Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (~0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns. Conclusions: The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. © 2014 American Association for Cancer Research.


Baeva L.F.,Office of Science and Engineering Laboratories | Sarkar Das S.,Office of Science and Engineering Laboratories | Hitchins V.M.,Office of Science and Engineering Laboratories
Journal of Biomedical Materials Research - Part B Applied Biomaterials | Year: 2016

A simple and rapid method has been developed for testing bacterial endotoxin in hyaluronic acid (HA)-based medical devices. High-molecular-weight HA (HMW HA) in solution or HA-based medical devices was digested by the enzyme hyaluronidase to reduce solution viscosity by truncating the long chains of HA and to test for bacterial endotoxin. The bacterial endotoxin level was detected and measured by kinetic chromogenic Limulus Amebocyte Lysate (LAL) assay. The method was applied to two different ophthalmic viscosurgical devices (OVDs) and one dermal filler, and may easily be adapted to use with up to 3% HA solutions and other HA-based medical devices. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. J Biomed Mater Res Part B: Appl Biomater, 2016. © 2016 Wiley Periodicals, Inc..


Vertes A.,George Washington University | Hitchins V.,Office of Science and Engineering Laboratories | Phillips K.S.,Office of Science and Engineering Laboratories
Analytical Chemistry | Year: 2012

Microbial colonization of medical devices is a widespread problem that tests the limits of conventional analytical methods. Successful analytical endeavors require collaboration between clinicians, microbiologists, biomedical engineers, and analytical chemists. © 2012 American Chemical Society.


Sapsford K.E.,Office of Science and Engineering Laboratories | Blanco-Canosa J.B.,Scripps Research Institute | Dawson P.E.,Scripps Research Institute | Medintz I.L.,Center for Bio Molecular Science and Engineering
Bioconjugate Chemistry | Year: 2010

A simple bifunctional colorimetric/fluorescent sensing assay is demonstrated for the detection of HIV-1 specific antibodies. This assay makes use of a short peptide sequence coupled to an environmentally sensitive dye that absorbs and emits in the visible portion of the spectrum. The core peptide sequence is derived from the highly antigenic six-residue epitope of the HIV-1 p17 protein and is situated adjacent to a terminal cysteine residue which enables site-specific fluorescent labeling with Cy3 cyanine dye. Interaction of the Cy3-labeled p17 peptide with monoclonal anti-p17 antibody resulted in an up to 4-fold increase in dye absorption and greater than 5-fold increase in fluorescent emission, yielding a limit of detection as low as 73 pM for the target antibody. This initial study demonstrates both proof-of-concept for this approach and suggests that the resulting sensor could potentially be used as a rapid screening method for HIV-1 infection while requiring minimal equipment and reagents. The potential for utilizing this assay in simple field-portable point-of-care and diagnostic devices is discussed. © 2010 American Chemical Society.


Siegelman J.W.,Brigham and Women's Hospital | Supanich M.P.,Rush University Medical Center | Gavrielides M.A.,Office of Science and Engineering Laboratories
American Journal of Roentgenology | Year: 2015

OBJECTIVE. Pulmonary nodules of ground-glass opacity represent one imaging manifestation of a slow-growing variant of lung cancer. The objective of this phantom study was to quantify the effect of the radiation dose used for the examination (volume CT dose index [CTDIvol]), type of reconstruction algorithm, and choice of postreconstruction enhancement algorithms on the measurement error when assessing the volume of simulated lung nodules with CT, focusing on two radiodensity levels. MATERIALS AND METHODS. Twelve synthetic nodules of two radiodensities (?630 and ?10 HU), three shapes (spherical, lobulated, and spiculated), and two sizes (nominal diameters of 5 and 10 mm) were inserted into an anthropomorphic chest phantom and scanned with techniques varying in CTDIvol (from subscreening dose [0.8 mGy] to diagnostic levels [6.5 mGy]), reconstruction algorithms (iterative reconstruction and filtered back projection), and different postreconstruction enhancement algorithms. Nodule volume was measured from the resulting reconstructed CT images with a matched filter estimator. RESULTS. No significant over-or underestimation of nodule volume was observed across individual variables, with low percentage error overall (?1.4%) and for individual variables (range, ?3.4% to 0.4%). The magnitude of percentage error was also low (overall average percentage error < 6% and SD values < 4.5%) and for individual variables (absolute percentage error range 3.3-5.6%). No clinically significant differences were observed between different levels of CTDIvol, use of iterative reconstruction algorithms, or use of different postreconstruction enhancement algorithms. CONCLUSION. These results indicate that, if validated for other measurement tools and scanners, lung nodule volume measurements from scans acquired and reconstructed with significantly different acquisition and reconstruction techniques can be reliably compared. © American Roentgen Ray Society.


