Diagnostic Ultrasound Induced Inertial Cavitation To Non-Invasively Restore Coronary And Microvascular Flow In Acute Myocardial Infarction

Ultrasound induced cavitation has been explored as a method of dissolving intravascular and microvascular thrombi in acute myocardial infarction. The purpose of this study was to determine the type of cavitation required for success, and whether longer pulse duration therapeutic impulses (sustaining the duration of cavitation) could restore both microvascular and epicardial flow with this technique. Accordingly, in 36 hyperlipidemic atherosclerotic pigs, thrombotic occlusions were induced in the mid-left anterior descending artery. Pigs were then randomized to either a) 1/2 dose tissue plasminogen activator (0.5 mg/kg) alone; or same dose plasminogen activator and an intravenous microbubble infusion with either b) guided high mechanical index short pulse (2.0 MI; 5 usec) therapeutic ultrasound impulses; or c) guided 1.0 mechanical index long pulse (20 usec) impulses. Passive cavitation detectors indicated the high mechanical index impulses (both long and short pulse duration) induced inertial cavitation within the microvasculature. Epicardial recanalization rates following randomized treatments were highest in pigs treated with the long pulse duration therapeutic impulses (83% versus 59% for short pulse, and 49% for tissue plasminogen activator alone; p \u3c 0.05). Even without epicardial recanalization, however, early microvascular recovery occurred with both short and long pulse therapeutic impulses (p \u3c 0.005 compared to tissue plasminogen activator alone), and wall thickening improved within the risk area only in pigs treated with ultrasound and microbubbles. We conclude that although short pulse duration guided therapeutic impulses from a diagnostic transducer transiently improve microvascular flow, long pulse duration therapeutic impulses produce sustained epicardial and microvascular re-flow in acute myocardial infarction

Diagnostic Ultrasound High Mechanical Index Impulses Restore Microvascular Flow In Peripheral Arterial Thromboembolism

We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p \u3c 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses

Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites

Aldehydes that are produced following the breakdown of ethanol (acetaldehyde) and lipid peroxidation of membranes (malondialdehyde) have been shown to bind (adduct) proteins. Additionally, these two aldehydes can combine (MAA) on non-syngeneic and syngeneic proteins to initiate numerous immune responses to the unmodified part of the protein in the absence of an adjuvant. Therefore, these studies provide a potential mechanism for the development of antigen-specific immune responses resulting in liver damage should syngeneic liver proteins be adducted with MAA

Open and distance language learning at the Shantou Radio and TV University, China, and the Open University, United Kingdom: a cross‐cultural perspective

Open and distance learning is experiencing rapid growth throughout the world. China in particular is undergoing a massive expansion of its distance EFL programmes. This global phenomenon challenges all those involved in delivering distance learning materials to examine current practice and the assumptions and expectations that underlie it, with particular regard to the factors influencing approaches to learning, not least the extent of the effect of differing cultural backgrounds. The cross‐cultural study which forms the subject of this paper investigates foreign language students in two very different open and distance learning cultures, The Open University, United Kingdom and the Shantou Radio and TV University, China. It seeks to investigate different attitudes to the distance teaching of languages as spelt out in the two groups’ answers to questions relating to beliefs, difficulties and learning strategies

QuantCrit: education, policy, ‘Big Data’ and principles for a critical race theory of statistics

Quantitative research enjoys heightened esteem among policy-makers, media and the general public. Whereas qualitative research is frequently dismissed as subjective and impressionistic, statistics are often assumed to be objective and factual. We argue that these distinctions are wholly false; quantitative data is no less socially constructed than any other form of research material. The first part of the paper presents a conceptual critique of the field with empirical examples that expose and challenge hidden assumptions that frequently encode racist perspectives beneath the façade of supposed quantitative objectivity. The second part of the paper draws on the tenets of Critical Race Theory (CRT) to set out some principles to guide the future use and analysis of quantitative data. These ‘QuantCrit’ ideas concern (1) the centrality of racism as a complex and deeply-rooted aspect of society that is not readily amenable to quantification; (2) numbers are not neutral and should be interrogated for their role in promoting deficit analyses that serve White racial interests; (3) categories are neither ‘natural’ nor given and so the units and forms of analysis must be critically evaluated; (4) voice and insight are vital: data cannot ‘speak for itself’ and critical analyses should be informed by the experiential knowledge of marginalized groups; (5) statistical analyses have no inherent value but can play a role in struggles for social justice