PubMed | Office of Science and Engineering Laboratories
Type: Journal Article | Journal: Medical physics | Year: 2017

This symposium will review recent advances in the simulation methods for evaluation of novel breast imaging systems - the subject of AAPM Task Group TG234. Our focus will be on the various approaches to development and validation of software anthropomorphic phantoms and their use in the statistical assessment of novel imaging systems using such phantoms along with computational models for the x-ray image formation process. Due to the dynamic development and complex design of modern medical imaging systems, the simulation of anatomical structures, image acquisition modalities, and the image perception and analysis offers substantial benefits of reduced cost, duration, and radiation exposure, as well as the known ground-truth and wide variability in simulated anatomies. For these reasons, Virtual Clinical Trials (VCTs) have been increasingly accepted as a viable tool for preclinical assessment of x-ray and other breast imaging methods. Activities of TG234 have encompassed the optimization of protocols for simulation studies, including phantom specifications, the simulated data representation, models of the imaging process, and statistical assessment of simulated images. The symposium will discuss the state-of-the-science of VCTs for novel breast imaging systems, emphasizing recent developments and future directions. Presentations will discuss virtual phantoms for intermodality breast imaging performance comparisons, extension of the breast anatomy simulation to the cellular level, optimized integration of the simulated imaging chain, and the novel directions in the observer models design.1. Review novel results in developing and applying virtual phantoms for inter-modality breast imaging performance comparisons; 2. Discuss the efforts to extend the computer simulation of breast anatomy and pathology to the cellular level; 3. Summarize the state of the science in optimized integration of modules in the simulated imaging chain; 4. Compare novel directions in the design of observer models for task based validation of imaging systems. PB: Research funding support from the NIH, NSF, and Komen for the Cure; NIH funded collaboration with Barco, Inc. and Hologic, Inc.; Consultant to Delaware State Univ. and NCCPM, UK. AA: Employed at Barco Healthcare.; P. Bakic, NIH: (NIGMS P20 #GM103446, NCI R01 #CA154444); M. Das, NIH Research grants.


PubMed | Office of Science and Engineering Laboratories
Type: Journal Article | Journal: Medical physics | Year: 2017

Research and development in radiomics for precision medicine have been advancing at a rapid pace, and can be extended to eventually be mature enough for integration into clinical practice. To facilitate advances in this field, investigators need updated information on research funding, regulatory matters, and clinical translation efforts. In this special radiomics symposium, the attendee will learn of various novel funding mechanisms - both past and present - that have been used to support a number of quantitative imaging and radiomics research and resource infrastructures. In addition, a regulatory presentation will be given to provide the attendee with an understanding of when a radiomics tool might require FDA clearance or approval, and with what supporting performance data. We will end with insights from a clinical radiologist who is greatly involved in quantitative imaging in order to enable the attendee to appreciate the needs and subtleties involved in moving radiomics into the clinical workflow. J. Boone, This is a memorial and not a funded event.


PubMed | Office of Science and Engineering Laboratories
Type: Journal Article | Journal: Medical physics | Year: 2017

Research and development in radiomics for precision medicine have been advancing at a rapid pace, and can be extended to eventually be mature enough for integration into clinical practice. To facilitate advances in this field, investigators need updated information on research funding, regulatory matters, and clinical translation efforts. In this special radiomics symposium, the attendee will learn of various novel funding mechanisms - both past and present - that have been used to support a number of quantitative imaging and radiomics research and resource infrastructures. In addition, a regulatory presentation will be given to provide the attendee with an understanding of when a radiomics tool might require FDA clearance or approval, and with what supporting performance data. We will end with insights from a clinical radiologist who is greatly involved in quantitative imaging in order to enable the attendee to appreciate the needs and subtleties involved in moving radiomics into the clinical workflow. J. Boone, This is a memorial and not a funded event.

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