Aberrant function of the C-terminal tail of HIST1H1E Aacelerates cellular senescence and causes premature aging

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging

Broadband Spectral Modeling of the Extreme Gigahertz-Peaked Spectrum Radio Source PKS B0008-421

J. R. Callingham, et al., “Broadband Spectral Modeling of the Extreme Gigahertz-Peaked Spectrum Radio Source PKS B0008-421”, Astrophysical Journal, Vol. 809(2), August 2015. © 2015. The American Astronomical Society. All rights reserved.We present broadband observations and spectral modeling of PKS B0008-421, and identify it as an extreme gigahertz-peaked spectrum (GPS) source. PKS B0008-421 is characterized by the steepest known spectral slope below the turnover, close to the theoretical limit of synchrotron self-absorption, and the smallest known spectral width of any GPS source. Spectral coverage of the source spans from 0.118 to 22 GHz, which includes data from the Murchison Widefield Array and the wide bandpass receivers on the Australia Telescope Compact Array. We have implemented a Bayesian inference model fitting routine to fit the data with various absorption models. We find that without the inclusion of a high-frequency exponential break the absorption models can not accurately fit the data, with significant deviations above and below the peak in the radio spectrum. The addition of a high-frequency break provides acceptable spectral fits for the inhomogeneous free-free absorption and double-component synchrotron self-absorption models, with the inhomogeneous free-free absorption model statistically favored. The requirement of a high-frequency spectral break implies that the source has ceased injecting fresh particles. Additional support for the inhomogeneous free-free absorption model as being responsible for the turnover in the spectrum is given by the consistency between the physical parameters derived from the model fit and the implications of the exponential spectral break, such as the necessity of the source being surrounded by a dense ambient medium to maintain the peak frequency near the gigahertz region. The discovery of PKS B0008-421 suggests that the next generation of low radio frequency surveys could reveal a large population of GPS sources that have ceased activity, and that a portion of the ultra-steep spectrum source population could be composed of these GPS sources in a relic phase.Peer reviewedFinal Published versio

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function

Statistics of VHE \u3b3-rays in temporal association with radio giant pulses from the Crab pulsar

Aims. The aim of this study is to search for evidence of a common emission engine between radio giant pulses (GPs) and very-high-energy (VHE, E& x2004;> & x2004;100 GeV) gamma-rays from the Crab pulsar. Methods. We performed 16 h of simultaneous observations of the Crab pulsar at 1.4 GHz with the Effelsberg radio telescope and the Westerbork Synthesis Radio Telescope (WSRT), and at energies above 60 GeV we used the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes. We searched for a statistical correlation between the radio and VHE gamma-ray emission with search windows of different lengths and different time lags to the arrival times of a radio GP. A dedicated search for an enhancement in the number of VHE gamma-rays correlated with the occurrence of radio GPs was carried out separately for the P1 and P2 phase ranges, respectively. Results. In the radio data sample, 99444 radio GPs were detected. We find no significant correlation between the GPs and VHE photons in any of the search windows. Depending on phase cuts and the chosen search windows, we find upper limits at a 95% confidence level on an increase in VHE gamma-ray events correlated with radio GPs between 7% and 61% of the average Crab pulsar VHE flux for the P1 and P2 phase ranges, respectively. This puts upper limits on the flux increase during a radio GP between 12% and 2900% of the pulsed VHE flux, depending on the search window duration and phase cuts. This is the most stringent upper limit on a correlation between gamma-ray emission and radio GPs reported so far